Pathology Final PDF

29 CELL ADAPTATIONS TO STRESS ILOs By the end of this lecture, students will be able to 1. Compare adaptive responses as regards Etiology, pathogenesis, and morphology. 2. Classify adaptive responses into physiological or pathological and reversible or irreversible....

29 CELL ADAPTATIONS TO STRESS ILOs By the end of this lecture, students will be able to 1. Compare adaptive responses as regards Etiology, pathogenesis, and morphology. 2. Classify adaptive responses into physiological or pathological and reversible or irreversible. 3. Relate adaptive responses to most common corresponding clinical conditions. Adaptations are reversible changes in the size, number, phenotype, metabolic activity, or functions of cells in response to changes in their environment. Adaptations may take several distinct forms; hypertrophy, hyperplasia, atrophy and metaplasia. 1. Cells capable of division may respond to stress by undergoing both hyperplasia and hypertrophy, whereas nondividing cells as myocardial fibers increase tissue mass due to hypertrophy only. Hypertrophy and hyperplasia may coexist, occur due to the same triggers and both contributing to increased organ size. 2. If the limits of adaptive responses are exceeded or if cells are exposed to damaging insults, deprived of critical nutrients, or compromised by mutations that affect essential cellular functions, a sequence of events follows that is termed cell injury, whether reversible or irreversible. 1. Hypertrophy: Hypertrophy is an increase in the size of cells that results in an increase in the size of the affected organ. The hypertrophied organ has no new cells, just larger cells. Pathogenesis: The most common stimulus for hypertrophy of skeletal and cardiac muscle is increased workload. Muscle cells respond by synthesizing more protein, increasing production of growth factors and genetic modulation of some muscle proteins, leading to increasing the number of myofilaments per cell and increasing the amount of force each myocyte can generate and thus the strength and work capacity of the muscle as a whole. Hypertrophy can be classified into; physiologic (due to increased functional demand) or pathologic (due to stimulation by hormones and growth factors). Physiologic hypertrophy. Example; Uterine hypertrophy during pregnancy: The massive physiologic growth of the uterus during pregnancy; is stimulated by estrogenic hormone signalling through oestrogen receptors that eventually result in increased synthesis of smooth muscle proteins and an increased cell size. The bulging muscles of bodybuilders engaged in “pumping iron” result from enlargement of individual skeletal muscle fibers in response to increased workload and increased cellular demand. Page 1 of 3  Pathologic hypertrophy. The striated muscle cells in the heart and skeletal muscles have only a limited capacity for division and respond to increased metabolic demands mainly by undergoing hypertrophy. Example; Concentric left ventricular hypertrophy of heart in response to pressure overload due to increased peripheral resistance to cardiac pumping of blood. this occurs in case of systemic hypertension, or aortic valve disease. 2- Hyperplasia Hyperplasia is an increase in the number of cells in an organ or tissue in response to a stimulus. Hyperplasia can only take place if the tissue contains cells capable of dividing, thus increasing the number of cells. It can be physiologic or pathologic. Mechanism of Hyperplasia Hyperplasia is the result of growth factor–driven proliferation of mature cells and activation of signalling pathways that stimulate cell proliferation by increasing output of new cells from stem cells. Physiologic hyperplasia occurs whenever there is a need to increase functional capacity of hormone sensitive organs, or when there is need for compensatory increase after damage or resection. 1. Hormonal hyperplasia: the proliferation of the glandular epithelium of the female breast at puberty and during pregnancy, and lactation usually accompanied by enlargement (hypertrophy) of the glandular epithelial cells. 