Cell Injury, Adaptation And Accumulations
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Cell Injury, Adaptation And Accumulations

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Cell Injury, Adaptation And Accumulations Cell Injury, Adaptation And Accumulations Presentation Transcript

  • CELLULAR INJURY, ADAPTATION, AND INTRACELLULAR ACCUMULATION ROBERTO D. PADUA JR.,MD, DPSP DEPARTMENT OF PATHOLOGY FATIMA COLLEGE OF MEDICINE
  • Adaptive responses resulting in increased tissue mass. Increased functional demand or endocrine stimulation are what usually cause hypertrophy and hyperplasia. These new patterns of growth are stable while the causative stimulus persists, but once it is removed the tissue returns to a normal pattern of growth.
  • Changes in growth pattern of cells
  • Hypertrophy of skeletal muscle in response to exercise. Hypertrophy in the absence of hyperplasia is typically seen in muscle where the stimulus is an increased demand for work. Taken at the same magnification, (a) shows muscle fibers in transverse section from the soleus muscle of a normal 50-year-old man, and (b) shows fibers from the same muscle in a veteran marathon runner. Note the dramatic increase in the size of the fibers in response to the demands of marathon running.
  • Hyperplasia and hypertrophy of myometrium in pregnancy. On the left is a normal uterus showing the normal mass of smooth muscle in its wall. On the right is a uterus from a recently pregnant woman, in which the striking increase in mass of smooth muscle is evident. At a cellular level, this is due to both hyperplasia and hypertrophy of uterine smooth muscle.
  • Hyperplasia of endometrium in response to estrogen. (a) Early proliferative endometrium. (b) Secretory phase endometrium. Micrograph (a) shows endometrial glands following the menstrual phase. Micrograph (b) shows that in response to estrogen secreted as part of the normal menstrual cycle there has been an increase in the number of cells in each gland, resulting in a much higher volume fraction of gland relative to stroma. This is an example of physiological hyperplasia.
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  • DIFFUSE THYROID HYPERPLASIA (GRAVES DISEASE. The follicles are lined by tall, columnar epithelium. The crowded, enlarged epithelial cells project into the lumens of the follicles. These cells actively resorb the colloid in the centers of the follicles, resulting in the scalloped appearance of the edges of the colloid.
  • Hypertrophy of cardiac muscle in response to valve disease. (a) Transverse slices of a normal heart and a heart with hypertrophy of the left ventricle. (b) Histology of cardiac muscle from a normal heart. (c) Histology of cardiac muscle from a hypertrophied heart. The upper macroscopic specimen (a) demonstrates the normal thickness of the left ventricular wall (L) for comparison with the greatly thickened wall (T) in the lower specimen, taken from a heart in which severe narrowing of the aortic valve caused resistance to systolic ventricular emptying. The increased mass of the left ventricle is due to enlargement of cardiac muscle cells as a result of hypertrophy. This can be seen by comparing the diameter of fibers from the normal heart (b) with those from the diseased heart (c). Note that the size of nuclei in the hypertrophied cardiac muscle is also increased; it has been found that such nuclei are frequently polyploid (i.e. contain several times the normal quantity of DNA).
  • HYPERTROPHY OF CARDIAC MUSCLE
  • Nodular hyperplasia of the prostate gland. (a) Normal prostate gland. (b) Nodular hyperplasia of prostate gland. These macroscopic specimens are transverse slices through the prostate gland. Note the nodules (N) in (b), which are the result of nodular hyperplasia. This is an extremely common condition in elderly men, resulting in compression of the prostatic urethra (U) and difficulty with micturition.
  • Adaptive responses resulting in reduced tissue mass. Reduced functional demand, reduction in trophic stimuli, or reduction in nutrients are the usual stimuli that cause involution or cell atrophy. Atrophic or involuted tissues are stable patterns of growth that persist while the lack of stimulation or demand causing them remains. However, once appropriate stimulation or demand returns, the tissue reverts to a normal pattern of growth.
