Introduction to Pathology: Cell and Tissue Injury PDF

Introduction to Pathology Cell and Tissue Injury Kenneth W. Hunter, Sc. D. Objectives Following this lecture, you should be able to: 1. Compare and contrast reversible and irreversible cellular injury, and discuss how adaptations maintain normal cellular homeostasis 2. Describe the biochemical and m...

Introduction to Pathology Cell and Tissue Injury Kenneth W. Hunter, Sc. D. Objectives Following this lecture, you should be able to: 1. Compare and contrast reversible and irreversible cellular injury, and discuss how adaptations maintain normal cellular homeostasis 2. Describe the biochemical and morphologic features of reversible cell injury (e.g. cell swelling) 3. List and describe the major cellular adaptations to stress (e.g., hypertrophy), and provide physiologic and pathologic examples 4. Compare and contrast the two major cell death pathways: necrosis and apoptosis 5. Describe the irreversible nuclear changes seen in necrosis (e.g. karyolysis), and describe the major gross patterns of tissue necrosis (e.g., coagulative necrosis) 6. Illustrate the biochemical and morphologic features of apoptosis 7. Distinguish between physiologic and pathologic apoptosis, and provide examples of each Objectives Continued 8. Summarize the mitochondrial (intrinsic) pathway of apoptosis 9. Describe the process of autophagy 10. List and discuss the major forms of injurious stimuli 11. Outline the major biochemical perturbations seen in ischemia and hypoxia; discuss the pathophysiology of ischemia-reperfusion injury 12. Discuss oxidative stress and articulate the pathologic role of free radicals; describe the protective role of antioxidants and enzymatic free radical scavenging systems 13. Discuss chemical (toxic) injury and provide examples 14. Describe the morphologic features and pathophysiologic processes seen in intracellular and extracellular accumulations of various endogenous and exogenous substances (e.g., hemosiderin) 15. Briefly summarize the process of cellular aging Introduction to Pathology Pathology is the study of the structural, biochemical, and functional changes in cells, tissues, and organs affected by various disease processes Before engaging in the study of organ-specific pathology, it is important to understand the general principles of pathology that apply to all organ systems This week and next you will be studying basic cell and tissue injury, the inflammatory process, and wound healing and repair/regeneration From Pathology to Clinical Medicine Etiology: underlying causes and modifying factors responsible for initiation and progression of disease Pathogenesis: mechanisms of development and progression of disease Thus, etiology refers to why disease arises; pathogenesis describes how a disease develops Virtually all forms of disease start with molecular or structural alterations in cells. This concept of the cellular basis of disease was first put forth in the nineteenth century by Rudolf Virchow, known as the father of modern pathology Cellular Responses to Stress and Noxious Stimuli The normal cell is confined to a fairly narrow range of structure and function called homeostasis Adaptations are reversible functional and structural responses to changes in physiologic states (e.g., pregnancy) and to pathologic stimuli Inability to adapt leads to cell injury which is reversible up to a point If the stimulus persists or is severe enough from the beginning, the cell suffers irreversible injury and ultimately undergoes cell death Sequence of Events in Cell Injury and Cell Death All stresses and noxious influences exert their effects first at the molecular or biochemical level Cells may become rapidly nonfunctional after injury, although they may still be viable, with potentially reversible damage A longer duration of injury may lead to irreversible injury and cell death With histochemical or ultrastructural techniques, changes may be seen in minutes to hours after injury It may take considerably longer (hours to days) before changes can be seen by light microscopy or on gross examination There is a time lag between the stress and the morphologic changes of cell injury or death; the duration of this delay may vary with the sensitivity of the methods used to detect these changes Histology of Reversible Injury Two features of reversible cell injury can be recognized under the light microscope: cellular swelling and fatty change Cellular swelling appears whenever cells are incapable of maintaining ionic and fluid homeostasis caused by failure of energy-dependent ion pumps in the plasma membrane; first manifestation of almost all forms of injury to cells (A) Fatty change occurs in hypoxic injury and various forms of toxic or metabolic injury. Lipid vacuoles appear in the cytoplasm; it is principally encountered in organs that are involved in lipid metabolism, such as the liver (B) A Normal renal tubules B Reversible Injury Irreversible Injury USMLE QUESTION A 48-year-old man has a history of chronic alcohol abuse. He is still able to perform work at his job. He has had no major illnesses. On physical examination, there are no significant