2. Compensatory hyperplasia: liver regeneration usually occurs in individuals who donate one lobe of the liver for transplantation, the remaining cells proliferate so that the organ soon grows back to its original size. 3. The bone marrow hyperplasia: in response to a deficiency of mature blood cells in the setting of blood donation, chronic bleeding, acute blood loss, haemolysis or high altitudes. Pathologic hyperplasia. Most forms of pathologic hyperplasia are caused by excessive or inappropriate actions of hormones or growth factors acting on target cells. Endometrial and Breast hyperplasia, under the effect of increased estrogen [whether due to excessive hormone production by a tumor of due to exogenous drug intake], a common cause of abnormal uterine bleeding and breast mass, respectively. NOTE; both may turn malignant. Benign prostatic hyperplasia: in response to hormonal stimulation by imbalanced estrogen and androgens in old aged males. 1. Atrophy Atrophy is a reduction in the size of an organ or tissue due to a decrease in cell size and number. Atrophy can be physiologic or pathologic. Mechanisms of Atrophy 1- Decreased protein synthesis Page 2 of 3  2- Increased protein degradation 3- Increased autophagy with presence of intracytoplasmic autophagic granules, containing debris from degraded organelles. Physiologic atrophy occurs during normal development as atrophy of embryonic structures, as notochord and thyroglossal duct during fetal development and uterine atrophy after menopause or reduction of uterine size after delivery. Pathologic atrophy may be local or generalized. Example; 1. Disuse atrophy; caused by decreased workload, e.g., following complete bed rest due to fractured bone with prolonged immobilization. It is reversible once activity is resumed. 2. Loss of innervation (denervation atrophy). Damage to the nerves leads to atrophy of the muscle fibers supplied by those nerves since metabolism and function of skeletal muscle are dependent on its nerve supply. (Irreversible) 3. Diminished blood supply. chronic ischemia as a result of slowly developing arterial occlusion results in tissue atrophy. Example is senile atrophy of brain, and renal atrophy mainly because of reduced blood supply as a result of atherosclerosis. (Irreversible) 4. 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: Cachexia. 5. Loss of endocrine stimulation. Postmenopausal loss of estrogen stimulation results in atrophy of the endometrium, vagina, and breast. The prostate atrophies following chemical or surgical castration (e.g., for treatment of prostate cancer). 6. Pressure atrophy. Prolonged tissue compression causes atrophy. 2. Metaplasia Metaplasia is a reversible change in which one differentiated\mature cell type (epithelial or mesenchymal) is replaced by another mature cell type. It occurs often in response to chronic irritation, or when one cell type is sensitive to a particular stress. These cells are replaced by another resistant cell type that is better able to withstand the adverse environment. Mechanisms of Metaplasia, it results from stimulation and reprogramming of local tissue stem cells or colonization by differentiated cell populations from adjacent sites. Examples; Squamous metaplasia of respiratory bronchial epithelium, gall bladder \ gland duct epithelium under chronic irritation by smoking or stones or due to Vit A deficiency. Squamous metaplasia of transitional epithelium of urinary bladder under chronic irritation by stone or bilharziasis eggs. Columnar cell \intestinal metaplasia of squamous esophageal epithelium under irritation by acidic gastric juice Page 3 of 3  30 REVERSIBLE RESPONSE TO INSULTS AND CYTOPLASMIC ACCUMULATES ILOs By the end of this lecture, students will be able to 1. Emphasis on the sequence of events in cell injury and cell death [adaptation response, reversible and irreversible cellular injury]. 2. Discuss reversible subcellular changes in case of mild to moderate cell injury 3. Identify cut-off subcellular changes that transform a reversible cell injury to an irreversible change. 4. Discuss biochemical mechanisms and morphological alterations associated with necrosis. REVERSIBLE CELL INJURY Reversible cell injury is characterized by functional and structural alterations in early stages or mild forms of injury, which are correctable if the damaging stimulus is removed. Two features are consistently seen in reversibly injured cells; 1- HYDROPIC CHANGE; Earliest alterations in reversible injury in response to non-lethal injury, include; A. Generalized swelling of the cell and its organelles B. Blebbing of the plasma membrane C. Detachment of ribosomes from the endoplasmic reticulum (ER) D. Clumping of nuclear chromatin. 