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Pathology_Robbins. Adhesion, local proliferation, and toxin production in the host. V. cholerae and enterotoxigenic E. coli bind to the intestinal epithelium and multiply in the overlying mucous layer, where they release exotoxins that cause epithelial cells to secrete large volumes of fluid, resulting in watery diarrhea. Invasion. Shigella, Salmonella, and Campylobacter invade locally and damage the intestinal mucosa and lamina propria, causing ulceration, inflammation, and hemorrhage—changes manifested clinically as bloody diarrhea (dysentery). S. enterica serotype Typhi passes from the damaged mucosa through Peyer patches and mesenteric lymph nodes and into the bloodstream, resulting in a systemic infection.


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Pathology_Robbins. Fungal infections of the gastrointestinal tract occur in immunologically compromised individuals. Candida, part of the normal gastrointestinal flora, shows a predilection for stratified squamous epithelium, causing oral thrush or membranous esophagitis, but also may spread to the stomach, lower gastrointestinal tract, and other organs. Most intestinal parasites enter the body by being ingested as cysts, eggs, or meat-borne larvae, but a few enter by penetrating the skin and finding their way to the intestine. Once in the intestine, these pathogens cause damage in several ways: • G. lamblia attaches to the epithelial brush border, but does not invade into cells or tissue. Attachment of the organisms leads to blunting of villi, loss of brush border, malabsorption, and chronic inflammation through mechanisms that are poorly understood. Cryptosporidia are taken up by enterocytes, in which they replicate, leading to extensive mucosal damage, villous atrophy, and inflammation.


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Pathology_Robbins. Cryptosporidia are taken up by enterocytes, in which they replicate, leading to extensive mucosal damage, villous atrophy, and inflammation. E. histolytica kills host cells by contact-mediated cytolysis through a channel-forming pore protein, with consequent ulceration and invasion of the colonic mucosa. Intestinal helminths cause disease when they are present in large numbers or travel to ectopic sites. Large numbers of A. lumbricoides can obstruct the gut, and this organism can invade and damage the bile ducts as well. Helminths also cause disease by depriving the host of nutrients. Hookworms cause iron-deficiency anemia by sucking blood from intestinal villi; Diphyllobothrium, the fish tapeworm, causes anemia by depriving the host of vitamin B12.


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Pathology_Robbins. A large number of microorganisms, including viruses, bacteria, and fungi, are inhaled daily by every individual. In many cases, the microbes are inhaled in dust or aerosol particles. The distance these particles travel into the respiratory system is inversely proportional to their size. Large particles are trapped in the mucociliary blanket that lines the nose and the upper respiratory tract. Microorganisms trapped in the mucus secreted by goblet cells are transported by ciliary action to the back of the throat, where they are swallowed or coughed out. Particles smaller than 5 µm travel directly to the alveoli, where they are phagocytosed by alveolar macrophages or by neutrophils recruited to the lung by cytokines.


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Pathology_Robbins. Microorganisms that invade the normal healthy respiratory tract have developed specific mechanisms to overcome mucociliary defenses or to avoid destruction by alveolar macrophages. Some successful respiratory viruses evade these defenses by attaching to and entering epithelial cells in the lower respiratory tract and pharynx. For example, influenza viruses possess hemagglutinin proteins that project from the surface of the virus and bind to sialic acid on the surface of epithelial cells. This attachment induces the host cell to engulf the virus, leading to viral entry and replication within the host cell.


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Pathology_Robbins. Certain bacterial respiratory pathogens release toxins that paralyze cilia. Examples include Haemophilus influenzae, Mycoplasma pneumoniae, and Bordetella pertussis. Some bacteria lack the ability to overcome the defenses of the healthy lung and can cause respiratory infections only in compromised hosts. Streptococcus pneumoniae and S. aureus can cause pneumonia subsequent to influenza because the viral infection leads to the loss of the protective ciliated epithelium. Chronic damage to mucociliary defense mechanisms occurs in smokers and individuals with cystic fibrosis, while acute injury occurs in intubated patients and in those who aspirate gastric acid.


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Pathology_Robbins. Some respiratory pathogens avoid phagocytosis or destruction after phagocytosis. M. tuberculosis, for example, gains a foothold in alveoli because it escapes killing within the phagolysosomes of macrophages. Opportunistic fungi infect the lungs when cellular immunity is depressed or when leukocytes are reduced in number (e.g., P. jiroveci in patients with AIDS, Aspergillus spp. after chemotherapy). http://ebooksmedicine.net


Pathology_Robbins

Pathology_Robbins. http://ebooksmedicine.net The urinary tract is almost always invaded from the exterior by way of the urethra. The regular flushing of the urinary tract with urine serves as a defense against invading microorganisms. Urine in the bladder is normally sterile or contains only small numbers of fastidious bacteria; however, successful pathogens (e.g., N. gonorrhoeae, E. coli) adhere to the urinary epithelium, overcoming the host defense of regular flushing. Anatomy plays an important role in infection. Women have many more urinary tract infections than men because the distance between the urinary bladder and skin (i.e., the length of the urethra) is 5 cm in women, in contrast with 20 cm in men. Obstruction of urinary flow, as in benign prostatic hyperplasia, or reflux can compromise normal defenses and increase susceptibility to urinary tract infections. Urinary tract infections can spread further up from the bladder to the kidney and cause acute and chronic pyelonephritis.


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Pathology_Robbins. From puberty until menopause, the vagina is protected from pathogens by a low pH resulting from catabolism of glycogen in the normal epithelium by lactobacilli. Antibiotics can kill the lactobacilli, allowing overgrowth of yeast, with resultant vaginal candidiasis. Some microorganisms proliferate locally, at the site of initial infection, whereas others penetrate the epithelial barrier and spread to distant sites by way of the lymphatics, the blood, or nerves ( Fig. 9.6 ). In contrast to those that disseminate, pathogens that cause superficial infections stay confined to the lumen of hollow viscera (e.g., V. cholerae) or interact exclusively with epithelial cells (e.g., papillomaviruses, dermatophytes). Microbes can spread within the body in several ways:


Pathology_Robbins

Pathology_Robbins. Microbes can spread within the body in several ways: Lysis and invasion. Some extracellular bacteria, fungi, and helminths secrete lytic enzymes that destroy tissue and allow direct invasion. For example, S. aureus secretes hyaluronidase, which degrades the extracellular matrix between host cells. Invasive microbes initially follow tissue planes of least resistance and drain to regional lymphatics. S. aureus may travel from a localized abscess to the draining lymph nodes. This can sometimes lead to bacteremia and spread to deep organs (heart, bone). Through blood and lymph. Microorganisms may be spread either in extracellular fluid or within host cells. Some viruses (e.g., poliovirus, HBV), most bacteria and fungi, some protozoa (e.g., African trypanosomes), and all helminths are transported in the plasma. Leukocytes can carry herpesviruses, HIV, mycobacteria, Leishmania, and Toxoplasma. The parasites Plasmodium and Babesia are found within red cells.


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Pathology_Robbins. Cell-to-cell transmission. Most viruses spread locally from cell to cell by replication and release of infectious virions, but others may propagate from cell to cell by causing fusion of host cells, or by transport within nerves (as with rabies virus and varicella-zoster virus). The consequences of bloodborne spread of pathogens vary widely depending on the virulence of the organism, Portal of entry Infection (skin, respiratory, gastrointestinal, M. tuberculosis virus, rabiesin macrophages Lymphatics


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Pathology_Robbins. Fig. 9.6 Routes of entry and dissemination of microbes. To enter the body, microbes penetrate epithelial or mucosal barriers. Infection may remain localized at the site of entry or spread to other sites in the body. Most common microbes (selected examples are shown) spread through the lymphatics or bloodstream (either freely or within inflammatory cells). However, certain viruses and bacterial toxins also may travel through nerves. (Adapted from Mims CA: The pathogenesis of infectious disease, ed 4, San Diego, 1996, Academic Press.) the magnitude of the infection, the pattern of seeding, and host factors such as immune status. Sporadic bloodstream invasion by low-virulence or nonvirulent microbes (e.g., during brushing of teeth) is common but is quickly controlled by normal host defenses. By contrast, disseminated viremia, bacteremia, fungemia, or parasitemia by virulent pathogens poses a serious danger and manifests as fever, hypotension, and multiple other systemic signs and


Pathology_Robbins

Pathology_Robbins. By contrast, disseminated viremia, bacteremia, fungemia, or parasitemia by virulent pathogens poses a serious danger and manifests as fever, hypotension, and multiple other systemic signs and symptoms of sepsis. Massive bloodstream invasion by bacteria can be rapidly fatal, even in previously healthy individuals.


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Pathology_Robbins. The major manifestations of infectious disease may appear at sites distant from the point of microbe entry. For example, varicella-zoster and measles viruses enter through the airways but cause rashes in the skin; polio-virus enters through the intestine but kills motor neurons to cause paralysis. Schistosoma mansoni parasites penetrate the skin but eventually localize in blood vessels of the portal system and mesentery, damaging the liver and intestine. Schistosoma hematobium also penetrates the skin, but localizes to the urinary bladder and causes cystitis. The rabies virus travels from the site of a bite by a rabid animal to the brain by retrograde transport in sensory neurons, where it then causes encephalitis and death.


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Pathology_Robbins. Transmission depends on the hardiness of the microbe. Some microbes can survive for extended periods in dust, food, or water. Bacterial spores, protozoan cysts, and thick-shelled helminth eggs can survive in a cool and dry environment. Less hardy microorganisms must be quickly passed from person to person, often by direct contact. For transmission of disease, the mode of exit of a microorganism from the host’s body is as important as entry into it. Every fluid or tissue that is normally secreted, excreted, or shed is used by microorganisms to leave the host for transmission to new victims. Skin. Skin flora, such as S. aureus and dermatophytes (fungi), are shed in the desquamated skin. Some sexually transmitted pathogens are transmitted from genital skin lesions, such as HSV and Treponema pallidum (causing syphilis). Oral secretions. Viruses that replicate in the salivary glands and are spread in saliva include mumps virus, CMV, and rabies virus.


Pathology_Robbins

Pathology_Robbins. Oral secretions. Viruses that replicate in the salivary glands and are spread in saliva include mumps virus, CMV, and rabies virus. Respiratory secretions. Viruses and bacteria can be shed in respiratory secretions during talking, coughing, and sneezing. Most respiratory pathogens, including influenza viruses, spread in large respiratory droplets, which travel no more than 3 feet. However, a few organisms, including M. tuberculosis and varicella-zoster virus, are spread from the respiratory tract in small respiratory droplets or within dust particles that can travel long distances in the air. These properties determine the type of isolation precautions that are used to prevent the spread of infection.


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Pathology_Robbins. Stool. Organisms shed in stool include many pathogens that replicate in the lumen or epithelium of the gut, such as Shigella, G. lamblia, and rotavirus. Pathogens that replicate in the liver (hepatitis A virus) or gallbladder (S. enterica serotype Typhi) enter the intestine in bile and are shed in stool. Blood. Pathogens spread via blood may be transmitted by invertebrate vectors, medical practices (blood transfusion, reuse of equipment), or sharing of needles by intravenous drug abusers. Bloodborne parasites, including Plasmodium spp. and arboviruses, are transmitted by biting insects. Urine. Urine is the usual mode of exodus from the human host for only a few organisms, including S. haematobium, which grows in the veins of the bladder and releases eggs that reach the urine.