  • In cellular atrophy, structural proteins and organelles of a cell are destroyed, with a parallel reduction in the size and functional capacity of the cell. This is an adaptive response as it allows the cell to survive in adverse conditions by reducing its metabolic overheads. Cell constituents are eliminated by a process of autophagy: unwanted cell organelles become enwrapped by membrane derived from the endoplasmic reticulum (ER) (a), forming an autophagic body (b) which subsequently fuses with vesicles containing lysosomal acid hydrolases (c). The action of the hydrolases brings about degradation of the organelles. Cells that are actively undergoing atrophy can be seen ultrastructurally to contain numerous autophagic vacuoles. These bodies become electron dense, but have internal tubular or vesicular profiles (derived from membrane-fusion events) that have earned them the alternative name of tubulovesicular bodies (d). Late autophagic bodies (e) become more electron dense and may form residual bodies (f) containing lamellar undigested lipid-rich cell material called lipofuscin (see Fig. 2.13).
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  • Lipofuscin in cellular atrophy, seen in the cardiac muscle of an elderly patient. Cellular atrophy is associated with autophagy of cellular structural elements and a consequent reduction in size of the cell. One effect of this is that indigestible material, principally phospholipids, accumulates in lysosomal-derived bodies. This material can be seen on light microscopy as yellow-brown granules (L) called lipofuscin, here shown in the myocardium of a 90-year-old woman. Ultrastructural examination of lipofuscin reveals it to consist of electron-dense material within membrane-bound granules of varying size, which often have myelin-like figures. Lipofuscin commonly accompanies the cellular atrophy that occurs in many tissues with aging, and thus is often called wear and tear pigment.
  • Atrophy of skeletal muscle with denervation. (a) Normal muscle. (b) Denervated muscle. Micrograph (a) shows normal skeletal muscle fibers. In micrograph (b) damage to many of the axons in the main nerve supplying the muscle has caused atrophy of fibers (A) which had been innervated by now-damaged axons. Fibers are small and angulated. With time, axon sprouting may reconnect some denervated fibers, which then return to normal size.
  • Atrophy of the adrenal gland. (a) Normal adrenal. (b) Atrophic adrenal. Specimen (a) is a slice of normal gland, in which yellow cortex (C) can be distinguished from the small amount of grey medulla (M); (b) is from a patient who had surgical ablation of the pituitary gland, leading to lack of ACTH causing a reduction in the size of the adrenal gland, specifically affecting the cortex.
  • Developmental causes of reduced cell mass.
  • Examples of metaplasia
  • Squamous metaplasia in urinary bladder. The transitional epithelium of the urinary bladder (T) has become severely traumatized by a bladder stone (calculus), not seen in this micrograph. In response, squamous metaplasia has occurred, with replacement of the normal transitional epithelium (T) by stratified squamous epithelium (S). Squamous metaplasia also occurs in the bladder when there is chronic irritation by the parasitic infection schistosomiasis. In such cases the squamous epithelium is better suited to withstand the new environment than is the native transitional urothelial epithelium.
  • CERVIX – NORMAL SECTION
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  • Key Facts – Cell Adaptation
    • Cells are adaptable within physiological limits
    • Cells can respond to injury by producing cell stress proteins, which protect them from damage and help in recovery
    • Increased demands are met by hypertrophy and hyperplasia
    • Reduced demand is met by atrophy
    • Cell loss from tissues can be achieved by programmed cell death (apoptosis)
    • Tissues can adapt to demand by a change in differentiation known as metaplasia
  • Summary of tissue response to environmental change. Adaptive responses allow cells to survive in the face of a change in the cellular environment. Failure to adapt is associated with cell damage or cell death.
  • Pathology of COPD. The normal airway is transformed in COPD by a combination of hyperplasia and metaplasia.
  • Cellular response to ischemia. ATP production by mitochondria relies on an adequate supply of oxygen and of energy substrates such as glucose. Mitochondrial function is therefore compromised soon after failure of blood supply, resulting in failure of production of ATP. One consequence of lack of ATP is failure of ATP-dependent membrane pumps, which normally pump sodium (and with it water) out of cells. Failure of membrane ion pumps leads to accumulation of sodium and water in the cell cytoplasm, with disruption of internal membrane systems. Failure of internal membrane pumps also allows free calcium to enter the cytosol, where it activates many destructive enzyme systems. Structural damage to internal membranes and the cytoskeleton, coupled with lack of ATP, leads to impairment of key synthetic pathways, including those of protein synthesis. Rupture of lysosomes and intracellular liberation of powerful hydrolytic enzymes, active at a low pH, brings about further cellular dissolution.
  • Cytosolic free calcium is a potent destructive agent.
  • Reactive oxygen metabolites damage cells.