2- FATTY CHANGE; Occurs in organs that are actively involved in lipid metabolism (e.g., liver). It results when toxic injury disrupts metabolic pathways and leads to rapid accumulation of triglyceride filled-vacuoles within cytoplasm. Cellular swelling\hydropic change \ vacuolar degeneration. Causes. Oxygen deficiency, which interferes with mitochondrial oxidative phosphorylation. Radiation and toxins leading to mitochondrial damage. Both lead to ATP depletion. Pathogenesis. Results from influx of water within cytoplasm caused by failure of the ATP-dependent Na+-K+ plasma membrane pump, which in turn occur as a result of ATP depletion. Morphology Grossly, the affected organ becomes pale, with increased turgor, and increased weight. Microscopic features, Small clear vacuoles may be seen within the cytoplasm (representing distended ER). The cytoplasm appears red (eosinophilic) when stained with hematoxylin and Page 1 of 3  Ultrastructure features, Loss of plasma membrane structures; cilia and microvilli, and develops cytoplasmic “blebs” at apical cell surfaces. Mitochondria, ER and Golgi complex are swollen or dilated. Accumulation of myeline figures; phospholipid-derived from damaged cell membranes. 2+ Proteins and Ca precipitate in the cytosol and in organelles, especially mitochondria leading to mitochondrial densities. 2-Steatosis (Fatty Change),abnormal intracellular fat accumulation Means excessive, abnormal accumulations of triglycerides within parenchymal cells. Causes; Alcohol abuse, diabetes mellitus, obesity, toxins, protein malnutrition, and anoxia. Location: often seen in the liver (fatty liver) because it is the major organ involved in fat metabolism, as well as the cardiac muscle, skeletal muscle, and kidney. Best example is fatty change of the liver. Morphology: Grossly, a yellow, greasy, soft organ. Histologically, intracellular clear fat vacuoles, the nucleus is shifted against the cell membrane. Irreversible cell injury\ CELL DEATH There are two principal types of cell death, necrosis and apoptosis, which differ in their mechanisms, morphology, and roles in physiology and disease. Lately, autophagy is becoming the third mode of cell death. Necrosis is almost always pathological and is associated with severe mitochondrial damage with depletion of ATP and rupture of lysosomal and plasma membranes. On the other hand, apoptosis is a physiological process, that may have some pathological aspects, and it has different pathways Necrosis is the consequence of severe injury that irreparable damages so many cellular components that the cell simply “falls apart.” It is usually associated with severe mitochondrial damage with depletion of ATP and rupture of lysosomal and plasma membranes. Causes: Loss of oxygen supply (ischemia) Exposure to toxins Microbial infection Burns and trauma Other forms of chemical and physical injury Pathogenesis: Mitochondrial damage with production of reactive oxygen species (ROS) leading to peroxidation of phospholipids in cell membranes and organelles membranes, nuclear damage and ATP depletion. Page 2 of 3  Leakage of lysosomal enzymes into the cytoplasm due to severe damage to cell membranes → digest the cell → denaturation of cellular proteins. Damaged plasma membrane →Leakage of cellular contents into the extracellular space → elicit a host reaction (inflammation). Leakage of intracellular proteins; as damage-associated molecular patterns (damps); ATP (released from damaged mitochondria), uric acid (a breakdown product of DNA) → recognized by macrophages → trigger phagocytosis of the debris as well as the production of cytokines that induce inflammation. Inflammatory cells produce more proteolytic enzymes, and the combination of phagocytosis and enzymatic digestion usually leads to clearance of the necrotic cells. MORPHOLOGY Cytoplasmic changes Increased eosinophilia in H&E stains, due to the loss of cytoplasmic RNA (which bind the blue dye hematoxylin) and accumulation of denatured cytoplasmic proteins (which bind the red dye eosin). Glassy homogeneous appearance as a result of the loss of glycogen particles. Moth -eaten and vacuolated due to enzymatic digestion of cell’s organelles By electron microscopy, necrotic cells are characterized by discontinuities in plasma and organelle membranes, marked dilation of mitochondria with the appearance of large amorphous densities, intracytoplasmic myelin figures, amorphous debris, and aggregates of fluffy material representing denatured protein. Nuclear changes appear in one of three patterns, all due to breakdown of DNA. Karyolysis, the basophilia of the chromatin, may fade, reflecting loss of DNA because of enzymatic degradation by endonucleases. A second Pyknosis, (also seen in apoptotic cell death) nuclear shrinkage and chromatin condenses into a dense, shrunken basophilic mass. Karyorrhexis, a pyknotic nucleus undergoes fragmentation, then totally disappears Within 1 or 2 days. Page 3 of 3  31 IRREVERSIBLE RESPONSE TO CELL INJURY: “NECROSIS\ APOPTOSIS” ILOs By the end of this lecture, students will be able to 1. Correlate different patterns of necrosis as coagulative, liquefactive, caseous, gangrenous, fatty fibrinoid necrosis to corresponding clinical situations. 