Pathology_Robbins

Pathology_Robbins. Urine. Urine is the usual mode of exodus from the human host for only a few organisms, including S. haematobium, which grows in the veins of the bladder and releases eggs that reach the urine. Genital tract. Sexually transmitted infections (STIs) spread from the urethra, vagina, cervix, rectum, or oral pharynx. Organisms that cause STIs depend on direct contact for person-to-person spread because these pathogens cannot survive in the environment. Transmission of STIs often is by asymptomatic individuals who do not realize that they are infected. Infection with one STI increases the risk for additional STIs, mainly because the risk factors are the same for all STIs. STIs are described in Chapters 18 and 19.


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Pathology_Robbins. Vertical transmission. Transmission of infectious agents from mother to fetus or newborn child is a common mode of transmission for some pathogens, and may occur through several different routes. Placental-fetal transmission is most likely to occur when the mother is infected with a pathogen during pregnancy. Some of the resulting infections interfere with fetal development, and the degree and type of damage depend on the age of the fetus at the time of infection. For example, rubella infection during the first trimester can lead to heart malformations, mental retardation, cataracts, or deafness, while rubella infection during the third trimester has little effect. Congenital microcephaly and other CNS complications have been associated with Zika virus infection during pregnancy. Much is still unknown about timing of infection relative to the trimester of pregnancy. Transmission during birth is caused by contact with infectious agents during passage through the birth canal. Examples


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Pathology_Robbins. still unknown about timing of infection relative to the trimester of pregnancy. Transmission during birth is caused by contact with infectious agents during passage through the birth canal. Examples include gonococcal and chlamydial conjunctivitis. Postnatal transmission in maternal milk can transmit CMV, HIV, and HBV.


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Pathology_Robbins. Microbes also can be transmitted from animal to human resulting in zoonotic infections, either through direct contact with or consumption of animal products or indirectly by an invertebrate vector. Transmissionofinfectionscanoccurvia: Insect/arthropodvectors. Apathogencanestablishinfectionifitpossessesvirulencefactorsthatovercomenormalhostdefensesorifthehostdefensesarecompromised. Hostdefensesagainstinfectioninclude: Skin:toughkeratinizedbarrier,lowpH,fattyacids,normalmicrobiota Respiratorysystem:alveolarmacrophagesandmucociliaryclearancebybronchialepithelium,IgA Gastrointestinalsystem:acidicgastricpH,viscousmucus,pancreaticenzymesandbile,defensins,IgA,andnormalflora Urogenitaltract:repeatedflushingandacidicenvironmentcreatedbycommensalvaginalflora Infectious agents establish infection and damage tissues by any of three mechanisms: They can contact or enter host cells and directly cause death of infected cells.


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Pathology_Robbins. Infectious agents establish infection and damage tissues by any of three mechanisms: They can contact or enter host cells and directly cause death of infected cells. They can release toxins that kill cells at a distance, release enzymes that degrade tissue components, or damage blood vessels and cause ischemic necrosis. http://ebooksmedicine.net • They can induce host immune responses that, although directed against the invader, cause additional tissue damage. Thus, the defensive responses of the host can be a mixed blessing, helping to overcome the infection but also contributing to tissue damage. Described next are some of the mechanisms whereby viruses and bacteria damage host tissues. Viruses can directly damage host cells by entering them and replicating at the host’s expense. The manifestations of viral infection are largely determined by the tropism of the virus for specific tissues and cell types. Tropism is influenced by a number of factors.


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Pathology_Robbins. Host receptors for viruses. Viruses are coated with surface proteins that bind with high specificity to particular host cell surface proteins. Entry of many viruses into cells commences with binding to normal host cell receptors. For example, HIV glycoprotein gp120 binds to CD4 and CXCR4 and CCR5 on T cells and macrophages (Chapter 5). Host proteases may be needed to enable binding of virus to host cells; for instance, a host protease cleaves and activates the influenza virus hemagglutinin. Specificity of transcription factors. The ability of the virus to replicate inside particular cell types depends on the presence of lineage-specific transcription factors that recognize viral enhancer and promoter elements. For example, the JC virus, which causes leukoencephalopathy (Chapter 23), replicates only in oligodendroglia in the CNS because the promoter and enhancer DNA sequences regulating viral gene expression are active in glial cells, but not in neurons or endothelial cells.


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Pathology_Robbins. Physical characteristics of tissues. Host environment and temperature can contribute to tissue tropism. For example, enteroviruses replicate in the intestine in part because they can resist inactivation by acids, bile, and digestive enzymes. Rhinoviruses infect cells only within the upper-respiratory tract because they replicate optimally at the lower temperatures characteristic of this site. Once viruses are inside host cells, they can damage or kill the cells by a number of mechanisms ( Fig. 9.7


Pathology_Robbins

Pathology_Robbins. Once viruses are inside host cells, they can damage or kill the cells by a number of mechanisms ( Fig. 9.7 Direct cytopathic effects. Viruses can kill cells by preventing synthesis of critical host macromolecules, by producing degradative enzymes and toxic proteins, or by inducing apoptosis. For example, poliovirus blocks synthesis of host proteins by inactivating cap-binding protein. HSV produces proteins that inhibit synthesis of cellular DNA and mRNA and other proteins that degrade host DNA. Viral replication also can trigger apoptosis of host cells by cell-intrinsic mechanisms, such as perturbations of the endoplasmic reticulum during virus assembly, which can activate caspases that mediate apoptosis.


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Pathology_Robbins. Anti-viral immune responses. Viral proteins on the surface of host cells may be recognized by the immune system, and lymphocytes may attack virus-infected cells. Cytotoxic T lymphocytes (CTLs) are important for defense against viral infections, but CTLs also can be responsible for tissue injury. Hepatitis B infection causes CTL- Fig. 9.7 Mechanismsbywhichvirusescauseinjurytocells.Virus Receptor Entry, uncoating Viral genome replication, mRNA synthesis Viral protein synthesis Virus assembly Viral antigens Neoplastic transformation Cell lysis or fusion Reduced host cell DNA, RNA, protein synthesis Metabolic derangements Host T cell–mediated injury Viral inclusions VIRAL PROTEINS mediated destruction of infected hepatocytes, a normal response that is attempting to clear the infection.


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Pathology_Robbins. • Transformation of infected cells. Different oncogenic viruses (e.g., HPV, EBV) can stimulate cell growth and survival by a variety of mechanisms, including hijacking the control of cell cycle machinery, anti-apoptotic strategies, and insertional mutagenesis (in which the insertion of viral DNA into the host genome alters the expression of nearby host genes). Mechanisms of viral transformation are discussed in Chapter 6.


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Pathology_Robbins. Bacterial damage to host tissues depends on the ability of the bacteria to adhere to host cells, invade cells and tissues, or deliver toxins. Pathogenic bacteria have virulence genes that are frequently found grouped together in clusters called pathogenicity islands. A small number of virulence genes can determine whether a bacterium is harmful. The Salmonella strains that infect humans are so closely related that they are a single species, but only a few virulence genes determine whether an isolate of Salmonella causes life-threatening typhoid fever or self-limited gastroenteritis.


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Pathology_Robbins. Plasmids (small independently replicating circular DNAs) and bacteriophages (viruses) are genetic elements that spread between bacteria and can carry virulence factors, including toxins or enzymes that confer antibiotic resistance. Exchange of these elements between bacteria can endow the recipient bacteria with a survival advantage and/or the capacity to cause disease. Plasmids or transposons encoding antibiotic resistance can convert an antibiotic-susceptible bacterium into a resistant one, making effective therapy difficult. Carbapenemase genes carried on plasmids have spread among gram-negative bacilli worldwide, resulting in strains for which there are no available effective antibiotics, causing the CDC to list these organisms as an urgent threat. http://ebooksmedicine.net Populations of bacteria also can act together in ways that alter their virulence.


Pathology_Robbins

Pathology_Robbins. http://ebooksmedicine.net Populations of bacteria also can act together in ways that alter their virulence. Quorum sensing. Many species of bacteria coordinately regulate gene expression within a large population in which specific genes, such as virulence genes, are expressed after bacteria reach high concentrations. This in turn may allow bacteria growing in discrete host sites, such as an abscess or consolidated pneumonia, to overcome host defenses. S. aureus coordinately regulates virulence factors by secreting autoinducer peptides. As the bacteria grow to increasing concentrations, the level of the autoinducer peptide increases, stimulating exotoxin production.


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Pathology_Robbins. Biofilms. Communities of bacteria can live within a viscous layer of extracellular polysaccharides that adhere to host tissues or devices such as intravascular catheters and artificial joints. Biofilms make bacteria inaccessible to immune effector mechanisms and increase their resistance to anti-microbial drugs. Biofilm formation seems to be important in the persistence and relapse of infections such as bacterial endocarditis, artificial joint infections, and respiratory infections in individuals with cystic fibrosis. Bacterial Adherence to Host Cells Bacterial surface molecules that bind to host cells or extracellular matrix are called adhesins. Diverse surface structures are involved in adhesion of various bacteria (see Fig.


Pathology_Robbins

Pathology_Robbins. Fig. 9.2 ). S. pyogenes has protein F and teichoic acid projecting from its cell wall that bind to fibronectin on the surface of host cells and in the extracellular matrix. Other bacteria have filamentous proteins called pili on their surfaces. Stalks of pili are structurally conserved, whereas amino acids on the tips of the pili vary and determine the binding specificity of the bacteria. Strains of E. coli that cause urinary tract infections uniquely express a specific P pilus that binds to a Gal(α1–4)Gal moiety expressed on uroepithelial cells. Pili on N. gonorrhoeae bacteria mediate adherence of the bacteria to host cells and also are targets of the host antibody response. Antigenic variation affecting the antigens expressed in the pili is an important mechanism by which N. gonorrhoeae escapes the immune response.


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Pathology_Robbins. Any bacterial substance that contributes to illness can be considered a toxin. Toxins are subclassified as endotoxins, which are components of the bacterial cell, or exotoxins, which are proteins that are secreted by the bacterium. Bacterial endotoxin is a lipopolysaccharide (LPS) that is a component of the outer membrane of gram-negative bacteria (see


Pathology_Robbins

Pathology_Robbins. Fig. 9.2 ). LPS is composed of a long-chain fatty acid anchor, termed lipid A, connected to a core sugar chain, both of which are very similar in all gram-negative bacteria. Attached to the core sugar is a variable carbohydrate chain (O antigen), which is used to serotype strains of bacteria to aid in diagnosis. Lipid A binds to CD14 on the surface of host leukocytes, and the complex then binds to Toll-like receptor 4, a pattern recognition receptor of the innate immune system that transmits signals to promote cell activation and inflammatory responses. Responses to LPS can be both beneficial and harmful to the host. The response is beneficial in that LPS activates protective immunity through induction of important cytokines and chemoattractants (chemokines), as well as increased expression of costimulatory molecules, which enhance T-lymphocyte activation. However, high levels of LPS play an important role in septic shock, disseminated intravascular coagulation, and acute respiratory


Pathology_Robbins

Pathology_Robbins. of costimulatory molecules, which enhance T-lymphocyte activation. However, high levels of LPS play an important role in septic shock, disseminated intravascular coagulation, and acute respiratory distress syndrome, mainly through induction of excessive levels of cytokines such as tumor necrosis factor (Chapter 4).


