Cell Injury Part 2 - University of Baghdad - 2024-2025 PDF

University of Baghdad College of Medicine 2024-2025 Title: Cell injury part 2 Grade: 2 Module: CLS Speaker: Assistant Prof. Dr. Zainab Khalid Almukhtar Date:29,30 /09-1,2/10/2024 Objectives : Define necrosis and mention its features Describe...

University of Baghdad College of Medicine 2024-2025 Title: Cell injury part 2 Grade: 2 Module: CLS Speaker: Assistant Prof. Dr. Zainab Khalid Almukhtar Date:29,30 /09-1,2/10/2024 Objectives : Define necrosis and mention its features Describe the patterns of necrosis Define apoptosis and list its causes Describe cellular accumulation and enumerate its pathways with examples Define calcification and mention its causes. Morphology of irreversible cell death : There are two morphological types of cell death 1. Necrosis 2. Apoptosis Necrosis: refers to the morphological changes that accompany cell death, largely resulting from the degradative action of enzymes on lethally injured cells. Necrotic cells are unable to maintain membrane integrity, and their contents often leak out. The enzymes responsible for digestion of the cell are derived either from the lysosomes of the dying cells themselves or from the lysosomes of leukocytes that are recruited as part of the inflammatory reaction to the dead cells. General morphologic features of necrosis : Cytoplasmic changes: The necrotic cells (e.g. as a result of oxygen deprivation) show increased eosinophilia i.e. appear deep pink in color than normal cells. This is attributable in part to increased binding of eosin to denatured cytoplasmic proteins and in part to loss of the basophilia that is normally imparted by the RNA in the cytoplasm (basophilia is the blue staining from the hematoxylin dye). The cell may have a more homogeneous appearance than viable cells, mostly because of the loss of glycogen particles. When enzymes have digested the cytoplasmic organelles, the cytoplasm becomes vacuolated and appears motheaten. Nuclear changes: assume one of three patterns, all due to breakdown of DNA and chromatin. Karyolysis i.e. the basophilia of the chromatin may fade, presumably secondary to deoxyribonuclease(endonuclease) (DNase) activity. Pyknosis characterized by nuclear shrinkage and increased basophilia; the DNA condenses into a solid shrunken mass. Karyorrhexis, the pyknotic nucleus undergoes fragmentation. In 1 to 2 days, the nucleus in a dead cell completely disappears. Patterns of Tissue Necrosis : There are several morphologically patterns of tissue necrosis, which may provide clues about the underlying cause. 1.Coagulative necrosis 2.Liquefactive necrosis 3.Gangrenous necrosis 4.Caseous necrosis 5.Fat necrosis 6.Fibrinoid necrosis 1.Coagulative necrosis: It is a form of tissue necrosis in which the fine structural details are lost but the basic tissue architecture is preserved. Grossly, the affected tissues have a firm texture. This appears to be due to denaturation not only of structural proteins but also of enzymes, which blocks proteolysis of the dead cells. these changes are reflected microscopically as homogeneously eosinophilic cells that are devoid of nuclei. Coagulative necrosis is characteristic of infarcts (areas of ischemic necrosis) in all solid organs except the brain. Coagulative necrosis A, A wedge-shaped kidney infarct (yellow). B, Microscopic view of the edge of the infarct, with normal kidney (N) and necrotic cells in the infarct (I) showing preserved cellular outlines with loss of nuclei and an inflammatory infiltrate (seen as nuclei of inflammatory cells in between necrotic tubules). Coagulative necrosis : Liquafactive necrosis : in this type of necrosis there is complete digestion of the dead cells, resulting in transformation of the affected tissue into a liquid viscous mass enclosed within a cystic cavity. Gangrenous necrosis Gangrenous necrosis is not a distinctive pattern of cell death; however, the term is still commonly used in clinical practice. It is usually applied to a limb, generally the lower leg that has lost its blood supply and has undergone coagulative necrosis involving multiple tissue layers (dry gangrene). When bacterial infection is superimposed, coagulative necrosis is modified by the liquefactive action of the bacteria and the attracted leukocytes (wet gangrene). Caseous necrosis : is encountered most often in foci of tuberculous infection. The term "caseous" (cheese-like) is derived from the friable yellow-white appearance of the area of necrosis. On microscopic examination, the necrotic focus appears as amorphous, granular in appearance. Unlike coagulative necrosis, the tissue architecture is completely lost and cellular outlines cannot be discerned. Caseous necrosis is often enclosed within a distinctive inflammatory border; this appearance is characteristic of granulomatous inflammation. Caseous Necrosis : Fat necrosis : typically seen in acute pancreatitis and results from release of activated pancreatic lipases into the substance of the pancreas and the peritoneal cavity. Pancreatic enzymes that have leaked out of acinar