2. Evaluate mechanisms of apoptosis in physiological and pathological removal of dead cells in relation to some clinical conditions. 3. Differentiate between morphological and diagnostic features of apoptosis vs necrosis. Biochemical changes in necrosis and its clinical applications Value of early biochemical testing in diagnosis of cell necrosis Necrosis is early associated with leakage of intracellular proteins through damaged plasma membranes into the circulation. This set the biochemical basics of early detection of tissue –specific cell injury by blood testing. It usually occurs very early before ultrastructural, histological or gross morphological changes. Examples; Damaged cardiac muscle cells express cardiac-specific variants of the contractile protein troponin. Damaged Liver cells express transaminases. Damaged Bile duct cells express alkaline phosphatases. Phenomena consistently characterize irreversibility; The inability to reverse mitochondrial dysfunction (lack of oxidative phosphorylation and ATP generation) even after resolution of the original injury Profound disturbances in membrane integrity with leakage of lysosomal enzymes. Nuclear changes. Patterns of necrosis 1. Coagulative necrosis is a form of necrosis in which the architecture of dead tissue is preserved for a span of at least some days. Caused due to ischemia or impairment of arterial supply. The localized area of coagulative necrosis is called an infarct. Pathogenesis The injury denatures structural proteins and enzymes and so blocks the proteolysis of the dead cells leading to intensely eosinophilic cells with distinct cellular outlines and indistinct or reddish nuclei that persist for days or weeks. The necrotic cells are broken down by the Page 1 of 4 action of lysosomal enzymes derived from infiltrating leukocytes, followed by removal of cell debris by phagocytosis. Clinical examples; Necrosis of myocardial cells [ myocardial infarction under the effect of ischemia due to inadequate blood supply by narrowed \occluded coronary arteries in context of atherosclerosis], and kidney [ renal infarction in similar condition to the heart]. 2. Liquefactive necrosis; characterized by release of hydrolytic enzymes that digest the dead cells, resulting in transformation of the tissue into a viscous liquid. Clinical examples; Abscess with pus formation Focal bacterial or fungal infections that stimulate the accumulation of leukocytes and the liberation of digestive enzymes transforming the necrotic material into creamy yellow pus containing dead tissue cells, and bacteria. Hypoxic death of the central nervous system cells often manifests as liquefaction of the necrosed tissue for unknown reasons. 3. Gangrenous necrosis a clinical terminology describing necrosis with superadded putrefaction infection. It is usually applied to an organ, that has lost its arterial blood supply and has undergone necrosis (typically coagulative necrosis) involving multiple tissue planes (giving rise to so-called gangrene e.g., dry gangrene of foot due to diabetes mellitus and wet gangrene of small intestine due to mesenteric vascular occlusion). 4. Caseous necrosis, It combines features of both coagulative and liquefactive necrosis, and is encountered in foci of tuberculous infection. Occurs in reaction of lipid content of cell wall of these organisms. Grossly, it resembles dry cheese and is soft, granular and yellow. On microscopic examination, the necrotic area appears as a structureless collection of fragmented or lysed cells and amorphous granular debris enclosed within a distinctive inflammatory border; this appearance is characteristic of a focus of inflammation known as a granuloma. 