Pathology_Robbins

Pathology_Robbins. Exotoxins are secreted proteins that cause cellular injury and disease. They can be classified into broad categories by their mechanism and site of action. Enzymes. Bacteria secrete enzymes (proteases, hyaluronidases, coagulases, fibrinolysins) that act on their respective substrates in vitro, but their role in disease is understood in only a few cases. For example, exfoliative toxins are proteases produced by S. aureus that cleave proteins known to hold keratinocytes together, causing the epidermis to detach from the deeper skin.


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Pathology_Robbins. A-B toxins: Toxins that alter intracellular signaling or regulatory pathways. The two-component toxins have an active (A) component with enzymatic activity and a binding (B) component that binds cell surface receptors and delivers the A protein into the cell cytoplasm. The effect of these toxins depends on the binding specificity of the B domain and the cellular pathways affected by the A domain. A-B toxins are made by many bacteria including Bacillus anthracis, V. cholerae, and Corynebacterium diphtheriae. The mechanism of action of the A-B anthrax toxin is well understood ( Fig. 9.8 ). Anthrax toxin has two alternate A components, edema factor (EF) and lethal factor (LF), which enter cells following binding to the B component, and each A component mediates specific pathologic effects.


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Pathology_Robbins. Superantigens stimulate very large numbers of T lymphocytes by binding to conserved portions of the T cell receptor, leading to massive T lymphocyte proliferation and cytokine release. The high levels of cytokines lead to capillary leak and the systemic inflammatory response syndrome (Chapter 4). Superantigens made by S. aureus and S. pyogenes cause toxic shock syndrome. Neurotoxins produced by Clostridium botulinum and Clostridium tetani inhibit release of neurotransmitters, resulting in paralysis. These toxins do not kill neurons; instead, the A domains cleave proteins involved in secretion of neurotransmitters at the synaptic junction. Tetanus and botulism can result in death from respiratory failure due to paralysis of the chest and diaphragm muscles. Enterotoxins affect the gastrointestinal tract causing varied effects, including nausea and vomiting (S. aureus), voluminous watery diarrhea (V. cholerae), and bloody diarrhea (C. difficile). http://ebooksmedicine.net


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Pathology_Robbins. http://ebooksmedicine.net Fig. 9.8 Mechanism of anthrax exotoxin action. The B subunit, also called protective antigen, binds a cell-surface receptor, is cleaved by a host protease, and forms a heptamer. Three A subunits of edema factor (EF) or lethal factor (LF) bind to the B heptamer, enter the cell, and are released into the cytoplasm. EF binds calcium and calmodulin to form an adenylate cyclase that increases intracellular cAMP, which causes efflux of water and interstitial edema. LF is a protease that destroys mitogen-activated protein kinase kinases (MAPKKs), leading to cell death. cAMP, cyclic adenosine monophosphate. Note that each B subunit binds either EF or LF, but not both (as shown for simplicity). (Adapted from Mourez M, Lacy DB, Cunningham, K, et al: 2011: A year of major advances in anthrax toxin research. Trends Microbiol 10:287, 2002.)


Pathology_Robbins

Pathology_Robbins. As mentioned earlier, the host immune response to microbes can sometimes be the cause of tissue injury. A few examples of types and mechanisms of injury are as follows: Granulomatous inflammation. Infection with M. tuberculosis results in a delayed hypersensitivity response and the formation of granulomas, which sequester the bacilli and prevent its spread, but also produce tissue damage (caseous necrosis) and fibrosis. T-cell–mediated inflammation. Damage from HBV and HCV infection of hepatocytes is due mainly to the immune response to the infected liver cells and not to cytopathic effects of the virus. Innate immune inflammation. Pattern recognition receptors bind to pathogen-associated molecular patterns (PAMPS) and to damage-associated molecular patterns (DAMPS) released from damaged host cells, activating the immune system and leading to inflammation (discussed in Chapter 5).


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Pathology_Robbins. Humoral immunity. Poststreptococcal glomerulonephritis can develop after infection with S. pyogenes. It is caused by antibodies that bind to streptococcal antigens and form immune complexes, which deposit in renal glomeruli and produce nephritis. Chronic inflammatory diseases. In the development of inflammatory bowel disease (Chapter 15), an important early event may be compromise of the intestinal epithelial barrier, which enables the entry of both pathogenic and commensal microbes and their interactions with local immune cells, resulting in inflammation. The cycle of inflammation and epithelial injury may be an important component of the disease, with microbes playing the central role.


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Pathology_Robbins. Cancer. Viruses, such as HBV and HCV, and bacteria, such as H. pylori, that are not known to carry or to activate oncogenes are associated with cancers, presumably because these microbes trigger chronic inflammation with subsequent tissue regeneration, which provides fertile ground for the development of cancer (Chapter 6). Diseases caused by microbes involve an interplay of microbialvirulence and host responses. Infectious agents can cause cell death or dysfunction by directlyinteracting with the cell. Injury may be due to local or systemic release of bacterialproducts, including endotoxins (LPS), exotoxins, or superantigens, combined with the immune response. Absence of an immune response may reduce the damageinduced by some infections; conversely, immunocompromisecan allow uncontrolled expansion of opportunistic infectionsthat can directly cause injury. Chronic immunological and inflammatory diseases and cancerhave been associated with specific microorgansims.


Pathology_Robbins

Pathology_Robbins. Chronic immunological and inflammatory diseases and cancerhave been associated with specific microorgansims. Humoral and cellular immune responses that protect the host from most infections are discussed in Chapter 5. Not surprisingly, microorganisms have developed many means to resist and evade the immune system ( Fig. 9.9 ). These mechanisms of escaping the immune response are important determinants of microbial virulence and pathogenicity. Antigenic variation. Neutralizing antibodies against microbial antigens block the ability of microbes to infect cells and recruit immune cells to kill pathogens. To escape recognition, microbes use many strategies that involve genetic mechanisms for generating antigenic variation. The low fidelity of viral RNA polymerases (HIV and influenza virus) and reassortment of viral genomes (influenza viruses) create viral antigenic variation (


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Pathology_Robbins. Table 9.7 ). Borrelia species switch their surface antigens via gene rearrangement. Trypanosoma species have many genes for their major surface antigen, VSG, and vary the expression of this surface protein. There are more than 90 different serotypes of S. pneumoniae, each with a different capsular polysaccharide. Modification of surface proteins. Host cationic antimicrobial peptides, including defensins, cathelicidins, Modulation of surface structure Inhibition of phagocytosis to avoid recognition (e.g., antigenic variability) Inhibition of phagosome Modulate: Signal transduction Gene expression Cell death and thrombocidins, provide important initial defenses against invading microbes. These peptides bind the bacterial membrane and form pores, killing the bacterium by osmotic lysis. Bacterial pathogens (Shigella spp., S. aureus) avoid killing by making surface molecules that resist binding of anti-microbial peptides, or that inactivate or downregulate anti-microbial peptides.


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Pathology_Robbins. • Overcoming antibodies and complement. Host defense includes coating of bacteria with antibodies or the complement protein C3b (opsonization) to facilitate phagocytosis by macrophages. However, the facultative intracellular pathogen M. tuberculosis subverts the complement response by activating the alternative Table 9.7 Mechanisms of Anti-genic Variation Genetic rearrangement Borrelia burgdorferi Lyme disease(e.g., gene recombination, Neisseria gonorrhoeae Gonorrheagene conversion, Trypanosoma spp. African sleeping site-specific inversion)sickness Plasmodium spp. Malaria


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Pathology_Robbins. Plasmodium spp. Malaria Large diversity of serotypesRhinovirusesColdsStreptococcus Pneumonia, pneumoniae meningitis complement pathway in the extracellular environment, and complement products coat the bacteria, resulting in uptake of the organism by monocytes; by this means, the organism reaches its site of replication. Many bacteria (such as Shigella, enteroinvasive E. coli, M. tuberculosis, M. leprae, S. enterica serotype Typhi) use the inside of cells as a “hideout” that allows them to escape from antibodies and complement. Listeria monocytogenes can manipulate the cell cytoskeleton to spread directly from cell to cell, thus allowing the bacteria to evade immune defenses.


Pathology_Robbins

Pathology_Robbins. Resisting phagocytosis and bacterial killing in phagosomes. Phagocytosis and killing of bacteria by neutrophils and macrophages constitute a critical host defense against extracellular bacteria. The carbohydrate capsule on the surface of many bacteria that cause pneumonia or meningitis (S. pneumoniae, Neisseria meningitidis, H. influenzae) makes them more virulent by preventing phagocytosis of the organisms by neutrophils. Surface proteins that inhibit phagocytosis include proteins A (S. aureus) and M (S. pyogenes). Macrophages usually kill bacteria by fusion of the phagosome with the lysosome to form a phagolysosome. M. tuberculosis blocks fusion of the lysosome with the phagosome, allowing the bacteria to proliferate unchecked within the macrophage. Legionella produces a pore-forming protein called listeriolysin O and two phospholipases that degrade the phagosome membrane, allowing the bacteria to escape into the cytoplasm and avoid destruction in the macrophage. Legionella also


Pathology_Robbins

Pathology_Robbins. protein called listeriolysin O and two phospholipases that degrade the phagosome membrane, allowing the bacteria to escape into the cytoplasm and avoid destruction in the macrophage. Legionella also secretes proteins that modulate small GTPases, master regulators of intracellular signaling to modify trafficking. Also, many bacteria make proteins that kill phagocytes, prevent their migration, or diminish their oxidative burst.


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Pathology_Robbins. Escaping the inflammasome. The activation of the cytosolic inflammasome is one pathway of innate immune responses to microbes. It is stimulated by microbial products and culminates in the activation of caspases, which induce the secretion of the pro-inflammatory cytokines IL-1 and IL-18 and induce a form of cell death called pyroptosis (Chapter 5). Both inflammation and cell death limit microbial virulence and replication. Some bacteria, such as Yersinia and Salmonella, express virulence proteins that inhibit the formation of the mature inflammasome, suppress caspase activation, block signaling pathways that are required for inflammasome activation, or limit the access of other bacterial proteins to the inflammasome. All these mechanisms serve to disable various components of this host antimicrobial defense reaction.


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Pathology_Robbins. Disruption of interferon pathways. Viruses have developed a large number of strategies to combat interferons (IFNs), which are mediators of early antiviral defense. Some viruses produce soluble homologues of IFN receptors that bind to and block the actions of secreted IFNs, or produce proteins that inhibit intracellular JAK/STAT signaling downstream of IFN receptors. RIG-I (RNA helicase retinoic acid inducible gene I protein) is a host cytoplasmic pattern recognition receptor for intracellular double-stranded RNA viruses. RIG-I inhibits signaling by this receptor, thus blocking the downstream IFN pathway and overcoming this host defense. Some viruses encode within their genomes homologs of cytokines, chemokines, or their receptors that act as competitive antagonists to inhibit immune responses. Finally, viruses have developed strategies to block apoptosis, which may give the viruses time to replicate, persist, or transform the infected host cell.