  • Key Facts – Cell Injury
    • The main targets for cell injury are cell membranes, mitochondria, cytoskeleton, and cellular DNA
    • Because of interdependence, damage to one cellular system leads to secondary damage to others
    • Reactive oxygen metabolites are extremely harmful to cells and are produced on reperfusion after ischemia
    • ATP loss causes failure of biosynthesis and membrane pumps
    • Free calcium in the cytosol activates intracellular enzymes and may cause cell death
  • Relationships between sublethal and lethal cell damage. Normal cells that are subject to a damaging stimulus may initiate apoptosis or may become sublethally damaged. If the stimulus abates, cells may recover by resynthesis of proteins and elimination of damaged components. If a damaging stimulus continues, either cells die through apoptosis or, when critical cell damage takes place, mainly through critical lack of ATP, cells die and undergo necrosis. Massively damaging stimuli, e.g. great heat or strong acids, cause immediate coagulation of proteins and death of cells.
  • Relationships between sublethal and lethal cell damage. Following sublethal damage a cell may recover or, with persistence of the damaging stimulus, cell death may result. The sequential structural changes of cell death are termed 'necrosis'.
  • After damage to mitochondrial membranes there is failure of ATP production and loss of the normal membrane potential of the mitochondrion. The mitochondrial membrane pores (PTPC megachannels) open and release proteins into the cytosol, which can cause apoptosis, as described below. If many mitochondria in a cell fail, causing a catastrophic reduction in ATP production, the cell will die by a non-apoptotic route.
  • Sublethal cell damage. (a) Hydropic degeneration. (b) Fatty change. Micrograph (a) shows a section of liver damaged by the poison paraquat. Normal liver cells (N) contrast with injured cells, which are swollen, pale and vacuolated (H). The normal cell cytoplasm is pink with a faint hint of purple, the purple coloration (basophilia) being due to ribosomes, mainly on the RER. With swelling of the ER, ribosomes become detached and reduced in number, so the normal purple cytoplasmic tint is reduced. Further cytoplasmic pallor is due to progressive swelling of the ER and mitochondria, known as cloudy swelling when mild, and hydropic degeneration when small, discrete vacuoles develop in the cytoplasm. Another example of sublethal damage is seen in micrograph (b), taken from the liver of an alcoholic patient. This shows extensive fatty change with large vacuoles (V) of fat within hepatocytes. As solvents used in conventional histological preparations dissolve out the fat to leave a clear space, lipid can be positively demonstrated only by using frozen sections.
  • NORMAL KIDNEY SECTION
  • CELLULAR SWELLING
  • RENAL INFARCT
  • LIVER – NORMAL SECTION
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  • Fatty change. This is a manifestation of sublethal metabolic derangement, seen in certain cells which have a high throughput of lipid as part of normal metabolic requirements. Such change is usually seen in the liver, but it also occurs less commonly in the myocardium and the kidney. Common causes of fatty change are toxins (particularly alcohol and halogenated hydrocarbons such as chloroform), chronic hypoxia and diabetes mellitus. Impaired metabolism of fatty acids leads to accumulation of triglycerides (fat), which form vacuoles in cells.There are four main metabolic reasons for the accumulation of triglyceride in cells: Increased peripheral mobilization of free fatty acids (FFA) and uptake into cells (diabetes mellitus and nutritional deprivation).Increased conversion of fatty acids to triglycerides (alcohol).Reduced oxidation of triglycerides to acetyl-CoA (hypoxia and toxins including ethanol).Deficiency of lipid acceptor proteins, preventing export of formed triglycerides (carbon tetrachloride and protein malnutrition). Fatty change is reversible if the abnormality responsible is removed. It may be associated with other types of sublethal injury in cells.