findings. Laboratory studies show a serum albumin of 4.1 g/dL, ALT 30 U/L, AST 33 U/L, and total bilirubin 1.1 mg/dL. Which of the following microscopic findings in his liver is most likely to be present? A. Cholestasis B. Fatty change C. Hemochromatosis D. Hypertrophy of smooth endoplasmic reticulum E. Coagulative necrosis Cellular Adaptations to Stress Adaptations are reversible changes in the number, size, phenotype, metabolic activity, or functions of cells in response to changes in their environment Physiologic adaptations usually represent responses of cells to normal stimulation by hormones or endogenous chemical mediators (e.g., the hormoneinduced enlargement of the breast and uterus during pregnancy), or to the demands of mechanical stress (in the case of bones and muscles) Pathologic adaptations are responses to stress where cells modulate their structure and function to escape injury, but often at the expense of normal function Hypertrophy Increase in the size of cells that results in an increase in the size of the affected organ Increased size of the cells is due to the synthesis and assembly of additional intracellular structural components In non-dividing cells (e.g., myocardial cells) increased tissue mass in response to stress involves hypertrophy Can be physiologic or pathologic; the former is caused by increased functional demand or by stimulation by hormones and growth factors Physiologic Hypertrophy of the Uterus During Pregnancy The massive physiologic growth of the uterus during pregnancy is caused by hormone-induced hypertrophy of muscle fibers Uterine hypertrophy is stimulated by estrogenic hormones acting on smooth muscle estrogen receptors, eventually resulting in increased synthesis of smooth muscle proteins and an increase in cell size A. Gross appearance of a normal uterus (right) and a gravid uterus (removed for postpartum bleeding) (left) B. Small spindle-shaped uterine smooth muscle cells from a normal uterus, compared with A B C C. Large plump cells from the gravid uterus, at the same magnification Hypertrophy of Heart Muscle In response to increased hemodynamic loads (e.g. hypertension or faulty valves), heart muscle becomes enlarged (adaptation) If the blood supply to the myocardium is compromised or inadequate, the muscle first suffers reversible injury, manifested by certain cytoplasmic changes; eventually, the cells suffer irreversible injury and die Hyperplasia Increase in the number of cells in an organ or tissue in response to a stimulus (e.g., hormones or growth factors) Hyperplasia can only take place if the tissue contains cells capable of dividing; it can be physiologic or pathologic Although hyperplasia and hypertrophy are distinct processes, they frequently occur together, triggered by the same external stimulus Compensatory hyperplasia is best seen liver regeneration after transplantation Hyperplasia constitutes a fertile soil in which cancerous proliferations may eventually arise Normal Endometrium Endometrial Hyperplasia Endometrial hyperplasia is an example of abnormal estrogen-induced hyperplasia (photos). Benign prostatic hyperplasia is common example of pathologic hyperplasia induced in response to hormonal stimulation by androgens Metaplasia Reversible change in which one differentiated cell type is replaced by another cell type better suited for survival Not the result of a change in phenotype of an already differentiated cell type; involves reprogramming of stem cells in response to growth factors The most common epithelial metaplasia is columnar to squamous In response to chronic irritation (e.g. habitual cigarette smoker) respiratory epithelium becomes tough, but secretion and the ciliary action of the columnar epithelium are lost Persistent metaplasia can initiate malignant transformation in metaplastic epithelium Dysplasia The term literally means “disordered growth” and is seen principally in epithelia (A) Characterized by loss in uniformity of individual cells (pleomorphism), and a disorderly architecture (B) Cells with hyperchromatic nuclei and mitotic figures are more abundant than in the normal tissue May be a precursor to malignant transformation, but it does not always progress to cancer (neoplasia) B USMLE QUESTION A 20-year-old woman had Goodpasture syndrome which progressed to chronic renal failure. She is 165 cm tall and weighs 55 kg. She now has blood pressure measurements in the range of 150/90 to 180/110 mm Hg, but does not regularly take medications. Laboratory studies show her blood urea nitrogen is over 100 mg/dL and she requires chronic dialysis. A chest x-ray shows an enlarged heart. The size of her heart is most likely to be the result of which of the following processes involving the myocardial fibers? A. Hyperplasia B. Fatty infiltration C. Hypertrophy D. Fatty degeneration E. Edema USMLE QUESTION A 71-year-old man has difficulty with urination. His urinary retention leads to numerous trips to the restroom per day. On digital rectal examination is prostate is diffusely enlarged. His prostate specific antigen test is within normal limits. Which of the following represents a pathologic change leading to