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Pathology_Robbins. • Decreased T-cell recognition: DNA viruses (e.g., HSV, CMV, and EBV) can bind to or alter the localization of major histocompatibility complex (MHC) class I proteins, impairing peptide presentation to CD8+ cytotoxic T cells. Although downregulation of MHC class I molecules might cause virus-infected cells to be targets for NK cells, herpesviruses also express MHC class I homologuess that act as decoys that engage inhibitory receptors of NK cells. Herpesviruses can target MHC class II molecules for degradation, impairing antigen presentation to CD4+ helper T cells. Viruses also can infect leukocytes to directly compromise their function (e.g., HIV infects CD4+ T cells, macrophages, and dendritic cells). Afterbypassinghosttissuebarriers,infectiousmicroorganismsmustalsoevadehostinnateandadaptiveimmunitymechanismstosuccessfullyproliferateandbetransmittedtothenexthost.Strategiesincludethefollowing: Resistingphagocytosis(e.g.,byproducingacapsule)


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Pathology_Robbins. Resistingphagocytosis(e.g.,byproducingacapsule) Suppressingthehostadaptiveimmuneresponse(e.g.,byinhibitingantigenpresentationanddisruptinginterferonpathways) In contrast with the vast molecular diversity of microbes, the morphologic patterns of tissue responses to microbes are limited, as are the mechanisms directing these responses. Therefore, many pathogens produce similar reaction patterns, and few features are unique to or pathognomonic for a particular microorganism, adding to the challenge in histopathologic diagnosis. The interaction between the microbe and the host determines the histologic features of the response to the microbes. There are five major histologic patterns of tissue reaction in infections: suppurative, mononuclear/ granulomatous, cytopathic-cytoproliferative, necrosis, and chronic inflammation/scarring. Suppurative inflammation is discussed in Chapter 3.


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Pathology_Robbins. Diffuse, predominantly mononuclear, interstitial infiltrates are a common feature of all chronic inflammatory processes, but sometimes they appear acutely in response to viruses, intracellular bacteria, or intracellular parasites. In addition, spirochetes and some helminths also provoke chronic inflammation. Eosinophilia can be prominent with some helminthic infections. MORPHOLOGYWhichmononuclearcellpredominateswithintheinflammatorylesiondependsonthehostimmuneresponsetotheorganism.Thus,lymphocytespredominateinHBVinfection (Fig. 9.10A ),whereasplasmacellsarecommonintheprimaryandsecondarylesionsofsyphilis(see


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Pathology_Robbins. 9.10A ),whereasplasmacellsarecommonintheprimaryandsecondarylesionsofsyphilis(see Fig.9.10B).The presenceoftheselymphoidcellsreflectscell-mediatedimmuneresponsesagainstthepathogenorpathogen-infectedcells.Granulomatousinflammationisadistinctiveformofmononuclearinflammationusuallyevokedbyinfectiousagentsthatresisteradication,butneverthelessarecapableofstimulatingstrongT-cell–mediatedimmunity(e.g.,M. tuberculosis, Histoplasma capsulatum, schistosomeeggs).Granulomatousinflammation(Chapter3)ischaracterizedbyaccumulationofactivatedmacrophagescalledepithelioidcells,whichmayfusetoformgiantcells.Insomecases,thereisacentralareaofcaseousnecrosis(see Fig.9.10C Cytopathic-cytoproliferative reactions usually are produced by viruses. The lesions are characterized by cell necrosis or cellular proliferation, usually with sparse inflammatory cells.


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Pathology_Robbins. Fig.9.10C Cytopathic-cytoproliferative reactions usually are produced by viruses. The lesions are characterized by cell necrosis or cellular proliferation, usually with sparse inflammatory cells. Fig. 9.10 Mononuclearandgranulomatousinflammation.(A)Acuteviralhepatitischaracterizedbyapredominantlylymphocyticinfiltrate.(B)Secondarysyphilisinthedermiswithperivascularlymphoplasmacyticinfiltrateandendothelialproliferation.(C)Granulomatousinflammationinresponsetotuberculosis.Notethezoneofcaseation(asterisk), whichnormallyformsthecenterofthegranuloma,withasurroundingrimofactivatedepithelioidmacrophages,someofwhichhavefusedtoformgiantcells(arrows); thisinturnissurroundedbyazoneofactivatedTlymphocytes.Thishigh-magnificationviewhighlightsthehistologicfeatures;thegranulomatousresponsetypicallytakestheformofathree-dimensionalspherewiththeoffendingorganisminthecentralarea. http://ebooksmedicine.net


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Pathology_Robbins. http://ebooksmedicine.net MORPHOLOGYSomevirusesreplicatewithincellsandmakeviralaggregatesthatarevisibleasinclusionbodies(e.g.,herpesvirusesoradenovirus)orinducecellstofuseandformmultinucleatedcellscalledpolykaryons (e.g.,measlesvirusorherpesviruses)(see Fig.9.1 ).Focalcelldamageintheskinmaycauseepithelialcellstobecomedetached,formingblisters.Somevirusescancauseepithelialcellstoproliferate(e.g.,venerealwartscausedbyHPVortheumbilicatedpapulesofmolluscumcontagiosumcausedbypoxviruses).Finally,virusescancontributetothedevelopmentofmalignantneoplasms(Chapter6). Clostridium perfringens and other organisms that secrete powerful toxins can cause such rapid and severe necrosis that tissue damage is the dominant feature.


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Pathology_Robbins. Clostridium perfringens and other organisms that secrete powerful toxins can cause such rapid and severe necrosis that tissue damage is the dominant feature. MORPHOLOGYBecausefewinflammatorycellsarepresent,necroticlesionsresembleinfarctswithdisruptionorlossofbasophilicnuclearstainingandpreservationofcellularoutlines.Clostridia oftenareopportunisticpathogensthatareintroducedintomuscletissuebypenetratingtraumaorinfectionofthebowelinaneutropenichost.Similarly,theparasiteE. histolytica causescoloniculcersandliverabscessescharacterizedbyextensivetissuedestructionandliquefactivenecrosiswithoutaprominentinflammatoryinfiltrate.Byentirelydifferentmechanisms,virusescancausewidespreadnecrosisofhostcellsassociatedwithinflammation,asexemplifiedbydestructionofthetemporallobesofthebrainbyHSVortheliverbyHBV.ThepowerfulexotoxinsofC. diphtheriae causenecrosisoflaryngealepitheliumgivingrisetoapseudo-membranecomprisedofnecroticcellsenmeshedinafibrinousexudate.Thiscancauseasphyxia.


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Pathology_Robbins. Many infections elicit chronic inflammation, which can either resolve with complete healing or lead to extensive scarring. Fig. 9.11 Schistosoma haematobium infectionofthebladderwithnumerouscalcifiedeggsandextensivescarring. MORPHOLOGYSometimesanexuberantscarringresponseisthemajorcauseofdysfunction.Forexample,schistosomeeggscause“pipestem”fibrosisoftheliverorfibrosisofthebladderwall( Fig.9.11 ).M. tuberculosis causesconstrictivefibrouspericarditis.ChronicHBVinfectionmaycausecirrhosisoftheliver,inwhichdensefibrousseptasurroundnodulesofregeneratinghepatocytes.


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Pathology_Robbins. The patterns of tissue reactions described above are useful guidelines for analyzing microscopic features of infectious processes, but in practice it must be remembered that different types of host reactions often occur at the same time. For example, the lung of a patient with AIDS may be infected with CMV, which causes cytolytic changes, and, at the same time, by Pneumocystis, which causes interstitial inflammation. Similar patterns of inflammation also can be seen in tissue responses to physical or chemical agents and in other inflammatory conditions of unknown cause. Finally, in immunocompromised individuals, the absence of a host inflammatory response frequently eliminates some of the histologic clues about the potential nature of infecting microorganism(s). Because of this potential for mixed infections and/or lack of host response, other diagnostic tests for infection in addition to pathologic examination are essential to make a definitive diagnosis.


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Pathology_Robbins. Inherited or acquired defects in immunity (Chapter 5) often impair only part of the immune system, rendering the affected individuals susceptible to specific types of infections. Patients with antibody deficiency, as in X-linked agammaglobulinemia, contract severe bacterial infections by extracellular bacteria and a few viral infections (rotavirus and enteroviruses). Patients with T-cell defects are susceptible to infections with intracellular pathogens, notably viruses and some parasites. Patients with deficiencies in early complement components are particularly susceptible to infections by encapsulated bacteria, such as S. pneumoniae, whereas deficiencies of the late components of complement are associated with Neisseria infections. Deficiencies in neutrophil function lead to increased infections with S. aureus, some gram-negative bacteria, and fungi.


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Pathology_Robbins. Deficiencies in neutrophil function lead to increased infections with S. aureus, some gram-negative bacteria, and fungi. Individuals with inherited deficiencies in specific components of innate and adaptive immunity sometimes show selective susceptibility to particular infections. These patterns reveal the essential roles of different molecules in mediating protective immunity to specific microorganisms. For example, patients with mutations in signaling molecules downstream of several TLRs are prone to pyogenic bacterial diseases, particularly with S. pneumoniae infections. Impaired TLR3 responses are associated with childhood HSV encephalitis. Inherited defects in IL-17 immunity (such as mutations in STAT3, a transcription factor needed for Th17 cell generation) are associated with chronic mucocutaneous candidiasis. http://ebooksmedicine.net


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Pathology_Robbins. Acquired immunodeficiencies have a variety of causes, the most widely known being infection with HIV, which causes AIDS (Chapter 5). HIV infects and kills CD4+ helper T lymphocytes, leading to profound immunosuppression and a multitude of infections. Other causes of acquired immunodeficiency include infiltrative processes that suppress bone marrow function (e.g., leukemia), immunosuppressive drugs (such as those used to treat certain autoimmune diseases), and hemopoietic stem cell transplantation. Diseases of organ systems other than the immune system also can make patients susceptible to disease due to specific microorganisms. Individuals with cystic fibrosis and impaired respiratory clearance commonly get infections dominated by Pseudomonas aeruginosa. Lack of splenic function in individuals with sickle cell disease makes them susceptible to infection with encapsulated bacteria such as S. pneumoniae. Burns destroy skin, removing this barrier to microbes, allowing infection with


Pathology_Robbins

Pathology_Robbins. with sickle cell disease makes them susceptible to infection with encapsulated bacteria such as S. pneumoniae. Burns destroy skin, removing this barrier to microbes, allowing infection with pathogens such as P. aeruginosa. Finally, malnutrition impairs immune defenses.