5. Fat necrosis death of fat cells under effects of lytic enzymes. Fat necrosis occurs at fat-rich locations in the body. Fat necrosis: occurs in two forms: a. Traumatic fat necrosis, which occurs after a severe injury to tissue with high fat content, such as the breast. b. Enzymatic mesenteric fat necrosis, which is a complication of acute pancreatitis, with diffusion of proteolytic and lipolytic pancreatic enzymes into inflamed tissue and literally digest the parenchyma. Gross examination, visible chalky-white areas (fat saponification), which enable the surgeon and the pathologist to identify the underlying disorder. Fate of necrosis Within the living patient most necrotic cells and their contents disappear due to enzymatic digestion and phagocytosis of the debris by leukocytes. Page 2 of 4  If necrotic cells and cellular debris are not promptly destroyed and reabsorbed, they provide a nidus for the deposition of calcium salts and other minerals and thus tend to become calcified, dystrophic calcification. Apoptosis: Cell proliferation and cell death are usually balanced in all the normal tissues of multicellular organisms. Apoptosis is programmed cell death, induced by a tightly regulated suicide program. Cells destined to die will activate intrinsic enzymes that degrade the cells’ genomic DNA and nuclear and cytoplasmic proteins. Apoptosis affects only single cells or few cells. Mechanism of Apoptosis Apoptosis occurs in two broad contexts as part of normal physiologic processes, and as a pathophysiologic mechanism of cell loss in many different diseases. It occurs in a cascade of molecular events that include the activation of caspases initiation phase followed by an execution phase [when the enzymes cause cell death]. Apoptosis in physiological conditions; Cells undergo apoptosis because they are deprived of necessary survival signals, such as growth factors and interactions with the extracellular matrix, or they receive pro-apoptotic signals from other cells or the surrounding environment. During Embryogenesis (for normal development) ; it is critical for involution of primordial structures and remodelling of maturing tissues. Example; The formation of the digits during embryogenesis in the foetus occurs by the apoptosis of interdigital tissues. Hormone-dependent involution of tissues; During Menstrual Cycle, the sloughing off the inner lining of the uterus (the endometrium) after withdrawal of oestrogens and progesterone, ovarian follicular atresia in menopause, and regression of the lactating breast after weaning. Cell turnover in proliferating cell populations to maintain a constant cell number, such as immature lymphocytes in the bone marrow and thymus. Elimination of potentially harmful \ dangerous cells as Virus infected cells [eliminated by Cytotoxic T cells] and cells with DNA damage that fail to repair by p53 activation, then, they will undergo apoptosis to protect cells from risk of mutations. Autoreactive T cells: Autoreactive T cells in the thymus are killed by apoptosis. Page 3 of 4 Apoptosis in pathological conditions The main purpose of apoptosis is to eliminate cells that are injured beyond repair without eliciting a host reaction, thus limiting collateral tissue damage. Dysregulated (“too little or too much”) apoptosis may prolong the survival or reduce the turnover of abnormal cells, Such abnormally accumulated cells may lead to: 1. Tumorigenesis: under normal situations, radiation and cytotoxic drugs can damage DNA, either directly or via production of free radicals. If repair mechanisms cannot correct the damage, the cell triggers intrinsic mechanisms that induce apoptosis as a protective effect by preventing the survival of cells with DNA mutations that can lead to malignant transformation. On the other hand, In case of mutated apoptosis genes; carcinogenic agents can damage p53 tumor suppressor gene that lead to inhibition of apoptosis and immortalization of abnormal cells and development of malignant cells. 2. Accumulation of abnormal proteins. Cell death triggered by improperly folded intracellular proteins and the subsequent endoplasmic reticulum response → Neurodegenerative disorders. 3. Autoimmune Diseases; A decrease in apoptosis of self-reactive immune cells can lead to the development of autoimmune diseases. 4. Infectious conditions; elimination of viral infected cells (e.g., hepatitis), is mediated by apoptosis induced mechanisms. Dysregulation of this pathway , will fail the body ‘s defensive mechanisms. Morphologic features of apoptosis include: Involves single isolated cells or small clusters of cells within a tissue. Lack of inflammatory response Blebbing of plasma membrane Cytoplasmic and cellular shrinkage Chromatin condensation and fragmentation Budding of cell and Fragmentation into apoptotic bodies (membrane-bound segments) Phagocytosis of apoptotic bodies by adjacent healthy cells or macrophages. Page 4 of 4