this man's problem? A. Dysplasia B. Hypertrophy C. Hyperplasia D. Metaplasia E. Neoplasia USMLE QUESTION A 43-year-old man has complained of mild burning substernal pain following meals for the past 3 years. Upper GI endoscopy is performed and biopsies are taken of an erythematous area of the lower esophageal mucosa 3 cm above the gastroesophageal junction. There is no mass lesion, no ulceration, and no hemorrhage noted. The biopsies show the presence of columnar epithelium with goblet cells. Which of the following mucosal alterations is most likely represented by these findings? A. Dysplasia B. Hyperplasia C. Carcinoma D. Ischemia E. Metaplasia USMLE QUESTION A 19-year-old woman has a routine Pap smear performed during an annual physical examination. The pathology report indicates that some cells are found cytologically to have larger, more irregular nuclei. A follow-up cervical biopsy microscopically demonstrates disordered maturation of the squamous epithelium, with hyperchromatic and pleomorphic nuclei extending nearly the full thickness of the epithelial surface. No inflammatory cells are present. Which of the following descriptive terms is best applied to these Pap smear and biopsy findings? A. Dysplasia B. Hypertrophy C. Hyperplasia D. Metaplasia E. Neoplasia Atrophy Reduction in organ or tissue size due to a decrease in cell size and number Can be physiologic (A) or pathologic (B) The initial response is a decrease in cell size and organelles, which may reduce the metabolic needs of the cell sufficiently to permit survival Atrophy results from decreased protein synthesis and increased protein degradation in cells A B Causes of Pathologic Atrophy Decreased workload (atrophy of disuse): when a fractured bone is immobilized in a plaster cast or when a patient is restricted to complete bed rest, skeletal muscle atrophy can result Loss of innervation (denervation atrophy): the normal metabolism and function of skeletal muscle are dependent on its nerve supply; damage to the nerves leads to atrophy of the muscle fibers Diminished blood supply. A gradual decrease in blood supply (ischemia) to a tissue as a result of slowly developing arterial occlusive disease results in atrophy of the tissue Inadequate nutrition: profound protein-calorie malnutrition (marasmus) is associated with the utilization of skeletal muscle proteins as a source of energy after other reserves such as adipose stores have been depleted Loss of endocrine stimulation: the loss of estrogen stimulation after menopause results in physiologic atrophy of the endometrium, vaginal epithelium, and breast Pressure: Tissue compression for any length of time can cause atrophy. An enlarging benign tumor can cause atrophy in the surrounding uninvolved tissues Senile Atrophy of the Brain In late adult life, the brain may undergo progressive atrophy, mainly because of reduced blood supply as a result of atherosclerosis A. Normal brain of a young adult. B. Atrophy of the brain in an 82-year-old man with atherosclerotic cerebrovascular disease, resulting in reduced blood supply. Note that loss of brain substance narrows the gyri and widens the sulci. The meninges have been stripped from the right half of each specimen to reveal the surface of the brain. Cellular Adaptations to Stress: Summary Hypertrophy: increased cell and organ size, often in response to increased workload; induced by growth factors produced in response to mechanical stress or other stimuli; occurs in tissues incapable of cell division Atrophy: decreased cell and organ size, as a result of decreased nutrient supply or disuse; associated with decreased synthesis of cellular building blocks and increased breakdown of cellular organelles Hyperplasia: increased cell numbers in response to hormones and other growth factors; occurs in tissues whose cells are able to divide or contain abundant tissue stem cells Metaplasia: replacement of one type of cell with another, usually in association with tissue damage, repair, and regeneration from stem cells. The replacing cell type is better suited to some alteration in the local environment. Dysplasia: A precancerous change in an epithelium characterized by cellular pleomorphism and disruption of normal tissue architecture Cell and Tissue Death: Necrosis Denaturation of intracellular proteins and enzymatic digestion of the lethally injured cell Necrotic cells are unable to maintain membrane integrity; contents often leak out, often causing inflammation in the tissue Enzymes that digest the necrotic cell are derived from the lysosomes of the dying cells themselves, and from the lysosomes of inflammatory leukocytes Irreversible Nuclear Changes in Necrosis Nuclear changes assume one of three patterns, all resulting from a breakdown of DNA and chromatin Pyknosis (A) is characterized by nuclear shrinkage and increased basophilia; the DNA condenses into a dark shrunken mass The pyknotic nucleus can undergo fragmentation; this change is called karyorrhexis (B) Ultimately, the nucleus may undergo karyolysis (C), in which the basophilia fades because of digestion of DNA by DNase activity In 1 to 2 days, the nucleus in a dead cell may completely