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Pathology_Robbins. Fig.9.12 Fig. 9.12 IntheabsenceofappropriateT-cell–mediatedimmunity,granulomatoushostresponsedoesnotoccur.Mycobacterium avium infectioninaduodenalbiopsyfromapatientwithAIDS,showingmassiveintracellularmacrophageinfectionwithacid-fastorganisms(filamentousandpinkinthisacid-faststainpreparation).Theintracellularbacteriapersistandevenproliferatewithinmacrophages,becausethereareinadequateTcellstomountagranulomatousresponse.AIDS,acquiredimmunodeficiencysyndrome. (Courtesy of Dr. Arlene Sharpe, Department of Microbiology and Immunology, Harvard Medical School, Boston, Massachusetts.) Innormal(immunocompetent)individuals,thepatternsofhostresponsesarefairlystereotypicalfordifferentclassesofmicrobes;theseresponsepatternscanbeusedtoinferpossiblecausalorganisms. Neutrophil-richacutesuppurativeinflammationistypicalofinfectionswithmanybacteria(“pyogenic”bacteria)andsomefungi. Mononuclearcellinfiltratesarecommoninmanychronicinfectionsandsomeacuteviralinfections. M.


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Pathology_Robbins. Mononuclearcellinfiltratesarecommoninmanychronicinfectionsandsomeacuteviralinfections. M. tuberculosis andcertainfungi. Cytopathicandproliferativelesionsarecausedbysomeviruses. Necrosisresultsfromtissue-damagingtoxinsproducedbymicrobessuchasC. perfringens. Chronicinflammationandscarringrepresentthefinalcommonpathwayofmanyinfections. Arvanitis M, Anagnostou T, Fuchs BB, et al: Molecular and nonmolecular diagnostic methods for invasive fungal infections, Clin Microbiol Rev 27:490, 2014. [A very useful review of the many methods available for laboratory detection of fungal infections.] Belkaid Y, Segre JA: Dialogue between skin microbiota and immunity, Science 346:954, 2014. [An excellent review of interactions between the microbiome of the skin and the immune system.]


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Pathology_Robbins. Belkaid Y, Segre JA: Dialogue between skin microbiota and immunity, Science 346:954, 2014. [An excellent review of interactions between the microbiome of the skin and the immune system.] Bennett E, Dolan R, Blaser MJ: Mandell, Douglas, and Bennett’s principles and practice of infectious diseases, ed 8, Philadelphia, 2014, Elsevier Saunders. [A comprehensive reference for infectious diseases, including very good sections on microbial pathogenesis.] Bergsbaken T, Fink SL, Cookson BT: Pyroptosis: host cell death and inflammation, Nat Rev Microbiol 7:99, 2010. [A good introduction to the inflammasome and pyroptosis, including their role in the response to infections.] Blair JM, Webber MA, Baylay AJ, et al: Molecular mechanisms of antibiotic resistance, Nat Rev Microbiol 13:42, 2015. [An accessible, well-written review at the introductory level.]


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Pathology_Robbins. Blair JM, Webber MA, Baylay AJ, et al: Molecular mechanisms of antibiotic resistance, Nat Rev Microbiol 13:42, 2015. [An accessible, well-written review at the introductory level.] Buchan BW, Ledeboer NA: Emerging technologies for the clinical microbiology laboratory, Clin Microbiol Rev 27:783, 2014. [A timely review of emerging technologies in clinical microbiology.] Cadwell K: The virome in host health and disease, Immunity 42:805, 2015. [A good introduction to this emerging area, including a discussion of the interactions between the virome and other components of the microbiome.] Dantas G, Sommer MO, Degnan PH, et al: Experimental approaches for defining functional roles of microbes in the human gut, Annu Rev Microbiol 67:459, 2013. [A thoughtful and short review of experimental methods for microbiology research.]


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Pathology_Robbins. Galán JE, Lara-Tejero M, Marlovits TC, et al: Bacterial type III secretion systems: specialized nanomachines for protein delivery into target cells, Annu Rev Microbiol 68:415, 2014. [A review of the structure and mechanism of type III secretion systems.] Geno KA, Gilbert GL, Song JY, et al: Pneumococcal capsules and their types: past, present, and future, Clin Microbiol Rev 28:871, 2015. [Includes the significance of capsule in pathogenesis and vaccines, as well as methods for capsule typing.] Goo E, An JH, Kang Y, et al: Control of bacterial metabolism by quorum sensing, Trends Microbiol 23:567, 2015. [A review of this emerging area of study, with focus on non-enteric gram-negative bacilli.] http://ebooksmedicine.net Hobley L, Harkins C, MacPhee CE, et al: Giving structure to the biofilm matrix: an overview of individual strategies and emerging common themes, FEMS Microbiol Rev 39:649, 2015. [An exhaustive review of biofilm structure.]


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Pathology_Robbins. Jorgensen JH, Pfaller MA: Manual of clinical microbiology, ed 11, Washington, DC, 2015, ASM Press. [A comprehensive textbook of clinical microbiology at an advanced level.] Jucker M, Walker LC: Self-propagation of pathogenic protein aggregates in neurodegenerative diseases, Nature 501:45, 2013. [A short review of prions and other self-propagating proteins.] Keeney KM, Yurist-Doutsch S, Arrieta MC, et al: Effects of antibiotics on human microbiota and subsequent disease, Annu Rev Microbiol 68:217, 2014. [A timely review of how antibiotics can increase vulnerability to some diseases.] Khabbaz RF, Moseley RR, Steiner RJ, et al: Challenges of infectious diseases in the USA, Lancet 384:53, 2014. [A comprehensive but short review of current infectious disease challenges in the United States.]


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Pathology_Robbins. Lagier JC, Edouard S, Pagnier I, et al: Current and past strategies for bacterial culture in clinical microbiology, Clin Microbiol Rev 28:208, 2015. [An exhaustive review of the utility of bacterial culture.] Mackey TK, Liang BA, Cuomo R, et al: Emerging and reemerging neglected tropical diseases: a review of key characteristics, risk factors, and the policy and innovation environment, Clin Microbiol Rev 27:949, 2014. [A review of current challenges of emerging and neglected diseases in developing nations.] Nash AA, Dalziel RG, Fitzgerald JR: Mims’ pathogenesis of infectious disease, ed 6, San Diego, 2015, Academic Press. [A beautifully written timely and comprehensive classic text.] Okumura CY, Nizet V: Subterfuge and sabotage: evasion of host innate defenses by invasive gram-positive bacterial pathogens, Annu Rev Microbiol 68:439, 2014. [A very good review of this complex area.]


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Pathology_Robbins. Panchaud A, Stojanov M, Ammerdorffer A, et al: Emerging role of Zika v irus in adverse fetal and neonatal outcomes, Clin Microbiol Rev 29:659, 2016. [Review of emerging role of Zika virus in congenital brain defects.] Safronetz D, Feldmann H, de Wit E: Birth and pathogenesis of rogue respiratory viruses, Annu Rev Pathol 10:449, 2015. [Introduces zoonotic respiratory review, with a good emphasis on pathogenesis.] Sommer F, Backhed F: The gut microbiota—masters of host development and physiology, Nat Rev Microbiol 11:227, 2013. [An excellent introduction to intestinal microbiome and the role it plays in development of the immune response.] Wlodarska M, Johnston JC, Gardy JL, et al: A microbiological revolution meets an ancient disease: improving the management of tuberculosis with genomics, Clin Microbiol Rev 28:523, 2015. [A good example of the important trend toward whole-bacterial genome sequencing in clinical diagnostics.] http://ebooksmedicine.net studentconsult.com


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Pathology_Robbins. Epidemiology of Hypertension Mechanisms of Essential Hypertension Intimal Thickening: A Stereotypical Response to Vascular Injury Epidemiology of Atherosclerosis Clinicopathologic Consequences of Varicose Veins of the Extremities Varicosities of Other Sites Vascular diseases are responsible for some of the most common and lethal conditions afflicting mankind. Although most clinically significant disorders involve arterial lesions, venous pathologies also can wreak havoc. Vascular disease develops through two principal mechanisms: Narrowing or complete obstruction of vessel lumina, occurring either progressively (e.g., by atherosclerosis) or acutely (e.g., by thrombosis or embolism) Weakening of vessel walls, causing dilation and/or rupture We start with an overview of vascular structure and function, as background for the diseases of blood vessels discussed in the chapter.


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Pathology_Robbins. Weakening of vessel walls, causing dilation and/or rupture We start with an overview of vascular structure and function, as background for the diseases of blood vessels discussed in the chapter. Blood vessels are fundamentally all tubes composed of smooth muscle cells (SMCs) and extracellular matrix (ECM), with an inner luminal face covered by a continuous lining of endothelial cells (ECs). However, the relative amounts of SMCs and ECM, and the properties of the ECs, vary throughout the vasculature depending on unique functional needs (


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Pathology_Robbins. Fig. 10.1 ). To accommodate pulsatile flow and higher blood pressures, arterial walls are thicker than veins and invested with several reinforcing layers of SMCs. As arteries narrow to arterioles, the ratio of wall thickness to lumen diameter increases to allow more precise regulation of intravascular pressure. Veins, on the other hand, are distensible thin-walled vessels with high capacitance. To facilitate maximal diffusion, capillaries are essentially single-cell linings of ECs lying on a basement membrane. Since various vessels have unique structural features, it is not surprising that certain lesions characteristically involve only specific regions of the vasculature. For example, atherosclerosis occurs mainly in larger, muscular arteries, while hypertension affects small arterioles, and specific forms of vasculitis selectively involve vessels of only a certain caliber. Vessel walls are organized into three concentric layers: intima, media, and adventitia (see


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Pathology_Robbins. Vessel walls are organized into three concentric layers: intima, media, and adventitia (see Fig. 10.1 ). These layers are present in all vessels but are most apparent in larger vessels and particularly arteries. The intima consists of an EC monolayer on a basement membrane with minimal underlying ECM; it is separated from the media by a dense elastic membrane called the internal elastic lamina. The media is composed predominantly of SMCs and ECM, surrounded by loose connective tissue, nerve fibers, and smaller vessels of the adventitia. An external elastic lamina is present in some arteries and defines the transition between media and adventitia. Diffusion of oxygen and nutrients from the lumen is adequate to sustain thin-walled vessels and the innermost SMCs of all vessels. In large and medium-sized vessels, however, small arterioles within the adventitia (called vasa vasorum — literally, “vessels of the vessels”) perfuse the outer half to two-thirds of the media.


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Pathology_Robbins. http://ebooksmedicine.net Fig. 10.1 Regionalvascularspecializations.Althoughallvesselssharethesamegeneralconstituents,thethicknessandcompositionofthevariouslayersdifferasafunctionofhemodynamicforcesandtissuerequirements. Arteries are divided into three types based on their size and structure: Large elastic arteries (e.g., aorta, arch vessels, iliac and pulmonary arteries). In these vessels, elastic fibers alternate with SMCs throughout the media, which expands during systole (storing some of the energy of each cardiac contraction), and recoils during diastole to propel blood distally. With age and/or diseases, such as diabetes and hypertension, the elasticity is lost; the vessels become “stiff pipes” that transmit high arterial pressures to distal organs, or become dilated and tortuous (ectatic) and prone to rupture.


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Pathology_Robbins. Medium-sized muscular arteries (e.g., coronary and renal arteries). Here, the media is composed primarily of SMCs, with elastin limited to the internal and external elastic lamina. The medial SMCs are circularly or spirally arranged around the lumen, and regional blood flow is regulated by SMC contraction (vasoconstriction) and relaxation (vasodilation) controlled by the autonomic nervous system and local metabolic factors (e.g., acidosis). ECs also modulate arterial SMC tone, for example, by releasing nitric oxide (NO, causing vasodilation) or endothelin (causing vasoconstriction).