  • Key Facts – Sublethal Damage
    • Sublethal damage is recoverable, necrosis is not
    • The earliest viable sign of both lethal and sublethal damage is ultrastructural damage to mitochondria
    • Later sublethal damage can be seen as swelling of cellular organelles (hydropic degeneration)
    • Fatty change is a manifestation of sublethal impairment of metabolism and is common in the liver
  • Key Facts - Necrosis
    • Intense eosinophilia of the dead cell is due to loss of RNA and coagulation of proteins
    • Nuclei undergo phases of pyknosis, karyorrhexis, and karyolysis, leaving a shrunken cell devoid of nucleus
    • Proteins may be liberated from the dead cells and be detected in the blood in diagnosis
  • Cellular events in necrosis. These sections are from the liver of a person poisoned by paracetamol (acetaminophen), a hepatic toxin. Many of the changes seen in necrosis are caused by the action of lysosomal hydrolases, which are released into the cell when cell membrane integrity is lost.The nucleus of a necrotic cell first becomes small, condensed, and intensely stained with hematoxylin (basophilic). This appearance is termed pyknosis. Next, pyknotic nuclei become fragmented into several particles, a change known as karyorrhexis. Complete breakdown, or karyolysis, of the nucleus then takes place.When tissue is damaged in this way, tissue defenses are activated to limit the damage and restore tissue function (see Chapter 4).
  • Key Facts – Patterns of Necrosis
    • The most common pattern is coagulative necrosis caused by occlusion of vascular supply
    • Liquefactive necrosis is seen in the brain and in infections
    • Caseous necrosis is seen in tuberculosis
    • Gummatous necrosis is seen in syphilis
    • Fibrinoid necrosis is seen in vessel walls in hypertension and vasculitis
  • Patterns of tissue necrosis. (a) Coagulative necrosis: kidney. (b) Liquefactive necrosis: brain. (c) Caseous necrosis: kidney. (d) Gummatous necrosis: liver. (e) Hemorrhagic necrosis: testis. (f) Fibrinoid necrosis: artery. Micrograph (a) is an example of coagulative necrosis in an area of kidney which has been killed by interruption of its blood supply (infarction). The outlines of a glomerulus (G) and surrounding tubules (T) are recognizable, despite the fact that all the cells are dead. Micrograph (b) shows liquefaction in a cerebral infarct. In contrast to (a), no residual tissue architecture has been preserved. The necrotic brain area has been transformed into a semi-fluid mass of protein with phagocytic macrophages. Micrograph (c) shows an area of caseous necrosis from a kidney infected by Mycobacterium tuberculosis. The necrotic area (N) is homogeneously pink and, compared to (a), has no semblance of underlying renal architecture. This pattern is also illustrated in Chapter 4.Micrograph (d) shows an area of gummatous necrosis (N) in the liver of a patient with syphilis caused by long-standing infection by the spirochete Treponema pallidum. Micrograph (e) demonstrates an area of testicular hemorrhagic necrosis caused by torsion (twisting) of the testis on the end of the spermatic cord, such that the venous return is cut off. This leads to ischemia of the testis, as it becomes massively suffused with blood that cannot escape. Micrograph (f) shows a vessel that has undergone fibrinoid necrosis. The wall of the affected vessel is replaced by bright pink staining material (F). In this instance, damage to the vessels was due to severe hypertension.
  • Proteins used in diagnosis of tissue damage by blood testing
  • Apoptosis. Apoptosis of cells is a programmed and energy-dependent process designed specifically to switch cells off and eliminate them. This controlled pattern of cell death, termed programmed cell death, is very different from that which occurs as a direct result of a severe, damaging stimulus to cells.
  • Overview of the apoptotic process showing initiating factors.
  • Mitochondrial integrity is a key factor in apoptosis.
  • Summary overview of the apoptotic process.
  • COAGULATION NECROSIS
  • HEART – NORMAL SECTION
  • MYOCARDIAL INFARCTION - GROSS
  • MYOCARDIAL INFARCTION
  • MYOCARDIAL INFARCTION
  • MYOCARDIAL INFARCTION
  • MYOCARDIAL INFARCTION
  • MYOCARDIAL INFARCTION
  • MYOCARDIAL INFARCTION
  • CASEATION NECROSIS
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  • LIQUEFACTION NECROSIS
  • ENZYMATIC FAT NECROSIS
  • ANTHRACOSIS (BLACK PIGMENTS) - GROSS
  • ANTHRACOTIC PIGMENTS
  • BILIRUBIN
  • HEMOSIDERIN
  • LUNG – NORMAL SECTION
  • ALVEOLAR MACROPHAGES
  • “ HEART-FAILURE CELLS”
  • H EM OSIDE R O S I S
  • MELANIN
  • MALIGNANT MELANOMA
  • A T H E R O S C L E R O S I S
  • MONCKEBERG’S
  • GOUT – DEPOSITION OF MONOSODIUM URATE CRYSTALS