disappear A B C USMLE QUESTION A 53-year-old man has experienced severe chest pain for the past 6 hours. On physical examination he is afebrile, but has tachycardia. Laboratory studies show a serum troponin I of 10 ng/mL. A coronary angiogram is performed emergently and reveals >90% occlusion of the left anterior descending artery. In this setting, an irreversible injury to myocardial fibers will have occurred when which of the following cellular changes occurs? A. Glycogen stores are depleted B. Cytoplasmic sodium increases C. Nuclei undergo karyorrhexis D. Intracellular pH diminishes E. Blebs form on cell membranes USMLE QUESTION A 65-year-old woman has the sudden inability to move her right arm and to speak. MR angiography shows occlusion of a cerebral artery. She is given tissue plasminogen activator (tPA). Over the next week she regains some ability to move her arm and to speak. Which of the following cellular changes most likely subsided upon tPA therapy? A. Cell fragmentation B. Cell swelling C. Cytoplasmic eosinophilia D. Membrane disruption E. Nuclear karyorrhexis F. Nuclear pyknosis Patterns of Tissue Necrosis Under different conditions, necrosis in tissues may assume specific morphologic patterns: Coagulative necrosis Liquefactive necrosis Gangrenous necrosis Caseous necrosis Fat necrosis Fibrinoid necrosis Coagulative Necrosis Architecture of dead tissues is initially preserved Ischemia caused by obstruction in a vessel may lead to coagulative necrosis of the supplied tissue Localized, wedge-shaped area of coagulative necrosis is called an infarct (A, kidney) The injury denatures not only structural proteins but also enzymes; inhibits proteolysis of the dead cells Eosinophilic, anucleate cells may persist for days or weeks (B) Ultimately the necrotic cells are removed by phagocytosis of the cellular debris by infiltrating leukocytes Liquefactive Necrosis Digestion of the dead cells, resulting in transformation of the tissue into a liquid viscous mass A Seen in focal bacterial or fungal infections that stimulate leukocytes to release proteolytic enzymes Necrotic material is frequently creamy yellow because of the presence of dead leukocytes and is called pus A bacterial abscess is an example of liquefactive necrosis (A) Hypoxic death of cells within the central nervous system usually manifests as liquefactive necrosis (B) B Gangrenous Necrosis Gangrenous necrosis is not a specific pattern of cell death, but the term is commonly used in clinical practice It is usually applied to a limb, generally the lower leg (A), that has lost its blood supply and typically undergone coagulative necrosis (B) When bacterial infection is superimposed there is more liquefactive necrosis (giving rise to so-called wet gangrene) A B Caseous Necrosis Caseous necrosis is encountered most often in foci of tuberculous infection The term “caseous” (cheese-like) is derived from the friable off-white appearance of the area of necrosis (A) Necrotic area appears as a structure-less collection of lysed cells and amorphous granular debris within a distinctive inflammatory border (B) This appearance is characteristic of a focus of inflammation known as a granuloma A B Fat Necrosis Necrosis characterized by the action digestive enzymes on fat The enzyme lipase releases fatty acids from triglycerides The fatty acids then complex with calcium to form soaps that appear as white chalky deposits (A) Usually associated with acute pancreatitis; can occur in other tissues after trauma (e.g. breast) Histologically, necrosis takes the form of foci of shadowy outlines of necrotic fat cells, with basophilic calcium deposits, surrounded by an inflammatory reaction (B) A B Fibrinoid Necrosis Special form of necrosis usually seen in immune reactions involving blood vessels (vasculitis syndromes) Complexes of antigens and antibodies are deposited in the walls of arteries Deposits of these “immune complexes,” plus fibrin that has leaked out of vessels, result in a bright pink and amorphous appearance called “fibrinoid” (white arrow) An inflammatory infiltrate is usually present (yellow arrow) Biomarkers of Tissue-Specific Necrosis Leakage of intracellular proteins through the damaged cell membrane and ultimately into the circulation provides a means of detecting tissue-specific necrosis using blood or serum samples Cardiac muscle contains a unique isoform of the enzyme creatine kinase (CK-MB) and of the contractile protein troponin I that can indicate necrosis (e.g. myocardial infarction) Hepatic bile duct epithelium contains the enzyme alkaline phosphatase, and hepatocytes contain alanine aminotransferase (ALT) and aspartate transaminase (AST) : irreversible injury and cell death in these tissues elevate the serum levels of these proteins USMLE QUESTION A 73-year-old man suffers a stroke. On physical examination he cannot move his right arm. A cerebral angiogram demonstrates occlusion of the left middle cerebral artery. An echocardiogram reveals a thrombus within a dilated left atrium. Which of the following is the most likely pathologic alteration from this event that has occurred in his brain? A. Cerebral softening from