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Pathology_Robbins. • Small arteries (2 mm or less in diameter) and arterioles (20 to 100 µm in diameter) lie within the connective tissue of organs. The media in these vessels is mostly composed of SMCs. Arterioles are where blood flow resistance is regulated. As pressures drop during passage through arterioles, the velocity of blood flow is sharply reduced, and flow becomes steady rather than pulsatile. Because the resistance to fluid flow is inversely proportional to the fourth power of the diameter (i.e., halving the diameter increases resistance 16-fold), small changes in arteriolar lumen size have profound effects on blood pressure.


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Pathology_Robbins. Capillaries have lumen diameters slightly smaller than those of red blood cells (7 to 8 µm). These vessels are lined by ECs and partially surrounded by SMC-like cells called pericytes. Collectively, capillary beds have a very large total cross-sectional area and a low rate of blood flow. With their thin walls and slow flow, capillaries are ideally suited to the rapid exchange of diffusible substances between blood and tissue. The capillary network of most tissues is necessarily very rich, because diffusion of oxygen and nutrients is not efficient beyond 100 µm; metabolically active tissues (e.g., heart) have the highest capillary density. Veins receive blood from the capillary beds as postcapillary venules, which anastomose to form collecting venules and progressively larger veins. The vascular leakage (edema) and leukocyte emigration characteristic of inflammation occurs preferentially in postcapillary venules (Chapter 3). http://ebooksmedicine.net


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Pathology_Robbins. http://ebooksmedicine.net Compared with arteries at the same level of branching, veins have larger diameters, larger lumina, and thinner walls with less distinct layers, all adaptations to the low pressures found on the venous side of the circulation (see Fig. 10.1 ). Thus, veins are more prone to dilation, external compression, and penetration by tumors or inflammatory processes. In veins where blood flows against gravity (e.g., in the lower extremities), backflow is prevented by valves. Collectively, the venous system has a huge capacitance and normally contains approximately two thirds of the blood.


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Pathology_Robbins. Lymphatics are thin-walled, endothelium-lined channels that drain lymph (water, electrolytes, glucose, fat, proteins, and inflammatory cells) from the interstitium of tissues, eventually reconnecting with the blood stream via the thoracic duct. Lymphatics transport interstitial fluid and inflammatory cells from the periphery to lymph nodes, thereby facilitating antigen presentation and cell activation in the nodal tissues—and enabling continuous monitoring of peripheral tissues for infection. This can be a double-edged sword, however, as these channels can also disseminate disease by transporting microbes or tumor cells to distant sites. Endothelium is a continuous sheet of cells lining the entire vascular tree that regulates many aspects of blood and blood vessel function ( Table 10.1 ). Resting ECs maintain a non-thrombogenic blood-tissue interface (Chapter 4), modulate inflammation (Chapter 3), and influence the growth and behavior of other cell types, particularly SMCs.


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Pathology_Robbins. Table 10.1 Endothelial Cell Properties and Functions ProductionofextracellularmatrixCollagen,proteoglycans ModulationofbloodflowandVasoconstrictors: endothelin,ACEvascularreactivityVasodilators: NO,prostacyclin RegulationofinflammationandIL-1,IL-6,chemokinesimmunityAdhesionmolecules:VCAM-1,ICAM,E-selectin,P-selectinHistocompatibilityantigens ACE, Angiotensin-convertingenzyme;CSF, colony-stimulatingfactor;FGF, fibroblastgrowthfactor;ICAM, intercellularadhesionmolecule;IL, interleukin;LDL, low-densitylipoprotein;NO, nitricoxide;PDGF, platelet-derivedgrowthfactor;TGF-β, transforminggrowthfactor-β;VCAM, vascularcelladhesionmolecule. Normotension Laminar flow Non-adhesive, non-Growth factors (e.g., VEGF) thrombogenic surface Hypertension Increased expression ofCytokines procoagulants, adhesionComplement molecules, andBacterial products proinflammatory factorsLipid products Altered expression ofAdvanced glycation chemokines, cytokines,end-products and growth factorsHypoxia, acidosis


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Pathology_Robbins. In most regions, the interendothelial junctions normally are impermeable. However, these junctions open under the influence of hemodynamic stress (e.g., high blood pressure) and/or vasoactive agents (e.g., histamine in inflammation), flooding the adjacent tissues with electrolytes and protein. Vacuolar transcytosis also permits the movement of large amounts of solutes across intact endothelium. Relevant to pathologic processes, ECs also are active participants in the egress of leukocytes during inflammatory cell recruitment (Chapter 3), and EC dysfunction underlies development of atherosclerosis (discussed later).


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Pathology_Robbins. Although ECs throughout the vasculature share many attributes, they also show phenotypic variability and adaptations depending on the anatomic site and local environmental cues. Thus, EC populations from different parts of the vasculature (e.g., large vessels versus capillaries, or arteries versus veins) have distinct transcriptional programs and behaviors. Fenestrations (holes) in ECs lining hepatocyte cords, renal glomeruli, and choroid plexus are specializations that facilitate filtration. Conversely, in the central nervous system, ECs—in conjunction with astrocytes— collaborate to generate an impermeable blood-brain barrier. Maintenance of a “normal,” nonthrombogenic EC lining requires laminar flow, certain growth factors (e.g., vascular endothelial growth factor [VEGF]), and firm adhesion to the underlying basement membrane (


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Pathology_Robbins. Fig. 10.2 ). Trauma or other injuries that denude vessel walls of ECs tip the scales toward thrombosis and vasoconstriction. However, ECs also respond to various physiologic and pathologic stimuli by modulating their usual (constitutive) functions and by expressing new (inducible) properties—a process called endothelial activation. http://ebooksmedicine.net Inducers of endothelial activation include bacterial products, inflammatory cytokines, hemodynamic stresses and lipid products (relevant to atherosclerosis, discussed later), advanced glycation end products (important in diabetic vascular injury), viruses, complement, and various metabolic insults (e.g., hypoxia) (see Fig. 10.2 ). Activated ECs undergo shape changes, express adhesion molecules, and produce cytokines, chemokines, growth factors, pro-coagulant and anti-coagulant factors, and a host of other biologically active products—all presumably intended to respond to the original stimulus.


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Pathology_Robbins. Some of these responses are rapid (occurring within minutes), reversible, and independent of new protein synthesis (e.g., endothelial contraction induced by histamine); others involve alterations in gene and protein expression, and may take days to develop or abate. Exposure of ECs to high levels of stimuli for sustained periods can result in endothelial dysfunction, characterized by impaired endothelium-dependent vasodilation, hypercoagulable states, and increased oxygen free radical production. Dysfunctional endothelium can initiate thrombosis, promote atherosclerosis, or contribute to formation of the vascular lesions of hypertension and diabetes. SMCs participate in both normal vascular repair and pathologic processes such as atherosclerosis. When stimulated by various factors, SMCs can do the following: Upregulate ECM collagen, elastin, and proteoglycan production


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Pathology_Robbins. Upregulate ECM collagen, elastin, and proteoglycan production SMCs also mediate the vasoconstriction or vasodilation that occurs in response to physiologic or pharmacologic stimuli. The migratory and proliferative activities of SMCs are regulated by numerous factors. Among the most important pro–growth factors are platelet-derived growth factor (PDGF), endothelin, thrombin, fibroblast growth factors, and inflammatory mediators such as interferon-γ (IFN-γ) and interleukin-1 (IL-1). Factors that maintain SMCs in a quiescent state include heparan sulfate, NO, and transforming growth factor-α (TGF-α). Allvesselsarelinedbyendothelium;althoughallECssharecertainhomeostaticproperties,ECsinspecificvascularbedshavespecialfeaturesthatallowfortissue-specificfunctions(e.g.,fenestratedECsinrenalglomeruli). TherelativeSMCandECMcontentofvesselwalls(e.g.,inarteries,veins,andcapillaries)variesaccordingtohemodynamicdemands(e.g.,pressure,pulsatility)andfunctionalrequirements.


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Pathology_Robbins. TherelativeSMCandECMcontentofvesselwalls(e.g.,inarteries,veins,andcapillaries)variesaccordingtohemodynamicdemands(e.g.,pressure,pulsatility)andfunctionalrequirements. ECfunctionistightlyregulatedinboththebasalandactivatedstates.VariousphysiologicandpathophysiologicstimuliinduceendothelialactivationanddysfunctionthataltertheECphenotype(e.g.,procoagulativeversusanti-coagulative,proinflammatoryversusanti-inflammatory,nonadhesiveversusadhesive). Although rarely symptomatic, unusual anatomic variants of blood vessels can cause complications during surgery, as may occur when a vessel in an unexpected location is injured. Cardiac surgeons and interventional cardiologists also must be familiar with coronary artery variants that can occur in up to 1% to 5% of patients. Among the other congenital vascular anomalies, three deserve further mention:


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Pathology_Robbins. Berry aneurysms are thin-walled arterial outpouchings in cerebral vessels, classically at branch points around the circle of Willis; they occur where the arterial media is congenitally attenuated and can spontaneously rupture causing fatal intracerebral hemorrhage (Chapter 23). Arteriovenous (AV) fistulas are abnormal connections between arteries and veins without an intervening capillary bed. They occur most commonly as developmental defects but can also result from rupture of arterial aneurysms into adjacent veins, from penetrating injuries that pierce arteries and veins, or from inflammatory necrosis of adjacent vessels. AV fistulas can be created surgically to provide vascular access for hemodialysis. Extensive AV fistulas can cause high-output cardiac failure by shunting large volumes of blood from the arterial to the venous circulation.


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Pathology_Robbins. Fibromuscular dysplasia is a focal irregular thickening of the walls of mediumand large-sized muscular arteries due to a combination of medial and intimal hyperplasia and fibrosis. It can manifest at any age but occurs most frequently in young women. The focal wall thickening results in luminal stenosis or can be associated with vessel spasm that reduces vascular flow; in the renal arteries, it can lead to renovascular hypertension. Between the focal segments of thickened wall, the artery often exhibits medial attenuation; vascular outpouchings can develop in these portions of the vessel and sometimes rupture. Systemic and local blood pressure must be maintained within a narrow range to maintain health. Low blood pressure (hypotension) results in inadequate organ perfusion, organ dysfunction, and sometimes tissue death. Conversely, high blood pressure (hypertension) causes vessel and end-organ damage and is one of the major risk factors for atherosclerosis (see later).


Pathology_Robbins

Pathology_Robbins. Blood pressure is a function of cardiac output and peripheral vascular resistance, both of which are influenced by multiple genetic and environmental factors (Fig. 10.3 ). The integration of the various inputs ensures adequate systemic perfusion, despite regional demand differences. • Cardiac output is a function of stroke volume and heart rate. The most important determinant of stroke volume is the filling pressure, which is regulated through sodium homeostasis and its effect on blood volume. Heart rate and myocardial contractility (a second factor affecting stroke volume) are both regulated by the αand β-adrenergic systems (in addition to their effects on vascular tone). http://ebooksmedicine.net LOCAL FACTORS Autoregulation pH, hypoxia Fig. 10.3 Bloodpressureregulation.


Pathology_Robbins

Pathology_Robbins. http://ebooksmedicine.net LOCAL FACTORS Autoregulation pH, hypoxia Fig. 10.3 Bloodpressureregulation. • Peripheral resistance is regulated predominantly at the level of the arterioles by neural and humoral inputs. Vascular tone reflects a balance between the actions of vasoconstrictors (including angiotensin II, catecholamines, and endothelin) and vasodilators (including kinins, prostaglandins, and NO). Resistance vessels also exhibit autoregulation, whereby increased blood flow induces vasoconstriction to protect tissues against hyperperfusion. Finally, blood pressure is fine-tuned by tissue pH and hypoxia to accommodate local metabolic demands. Factors released from the kidneys, adrenal glands, and myocardium interact to influence vascular tone and to regulate blood volume by adjusting sodium balance ( Fig.


Pathology_Robbins

Pathology_Robbins. Factors released from the kidneys, adrenal glands, and myocardium interact to influence vascular tone and to regulate blood volume by adjusting sodium balance ( Fig. 10.4 ). Each day, the kidneys on average filter 170 liters of plasma containing 23 moles of salt. Thus, with a typical diet containing 100 mEq of sodium, 99.5% of the filtered salt must be reabsorbed to maintain total body sodium levels. About 98% of the filtered sodium is reabsorbed by several constitutively active transporters. Recovery of the remaining 2% of sodium occurs by way of the epithelial sodium channel (ENaC), which is tightly regulated by aldosterone, a downstream effector of the renin-angiotensin system; it is this pathway that determines net sodium balance.


Pathology_Robbins

Pathology_Robbins. Kidneys influence peripheral resistance and sodium excretion/retention primarily through the reninangiotensin system. The kidneys and heart contain cells that sense changes in blood pressure and/or blood volume. In response, these cells release several important regulators that act in concert to maintain normal blood pressure: Renin is a proteolytic enzyme produced by renal juxtaglomerular cells—myoepithelial cells that surround the glomerular afferent arterioles. It is released in response to low blood pressure in afferent arterioles, elevated levels of circulating catecholamines, or low sodium levels in the distal convoluted renal tubules. The latter occurs when the glomerular filtration rate falls (e.g., when the cardiac output is low) because a higher fraction of the filtered sodium is resorbed in the proximal tubules. Angiotensin. Renin cleaves plasma angiotensinogen to angiotensin I, which in turn is converted to angiotensin


Pathology_Robbins

Pathology_Robbins. Angiotensin. Renin cleaves plasma angiotensinogen to angiotensin I, which in turn is converted to angiotensin II by angiotensin-converting enzyme (ACE) in the periphery. Angiotensin II raises blood pressure by (1) inducing vascular SMC contraction, (2) stimulating aldosterone secretion by the adrenal gland, and (3) increasing tubular sodium resorption. Vasodilators. The kidney also produces a variety of vascular relaxing substances (including prostaglandins and NO) that presumably counterbalance the vasopressor effects of angiotensin. Aldosterone. Adrenal aldosterone increases blood pressure by its effect on blood volume; aldosterone increases sodium resorption (and thus water) in the distal convoluted and collecting tubules while also driving potassium excretion into the urine.


Pathology_Robbins

Pathology_Robbins. Natriuretic peptides. Myocardial natriuretic peptides are released from atrial and ventricular myocardium in response to volume expansion; these inhibit sodium resorption in the distal renal tubules, thus leading to sodium excretion and diuresis. They also induce systemic vasodilation. Bloodpressureisdeterminedbyvascularresistanceandcardiacoutput. Vascularresistanceisregulatedatthelevelofthearterioles,influencedbyneuralandhormonalinputs. Cardiacoutputisdeterminedbyheartrateandstrokevolume,thelatterofwhichisstronglyinfluencedbybloodvolume.Bloodvolumeinturnisregulatedmainlybyrenalsodiumexcretionorresorption. Renin,amajorregulatorofbloodpressure,issecretedbythekidneysinresponsetodecreasedbloodpressureinafferentarterioles.Inturn,renincleavesangiotensinogentoangiotensinI;subsequentperipheralcatabolismproducesangiotensinII,whichregulatesbloodpressurebyincreasingvascularSMCtoneandbyincreasingadrenalaldosteronesecretion,whichconsequentlyincreasesrenalsodiumresorption.


Pathology_Robbins

Pathology_Robbins. http://ebooksmedicine.net Fig. 10.4 Interplayofrenin,angiotensin,aldosterone,andatrialnatriureticpeptideinbloodpressureregulation(seetext).


Pathology_Robbins

Pathology_Robbins. Hypertension is a major health problem in the developed world. Although it occasionally manifests in an acute aggressive form, high blood pressure is typically asymptomatic for many years. This insidious condition has been dubbed essential hypertension, so called because the gradual age-associated rise in blood pressure was considered “essential” for normal perfusion of endorgans such as the brain. However, such increases are neither essential nor benign; besides increasing the risk for stroke and atherosclerotic coronary heart disease, hypertension can lead to cardiac hypertrophy and heart failure (hypertensive heart disease; see Chapter 11), aortic dissection, multi-infarct dementia, and renal failure. While the molecular pathways of blood pressure regulation are reasonably well understood, the mechanisms leading to hypertension in the vast majority of affected individuals remain unknown. The accepted wisdom is that “essential hypertension” results from the interplay of several


Pathology_Robbins

Pathology_Robbins. the mechanisms leading to hypertension in the vast majority of affected individuals remain unknown. The accepted wisdom is that “essential hypertension” results from the interplay of several genetic polymorphisms (which individually might be inconsequential) and environmental factors, which conspire to increase blood volume and/or peripheral resistance.


Pathology_Robbins

Pathology_Robbins. Like height and weight, blood pressure is a continuously distributed variable; moreover, detrimental consequences increase continuously as the pressure rises, with no rigidly defined threshold dependably predicting total safety. Nevertheless, sustained diastolic pressures greater than 90 mm Hg or sustained systolic pressures in excess of 140 mm Hg are reliably associated with an increased risk for atherosclerosis and are therefore used as cutoffs in diagnosing hypertension in clinical practice. By these criteria, over 25% of individuals in the general population are hypertensive. As noted however, these values are somewhat arbitrary, and in patients with other cardiovascular risk factors (e.g., diabetes), lower thresholds may be applicable.


Pathology_Robbins

Pathology_Robbins. The prevalence of pathologic effects of high blood pressure increases with age and is also higher in African Americans. Without appropriate treatment, some 50% of hypertensive patients die of ischemic heart disease (IHD) or congestive heart failure, and another third succumb to stroke. Reduction of blood pressure dramatically reduces the incidence and clinical sequelae (including death) of all forms of hypertension-related disease. Indeed, treatment of asymptomatic hypertension constitutes one of the few instances in which “preventive medicine” has a major demonstrated health benefit. http://ebooksmedicine.net


Pathology_Robbins

Pathology_Robbins. http://ebooksmedicine.net A small percentage of hypertensive patients (approximately 5%) present with a rapidly rising blood pressure that, if untreated, leads to death in within 1 to 2 years. Such malignant hypertension usually is severe (i.e., systolic pressures over 200 mm Hg or diastolic pressures over 120 mm Hg) and frequently is associated with renal failure and retinal hemorrhages, with or without papilledema. It can arise de novo but most commonly is superimposed on preexisting benign hypertension. Hypertension may be primary (idiopathic) or less commonly secondary to an identifiable underlying condition. In close to 95% of cases hypertension is idiopathic or “essential”. Most of the remaining cases (secondary hypertension) are due to primary renal disease, renal artery narrowing (renovascular hypertension), or adrenal disorders (


Pathology_Robbins

Pathology_Robbins. Table 10.2 ). Essential hypertension is compatible with long life unless a myocardial infarction, stroke, or other complication supervenes. Prognosis of secondary hypertension depends on adequate treatment of the underlying cause. Several relatively rare single-gene disorders cause hypertension (and hypotension) by affecting renal sodium resorption. Such disorders include the following: • Gene defects in enzymes involved in aldosterone metabolism (e.g., aldosterone synthase, 11β-hydroxylase, 17α Table 10.2 Types and Causes of Hypertension (Systolic and Diastolic) Adrenocorticalhyperfunction(Cushingsyndrome,primaryaldosteronism,congenitaladrenalhyperplasia,licoriceingestion) Exogenoushormones(glucocorticoids,estrogen[includingpregnancy-inducedandoralcontraceptives],sympathomimeticsandtyraminecontainingfoods,monoamineoxidaseinhibitors)


Pathology_Robbins

Pathology_Robbins. Exogenoushormones(glucocorticoids,estrogen[includingpregnancy-inducedandoralcontraceptives],sympathomimeticsandtyraminecontainingfoods,monoamineoxidaseinhibitors) PsychogenicIncreasedintracranialpressureSleepapneaAcutestress,includingsurgery hydroxylase), leading to increased aldosterone secretion, increased salt and water resorption, and plasma volume expansion • Mutations in proteins that affect sodium resorption (as in Liddle syndrome, which is caused by mutations that prevent the normal degradation of the ENaC sodium channel, leading to increased distal tubular resorption of sodium) Although the specific triggers are unknown, it appears that both altered renal sodium handling and increased vascular resistance contribute to essential hypertension.


Pathology_Robbins

Pathology_Robbins. Although the specific triggers are unknown, it appears that both altered renal sodium handling and increased vascular resistance contribute to essential hypertension. Reduced renal sodium excretion in the presence of normal arterial pressure probably is a key pathogenic feature; indeed, this is a common etiologic factor in most forms of hypertension. Decreased sodium excretion causes an obligatory increase in fluid volume and increased cardiac output, thereby elevating blood pressure (see Fig. 10.3 ). At the new higher blood pressure, the kidneys excrete additional sodium. Thus, a new steady state of sodium excretion is achieved, but at the expense of an elevated blood pressure. Increased vascular resistance may stem from vasoconstriction or structural changes in vessel walls. These are not necessarily independent factors, as chronic vasoconstriction may result in permanent thickening of the walls of affected vessels.


Pathology_Robbins

Pathology_Robbins. Genetic factors play an important role in determining blood pressure, as shown by familial clustering of hypertension and by studies of monozygotic and dizygotic twins. In a small proportion of cases of essential hypertension there is linkage to specific angiotensinogen polymorphisms and angiotensin II receptor variants; polymorphisms of the renin-angiotensin system also may contribute to the known racial differences in blood pressure regulation. Susceptibility genes for essential hypertension in the vast majority of cases are currently unknown but probably include those that influence renal sodium resorption, the production of endogenous pressors, and SMC growth. Environmental factors, such as stress, obesity, smoking, physical inactivity, and high levels of salt consumption, modify the impact of genetic determinants. Evidence linking dietary sodium intake with the prevalence of hypertension is particularly strong.