liquefactive necrosis B. Pale infarction with coagulative necrosis C. Predominantly the loss of glial cells D. Recovery of damaged neurons if the vascular supply is reestablished E. Wet gangrene with secondary bacterial infection USMLE QUESTION A 38-year-old woman has severe abdominal pain with hypotension and shock that has developed over the past 36 hours. On physical examination, her abdominal muscles are rigid and her abdomen is extremely tender. An abdominal CT scan reveals fluid density in the region of the pancreas, which appears to be enlarged. Which of the following laboratory test findings in her serum is most likely to be present? A. Alanine aminotransferase of 1123 U/L B. Total cholesterol of 324 mg/dL C. Creatine kinase of 869 U/L D. Urea nitrogen of 110 mg/dL E. Lipase of 1134 U/L USMLE QUESTION A 26-year-old man has had a high fever for the past 2 days. On exam he has a heart murmur. Echocardiography shows destruction of the aortic valve by large, irregular vegetations. Staphylococcus aureus is cultured from his blood. He develops left upper quadrant pain. Abdominal CT shows a wedgeshaped 1.5 x 3 cm splenic lesion with base on the capsule. The splenic lesion is most likely to result from which of the following cellular abnormalities? A. Coagulative necrosis B. Abscess formation C. Metaplasia D. Caseous necrosis E. Liquefactive necrosis USMLE QUESTION A 54-year-old man has sudden onset of severe, sharp chest pain with diaphoresis and dyspnea. On physical examination he has tachycardia with an irregular heart rhythm. Electrocardiographic changes suggest the possibility of focal myocardial damage involving the left lateral ventricular wall. Which of the following laboratory tests on the patient's serum is most useful in this situation? A. Total cholesterol B. Troponin I C. Triglyceride D. Lipase E. Sedimentation rate Cell and Tissue Death: Apoptosis Programmed cell death in which cells activate enzymes that degrade their own nuclear DNA and nuclear and cytoplasmic proteins Apoptotic cells break up into fragments, called apoptotic bodies, that contain portions of the cytoplasm and nucleus The dead cell and its fragments are phagocytized before the contents have leaked out, and therefore cell death by this pathway does not elicit an inflammatory reaction in the host Apoptosis in Physiologic Situations Apoptosis is a normal phenomenon that serves to eliminate cells that are no longer needed, and maintains cellular homeostasis Cells undergo apoptosis because they are deprived of necessary survival signals, such as growth factors It is important in the following physiologic situations: § Involution of hormone-dependent tissues upon hormone withdrawal (endometrial cell breakdown in the menstrual cycle) § Cell loss in proliferating cell populations to achieve homeostasis (maturation of hematopoietic cells in the bone marrow) § Elimination of potentially harmful self-reactive lymphocytes (to prevent autoimmune disease) § Death of host cells that have served their useful purpose (neutrophils in an acute inflammatory response, and lymphocytes at the end of an immune response) Apoptosis in Pathologic Conditions Apoptosis eliminates cells injured beyond repair without eliciting a host reaction, thus limiting collateral tissue damage and, in some cases, the risk of malignant transformation Apoptosis is responsible for loss of cells in a variety of pathologic states: § DNA damage (radiation, cytotoxic anticancer drugs, and hypoxia can damage DNA, either directly or via production of free radicals) § Accumulation of misfolded proteins (may arise because of mutations in the genes encoding these proteins or because of extrinsic factors, such as damage caused by free radicals) § Cell death in viral infections (cytotoxic T cell-mediated killing of virus-infected cells) § Pathologic atrophy in parenchymal organs (after duct obstruction in the pancreas, parotid gland, and kidney) Two Pathways of Apoptosis Block 6 The Mitochondrial (Intrinsic) Pathway of Apoptosis Cell viability maintained by induction of anti-apoptotic survival signals by proteins such as BCL2 (A) These proteins maintain integrity of mitochondrial membranes and prevent leakage of mitochondrial proteins Loss of survival signals, DNA damage, and other insults activate sensors (BH3) that block anti-apoptotic proteins (B) Pro-apoptotic proteins BAX and BAK are activated and form channels in the mitochondrial membrane Subsequent leakage of Cytochrome c and other proteins leads to caspase activation and apoptosis The Execution Phase of Apoptosis The mitochondrial pathway leads to activation of the initiator caspase-9 Executioner caspases (3,6,7) activate a cytoplasmic DNase that cleaves DNA The formation of apoptotic bodies breaks cells up into “bite-sized” fragments that are edible for phagocytes Apoptotic cells and their fragments express surface phosphatidylserine that is recognized by macrophage receptors Dead cells are removed, often within minutes, and inflammation is absent Cell shrinkage: eosinophilic cytoplasm and a condensed nucleus (A) Chromatin condensation: This is the most characteristic feature of apoptosis (B) Formation of cytoplasmic blebs and apoptotic bodies: apoptotic cells or cell bodies are phagocytized, usually by macrophages (C) USMLE QUESTION A 47-year-old man has a lung carcinoma with metastases. He receives chemotherapy. A month later, histologic examination of a metastatic lesion shows many foci in which individual tumor cells appear shrunken and deeply eosinophilic. Their nuclei exhibit condensed aggregates of chromatin under the nuclear membrane. The pathologic process affecting these shrunken tumor cells is most likely triggered by release of which of the following substances into the cytosol? A. BCL2 B. Catalase C. Cytochrome c D. Lipofuscin E. Phospholipase Features of Necrosis and Apoptosis Feature Necrosis Apoptosis Cell size Enlarged (swollen) Reduced (shrunken) Nucleus Pyknosis → karyorrhexis → karyolysis Fragmentation into nucleosome-size fragments Plasma membrane Disrupted Intact; membrane blebs Cellular contents Enzymatic digestion; may leak out of cell Intact; may be released in apoptotic bodies Adjacent inflammation Frequent No Physiologic or pathologic role Invariably pathologic (culmination of irreversible cell injury) Often physiologic, means of eliminating unwanted cells; may be pathologic after some forms of cell injury, especially DNA damage Autophagy (Greek: auto, self; phagy, eating) Sequestration of cellular organelles into cytoplasmic vacuoles (autophagosomes) that fuse with lysosomes and digest the enclosed material An adaptive response that is enhanced during nutrient deprivation, allowing the cell to cannibalize itself to survive Dysregulation of autophagy occurs in many disease states including cancers, inflammatory bowel diseases, and neurodegenerative disorders Autophagy can trigger cell death if it is inadequate to cope with the stress imposed on the cell Mechanisms of Cell Injury The cellular response to injurious stimuli depends on the nature of the injury, its duration, and its severity The consequences of cell injury depend on the type, state, and adaptability of the injured cell Cell injury results from different biochemical mechanisms acting on several essential cellular components Causes of Cell Injury Most injurious stimuli can be grouped into the following categories: Hypoxia and ischemia: Hypoxia refers to oxygen deficiency; ischemia means reduced blood supply. Both deprive tissues of oxygen, but ischemia also results in a deficiency of essential nutrients and a build up of toxic metabolites Nutritional imbalances: Protein-calorie malnutrition is a major cause of cell injury. Ironically, excessive dietary intake may result in disease (e.g. obesity) Infectious agents: All types of disease-causing pathogens, including viruses, bacteria, fungi, and protozoans, injure cells Immunologic reactions: Immune reactions protect against pathogenic microbes, but can also cause cell and tissue injury (e.g. autoimmune and allergic diseases) Causes of Cell Injury Cont’d Genetic abnormalities: Genetic defects may cause cell injury or death as a consequence of deficiency of functional proteins such as enzymes, or accumulation of damaged DNA Toxins: Potentially toxic agents are encountered daily in the environment (e.g., air pollutants, insecticides, CO, asbestos, cigarette smoke, ethanol, and drugs) Physical agents: Trauma, extremes of temperature, radiation, electric shock, and sudden changes in atmospheric pressure all have wide-ranging effects on cells Aging: Cellular senescence results in a diminished ability of cells to respond to stress. Eventually, it results in the death of the organism Hypoxia and Ischemia Oxygen deprivation is one of the most frequent causes of cell injury and necrosis in clinical medicine Persistent of severe hypoxia and ischemia ultimately lead to failure of ATP generation ATP-dependent sodium pumps fail, resulting in intracellular accumulation of sodium and efflux of potassium (cell swelling) The compensatory increase in anaerobic glycolysis leads to lactic acid accumulation Prolonged depletion of ATP causes ribosome detachment and inhibits protein synthesis Irreversible damage to mitochondrial and lysosomal membranes, and the cell undergoes necrosis Ischemic injury is more severe than hypoxia because it also involves decreased tissue perfusion with glycolytic substrates and removal of waste products Ischemia-Reperfusion Injury Restoration of blood flow to ischemic but viable tissues may result, paradoxically, in increased cell injury Can contribute significantly to tissue damage, especially after myocardial or cerebral ischemia (A) New damage may be initiated during reoxygenation by increased generation of reactive oxygen species (ROS) from damaged mitochondria or leukocytes Enhanced inflammation leads to influx of leukocytes and plasma proteins that cause further tissue damage A Ischemic stroke: CT shows an infarct involving the left temporal lobe below the Sylvian fissure USMLE QUESTION A 79-year-old man has a large myocardial infarction involving much of the left ventricular free wall. He develops congestive heart failure (CHF) with decreased cardiac output. Now, a year later, his CHF is worsening. By echocardiography there is a large, bulging