Pathology_Robbins


Pathology_Robbins

Pathology_Robbins. http://ebooksmedicine.net Fig. 10.5 Hypertensivevasculardisease.(A)Hyalinearteriolosclerosis.Thearteriolarwallisthickenedwiththedepositionofamorphousproteinaceousmaterial(hyalinized),andthelumenismarkedlynarrowed.(B)Hyperplasticarteriolosclerosis(“onion-skinning”)(arrow) causingluminalobliteration(periodicacid–Schiffstain).(B, Courtesy of Helmut Rennke, MD, Brigham and Women’s Hospital, Boston, Massachusetts.) •Hyperplastic arteriolosclerosis ismoretypicalofseverehypertension.Vesselsexhibit“onionskin,”concentric,laminatedthickeningofarteriolarwallsandluminalnarrowing(see Fig.10.5B ).ThelaminationsconsistofSMCsandthickened,reduplicatedbasementmembrane.Inmalignanthypertension,thesechangesareaccompaniedbyfibrinoiddepositsandvesselwallnecrosis(necrotizing arteriolitis), whichareparticularlyprominentinthekidney. Hypertensionisacommondisorderaffecting25%ofthepopulation;itisamajorriskfactorforatherosclerosis,congestiveheartfailure,andrenalfailure.


Pathology_Robbins

Pathology_Robbins. Hypertensionoccasionallyiscausedbysingle-genedisordersorissecondarytodiseasesoftherenalarteries,kidneys,adrenalglands,orotherendocrineorgans. Injury to the vessel wall—and in particular to ECs—is the fundamental basis for the vast majority of vascular disorders. Such injurious stimuli may be biochemical, immunologic, or hemodynamic. The integrated function of ECs—and the underlying SMCs—is critical for the vasculature to respond to various stimuli; such responses can be adaptive or may lead to pathologic lesions. Thus, EC injury or dysfunction (as discussed earlier) contributes to a host of pathologic processes including thrombosis, atherosclerosis, and hypertensive vascular lesions. Ensuing SMC proliferation and matrix synthesis can help to repair a damaged vessel wall, but also can eventually lead to luminal occlusion. IntimalThickening:AStereotypicalResponsetoVascularInjury


Pathology_Robbins

Pathology_Robbins. IntimalThickening:AStereotypicalResponsetoVascularInjury Vascular injury leading to EC loss or dysfunction stimulates SMC growth, ECM synthesis, and thickening of the vascular wall. Healing of injured vessels involves the migration of SMCs or SMC precursor cells into the intima. These cells then proliferate and synthesize ECM in much the same way that fibroblasts fill in a wound elsewhere in the body ( Fig. 10.6), forming a neointima that typically is covered by an intact EC layer. This neointimal response occurs with any form of vascular damage or dysfunction, including infection, inflammation, immune injury, physical trauma (e.g., from a balloon catheter or hypertension), or toxic exposure (e.g. oxidized lipids or cigarette smoke). Thus, intimal thickening is a stereotypical response of the vessel wall to any insult.


Pathology_Robbins

Pathology_Robbins. Of note, the phenotype of neointimal SMCs is distinct from medial SMCs. Thus, neointimal SMCs are not contractile like medial SMCs, but do have the capacity to divide and have a considerably greater synthetic capacity http://ebooksmedicine.net 1. Recruitment of smooth muscle 2. Smooth muscle 3. Elaboration of cells or smooth muscle precursor cell mitosis extracellular matrix Endothelium cells to the intima Fig. 10.6 Stereotypicalresponsetovascularinjury.Schematicdiagramofintimalthickening,emphasizingintimalsmoothmusclecellmigrationandprolifera-tionassociatedwithextracellularmatrixsynthesis.Intimalsmoothmusclecellsmayderivefromtheunderlyingmediaormayberecruitedfromcirculatingprecursors;theyaredepictedinacolordifferentfromthatofthemedialsmoothmusclecells,toemphasizetheirdistinctphenotype.


Pathology_Robbins

Pathology_Robbins. than their sleepy colleagues in the media. Although neointimal cells were previously thought to arise exclusively from dedifferentiated medial SMCs, at least a subset is derived from circulating precursor cells. The migratory, proliferative, and synthetic activities of the intimal SMCs are regulated by growth factors and cytokines produced by platelets, ECs, and macrophages, as well as by activated coagulation and complement factors (as discussed earlier).


Pathology_Robbins

Pathology_Robbins. With restoration and/or normalization of the EC layer, intimal SMCs can return to a nonproliferative state, but not before the healing response has produced intimal thickening. With persistent or recurrent insults, further thickening can occur that leads to the stenosis of smalland medium-sized blood vessels (e.g., as in atherosclerosis, discussed later). As a final note, it is also important to recognize that gradual ongoing intimal thickening appears to be a part of “normal aging.” Fortunately, such age-related intimal change typically is of no consequence, in part because compensatory outward remodeling of the vessel wall results in little net change in the luminal diameter. Arteriosclerosis literally means “hardening of the arteries”; it is a generic term reflecting arterial wall thickening and loss of elasticity. Four distinct types are recognized, each with different clinical and pathologic causes and consequences:


Pathology_Robbins

Pathology_Robbins. Arteriolosclerosis affects small arteries and arterioles and may cause downstream ischemic injury. The two variants, hyaline and hyperplastic arteriolosclerosis, were discussed earlier in relation to hypertension. Mönckeberg medial sclerosis is characterized by the presence of calcific deposits in muscular arteries, usually centered on the internal elastic lamina, and typically in individuals older than 50 years of age. The lesions do not encroach on the vessel lumen and usually are not clinically significant.


Pathology_Robbins

Pathology_Robbins. Fibromuscular intimal hyperplasia is a non-atherosclerotic process that occurs in muscular arteries larger than arterioles. This is predominantly an SMCand ECM-rich lesion driven by inflammation (as in a healed arteritis or transplant-associated arteriopathy; see Chapter 11), or by mechanical injury (e.g., associated with stents or balloon angioplasty, see later). Such a healing response can cause substantial stenosis of the vessel; indeed such intimal hyperplasia underlies in-stent restenosis and is the major long-term limitation of solid organ transplants. • Atherosclerosis, from Greek root words for “gruel” and “hardening,” is the most frequent and clinically important pattern and is the subject of the next section.


Pathology_Robbins

Pathology_Robbins. • Atherosclerosis, from Greek root words for “gruel” and “hardening,” is the most frequent and clinically important pattern and is the subject of the next section. Atherosclerosis is characterized by intimal lesions called atheromas (or atheromatous or atherosclerotic plaques) that impinge on the vascular lumen and can rupture to cause sudden occlusion. It underlies the pathogenesis of coronary, cerebral, and peripheral vascular disease, and causes more morbidity and mortality (roughly half of all deaths) in the Western world than any other disorder. Atheromatous plaques are raised lesions composed of soft friable (grumous) lipid cores (mainly cholesterol and cholesterol esters, with necrotic debris) covered by fibrous caps (


Pathology_Robbins

Pathology_Robbins. Fig. 10.7 ). As they enlarged, atherosclerotic plaques may mechanically obstruct vascular lumina, leading to stenosis. Of greater concern, however, atherosclerotic plaques also are prone to rupture, an event that may result in thrombosis and sudden occlusion of the vessel. The thickness of the intimal lesions also may be sufficient to impede the perfusion of the underlying media, which may be weakened by ischemia and by changes in the ECM caused by subsequent inflammation. Together, these two factors weaken the media, setting the stage for the formation of aneurysms. With better treatment of infectious disorders and increased access to Western dietary behaviors, atherosclerosis is also becoming increasingly prevalent in developing countries. Because coronary artery disease is an important manifestation of atherosclerosis, epidemiologic data related http://ebooksmedicine.net Fig. 10.7 Thebasicstructureofanatheromatousplaque.


Pathology_Robbins

Pathology_Robbins. Fig. 10.7 Thebasicstructureofanatheromatousplaque. FIBROUS CAP (smooth muscle cells, macrophages, foam cells, lymphocytes, collagen, elastin, proteoglycans, neovascularization) NECROTIC CENTER (cell debris, cholesterol crystals, foam cells, calcium) to atherosclerosis-related mortality typically reflect deaths caused by ischemic heart disease (IHD) (Chapter 11); indeed, myocardial infarction is responsible for roughly one quarter of all deaths in the United States.


Pathology_Robbins

Pathology_Robbins. Atherosclerosis is virtually ubiquitous among most developed nations, with prevalence increasing at an alarming pace in developing countries. The mortality rate for IHD in the United States is among the highest in the world, approximately five times higher than that in Japan. However, IHD is increasing in Japan, where it is now the second leading cause of death. Furthermore, Japanese emigrants who come to the United States and adopt American lifestyles and dietary customs acquire the same atherosclerosis risk as U.S.-born individuals, emphasizing the important etiologic role of environmental factors.


Pathology_Robbins

Pathology_Robbins. The prevalence and severity of atherosclerosis and IHD have been correlated with a number of risk factors in several prospective analyses including the landmark Framingham Heart Study; some of these risk factors are constitutional (and therefore less controllable), but others are acquired or related to modifiable behaviors ( 10.3 ). These risk factors have roughly multiplicative effects. Thus, two factors increase the risk for myocardial infarction approximately 4-fold, and three (i.e., hyperlipidemia, hypertension, and smoking) increase the rate by a factor of 7 ( Fig. 10.8 • Genetics. Family history is the most important independent risk factor for atherosclerosis. Certain mendelian disorders are strongly associated with atherosclerosis (e.g., familial hypercholesterolemia) (Chapter 7), but these account for only a small percentage of cases. Most Men 8.7 5.5 13.7 9.2 16.5 11.3 23.4 17 28.827.7 3836.8 57.556.4 Women


Pathology_Robbins

Pathology_Robbins. Men 8.7 5.5 13.7 9.2 16.5 11.3 23.4 17 28.827.7 3836.8 57.556.4 Women Fig. 10.8 Estimated10-yearriskforcoronaryarterydiseasein55-year-oldmenandwomenasafunctionofestablishedriskfactors—hyperlipidemia,hypertension,smoking,anddiabetes.BP,bloodpressure;ECG,electrocardiogram;HDL-C,high-densitylipoproteincholesterol;LVH,leftventricularhypertrophy.(Data from O’Donnell CJ, Kannel WB: Cardiovascular risks of hypertension: lessons from observational studies, JHypertension16[Suppl 6]:3, 1998.) http://ebooksmedicine.net Table 10.3 Major Risk Factors for Atherosclerosis familial risk is related to multifactorial traits that go hand-in-hand with atherosclerosis, including hypertension, and, diabetes. Age. Atherosclerosis usually remains clinically silent until lesions reach a critical threshold in middle age or later. Thus, the incidence of myocardial infarction increases 5-fold between 40 and 60 years of age. Death rates from IHD continue to rise with each successive decade.


Pathology_Robbins

Pathology_Robbins. Gender. All other factors being equal, premenopausal women are relatively protected against atherosclerosis (and its consequences) compared with age-matched men. Thus, myocardial infarction and other complications of atherosclerosis are uncommon in premenopausal women in the absence of other predisposing factors such as diabetes, hyperlipidemia, or severe hypertension. After menopause, however, the incidence of atherosclerosis-related disease increases and can even exceed that in men. Although a salutary effect of estrogen has long been proposed to explain this gender difference, clinical trials have shown no benefit of hormonal therapy for prevention of vascular disease. Indeed, estrogen replacement after 65 years of age appears to actually increase cardiovascular risk. In addition to atherosclerosis, gender also influences other factors that can affect outcome in patients with IHD, such as hemostasis, infarct healing, and myocardial remodeling.