akinetic area typical for a left ventricular aneurysm. Which of the following laboratory tests on serum would best indicate poor peripheral tissue perfusion in this patient? A. Elevated troponin I B. Increased sodium C. Elevated lactate D. Increased hematocrit E. Increased sedimentation rate USMLE QUESTION A 53-year-old man suffers a cardiac arrest and his wife calls emergency services. The paramedics arrive a few minutes later and begin life support measures. A regular heart rate is established after 40 minutes of resuscitative efforts as he is being transported to the hospital. A thrombolytic agent (tPA) is administered. Which of the following cellular processes is most likely to occur in his myocardium following administration of the tPA? A. Apoptosis B. Reperfusion injury C. Autophagy D. Squamous metaplasia E. Accumulation of cytokeratins Oxidative Stress Oxidative stress refers to cellular abnormalities that are induced by reactive oxygen species (ROS), which belong to a group of molecules known as free radicals (see below) ROS production is increased by many injurious stimuli (e.g., chemical and radiation injury, ischemia-reperfusion injury, cellular aging, and microbial killing by phagocytes) Excessive production or inadequate removal leads to accumulation of free radicals in cells, which may damage lipids (by peroxidation), proteins, and DNA, resulting in cell injury Free radicals are chemical species with at least one unpaired valence electron Removal of Free Radicals Free radicals are inherently unstable and generally decay spontaneously Cells have developed multiple nonenzymatic and enzymatic mechanisms to remove free radicals and thereby minimize injury Antioxidants either block free radical formation or scavenge free radicals (vitamins A, C, and E and glutathione in the cytosol) A series of enzymes act as free radical-scavenging systems: § Catalase in peroxisomes decomposes H2O2 § Superoxidase dismutases catalyze superoxide (O2−) radical § Glutathione peroxidases catalyse the breakdown of peroxides USMLE QUESTION An experiment is conducted in animals to determine if cell membrane injury caused by gamma radiation is lessened by the ingestion of antioxidants. Which of the following substances would inhibit the formation lipid peroxides by scavenging free radicals? A. Coenzyme A B. Ionized calcium C. Vitamin E D. Ceruloplasmin E. Lipase Chemical (Toxic) Injury Chemical injury remains a frequent problem in clinical medicine and is a major limitation to drug therapy Many drugs are metabolized in the liver; this organ is a frequent target of drug toxicity Some chemicals can injure cells directly by combining with critical molecular components (e.g., cyanide poisons mitochondrial cytochrome oxidase and inhibits oxidative phosphorylation) Most toxic chemicals are not biologically active in their native form: must be converted to reactive toxic metabolites (acetaminophen is converted to a toxic product during detoxification in the liver by the cytochrome P-450 mixedfunction oxidases) Intracellular Accumulations Metabolic derangements in cells can lead to intracellular accumulation of abnormal amounts of various substances that may be harmless or associated with varying degrees of injury The substance may be located in the cytoplasm, within organelles (typically lysosomes), or in the nucleus, and it may be synthesized by the affected cells or may be produced elsewhere In many cases, if the overload can be controlled or stopped, the accumulation is reversible In inherited storage diseases, accumulation is progressive, and the overload may cause cellular injury, leading in some instances to death of the tissue and the patient Accumulation of Lipids All major classes of lipids can accumulate in cells: triglycerides, phospholipids, and cholesterol/cholesterol esters Steatosis or fatty change describe abnormal accumulations of triglycerides within parenchymal cells Fatty change is often seen in the liver because it is the major organ involved in fat metabolism (A) but it also occurs in heart, muscle, and kidney Causes include alcohol abuse, protein malnutrition, toxins, diabetes mellitus, obesity, and anoxia In atherosclerotic plaques, smooth muscle cells and macrophages within the intimal layer large arteries are filled with lipid vacuoles, most of which are made up of cholesterol and cholesterol esters (B) A In the section of liver, most cells have a wellpreserved nucleus squeezed into the displaced rim of cytoplasm about the fat vacuole B Atherosclerotic plaque in the coronary artery Accumulation of Proteins Intracellular accumulations of proteins usually appear as rounded, eosinophilic droplets, vacuoles, or aggregates in the cytoplasm (hyaline change) The proteins that accumulate may be normal secreted proteins that are produced in excessive amounts (immunoglobulins in plasma cells) Accumulation of cytoskeletal proteins (neurofibrillary tangle in Alzheimer disease, A) Aggregation of abnormal proteins (amyloidosis, B) A B Accumulation of Pigments Pigments are colored substances, some of which are normal constituents of cells (e.g., melanin); others are abnormal and accumulate in cells only under special circumstances (endogenous or exogenous) The most common exogenous pigment is carbon (anthracosis) Lipofuscin or wear-and-tear pigment is an insoluble lipid/phospholipid material; it is not itself injurious to the cell, but indicates cell injury Hemosiderin, a hemoglobin-derived, golden yellow-to-brown, granular or crystalline pigment is one of the major storage forms of iron; may be deposited in tissues during iron overload (hemosiderosis) or RBC lysis A B B Lipofuscin granules in a cardiac myocyte shown by (A) light microscopy (deposits indicated by arrows ), and (B) electron microscopy (note the perinuclear, intralysosomal location) USMLE QUESTION A 69-year-old woman has had transient ischemic attacks for the past 3 months. On physical examination, she has an audible bruit on auscultation of the neck. A right carotid endarterectomy is performed. The curetted atheromatous plaque has a grossly yellow-tan, firm appearance. Microscopically, which of the following materials can be found in abundance in the form of crystals within cleft-like spaces? A. Cholesterol B. Glycogen C. Hemosiderin D. Immunoglobulin E. Lipofuscin USMLE QUESTION A 22-year-old woman has a congenital anemia. She has required multiple transfusions of red blood cells for many years. She now has no significant findings on physical examination. Which of the following microscopic findings would most likely present in her liver? A. Steatosis in hepatocytes B. Bilirubin in canaliculi C. Hemosiderin in hepatocytes D. Glycogen in hepatocytes E. Amyloid in portal triads USMLE QUESTION A 69-year-old woman has had a chronic cough for the past year. A chest radiograph shows a 6-cm mass in the left lung. A needle biopsy specimen of the mass shows carcinoma. A pneumonectomy is performed, and examination of the hilar lymph nodes reveals a uniform, dark black cut surface. Which of the following factors most likely accounts for the appearance of these lymph nodes? A. Aging effects B. Bleeding disorder C. Cigarette smoking D. Liver failure E. Multiple metastases Pathologic Calcification Abnormal tissue deposition of calcium salts, together with smaller amounts of iron, magnesium, and other mineral salts (A) A Can be intracellular, extracellular, or in both locations. May lead to heterotrophic bone formation in the focus of calcification Single necrotic cells may constitute seed crystals that become encrusted by lamellated mineral deposits (psammoma bodies,B) Dystrophic calcification: deposition of calcium at sites of cell injury and necrosis; normocalcemia Metastatic calcification: Deposition of calcium in normal tissues, caused by hypercalcemia B Dystrophic Calcification Encountered in areas of necrosis and in foci of enzymatic necrosis of fat Serum calcium is normal in dystrophic calcification The calcium salts appear macroscopically as fine, white granules or clumps, often felt as gritty deposits (A) Although it may simply be a telltale sign of previous cell injury, it is often a cause of organ dysfunction A Dystrophic calcification of the aortic valve. View looking down onto the unopened aortic valve in a heart with calcific aortic stenosis. The semilunar cusps are thickened and fibrotic, irregular masses of piled-up dystrophic calcification Metastatic Calcification May occur in normal tissues whenever there is hypercalcemia Often a consequence of parathyroid hormone excess, resorption of bone, vitamin D disorders, and renal failure Principally affects the interstitial tissues of the gastric mucosa, kidneys, lungs, systemic arteries, pulmonary veins, and synovia (A) Usually the mineral salts cause no clinical dysfunction, but massive deposits in the kidney (nephrocalcinosis, B) may in time cause renal damage A B USMLE QUESTION A 38-year-old man from India has a health screening examination. He has a routine chest x-ray that shows a 2 cm nodule in the right lower lobe. The nodule has focal calcifications. A wedge resection of the nodule is done. On microscopic examination the nodule shows caseous necrosis and calcification. Which of the following processes explains the appearance of the calcium deposition: A. Dystrophic calcification B. Apoptosis C. Hypercalcemia D. Metastatic calcification E. Excessive ingestion of calcium Cellular Aging Accumulation of DNA damage: Defective DNA repair mechanisms. Caloric restriction activates DNA repair and is known to prolong aging in model organisms Defective protein homeostasis: Resulting from impaired chaperone and proteasome functions Replicative senescence: Reduced capacity of cells to divide secondary to progressive shortening of chromosomal ends (telomeres) USMLE QUESTION An 18-year old G2 P1 woman has an amniocentesis performed at 17 weeks gestation. Fibroblasts recovered from amniocentesis are grown in culture to assess the karyotype of fetal cells. These cells are subcultured for additional experimental work, but the culture is lost after 50 doublings of the cells has occurred, and the fibroblasts no longer grow. Which of the following factors affecting these cells is most likely demonstrated by this phenomenon? A. Nutrition B. Mutation C. Apoptosis D. Aging E. Oxidation