cells liquefy the membranes of fat cells in and outside the pancrease (e.g.) the peritoneum). Lipases split the triglycerides contained within fat cells releasing fatty acids that combine with calcium to produce grossly visible chalky white areas (fat saponification). Fat Necrosis : Fat necrosis. The areas of white chalky deposits represent foci of fat necrosis with calcium soap formation (saponification) at sites of lipid breakdown in the mesentery. Fibrinoid Necrosis : Necrosis with protein deposition and inflammation (dark nuclei of neutrophils ) Apoptosis: This form of cell death is a regulated suicide program in which the relevant cells activate enzymes capable of degrading the cells' own nuclear DNA and other nuclear and cytoplasmic proteins. Fragments of the apoptotic cells then break off (apoptosis, "falling off"). The plasma membrane of the apoptotic cell remains intact, but is altered in such a way that the cell and its fragments become avid targets for phagocytes. The dead cell is rapidly cleared before its contents have leaked out, and therefore cell death by this pathway does not elicit an inflammatory reaction in the host. Thus, apoptosis differs from necrosis; the latter is characterized by loss of membrane integrity, leakage of cellular contents, and frequently a host reaction. Microscopic features : Apoptotic cells may appear as round or oval masses with intensely eosinophilic cytoplasm. Nuclei show chromatin condensation and aggregation and, ultimately fragmentation (karyorrhexis). The cells rapidly shrink, form cytoplasmic buds, and fragment into apoptotic bodies composed of membrane-bound vesicles of cytoplasm and organelles. Because these fragments are quickly extruded and phagocytosed without eliciting an inflammatory response, even substantial apoptosis may be histologically undetectable. Causes of Apoptosis : Apoptosis in Physiologic Situations Death by apoptosis is a normal phenomenon that serves to eliminate cells that are no longer needed. It is important in the following physiologic situations: 1. During embryogenesis (organogenesis and involution). 2. Involution of hormone-dependent tissues (hormone deprivation, as endometrial cell breakdown during the menstrual cycle, and regression of the lactating breast after weaning) ,prostatic atrophy after castration. 3. In proliferating cells, such as intestinal crypt epithelia (to maintain a constant number). 4. In cells that have served their useful purpose (as neutrophils in an acute inflammation & lymphocytes in immune response). 5. In self-reactive lymphocytes (to prevent self-tissue destruction). 6. Cytotoxic T lymphocytes-induced cell death (a defense mechanism against viruses and tumors that serves to kill and eliminate virus-infected & neoplastic cells) Apoptosis in Pathologic Conditions : Apoptosis eliminates cells that are genetically altered or injured beyond repair without eliciting a host reaction, thus keeping the damage as restricted as possible. Death by apoptosis is responsible for loss of cells in a variety of pathologic states: (DNA damage, Accumulation of misfolded proteins, Cell death in certain infections. Mechanism of Apoptosis: The fundamental event in apoptosis is the activation of enzymes caspases that culminate in activation of nucleases with DNA degredation. The two pathways of apoptosis: The two pathways of apoptosis differ in their induction and regulation, and both culminate in the activation of caspases. In the mitochondrial pathway, through proteins of Bcl-2 family, sense a lack of survival signals or DNA or protein damage that activate effector molecules that increase mitochondrial permeability. In concert with a deficiency of Bcl-2 the mitochondria become leaky and various substances, such as cytochrome c, enter the cytosol and activate caspases. Activated caspases induce the changes that culminate in cell death and fragmentation. In the death receptor pathway, signals from plasma membrane receptors lead to the assembly of adaptor proteins into a “death-inducing signaling complex,” which activates caspases, and the end result is the same. Cell accumulation: Cells may accumulate abnormal amounts of various substances. Harmless or harmful. Cytoplasmic, intranuclear or within the organelles. Pathways of abnormal intracellular accumulations: In adequate removal of a substance Defective transport of a substance. Failure to degrade a metabolite: An inherited defect in an enzyme Cell has neither the enzymatic machinery to degrade an abnormal exogenous substance nor the ability to transport it There are Four main pathways of abnormal intracellular accumulations: 1Inadequate removal of a normal substance secondary to defects in mechanisms of packaging and transport, as in fatty change (steatosis) in the liver 2 Accumulation of an abnormal endogenous substance as a result of genetic or acquired defects in its folding, packaging, transport, or secretion, as with certain mutated forms of α1-antitrypsin 3 Failure to degrade a metabolite due to inherited enzyme deficiencies. The resulting disorders are called storage diseases 4 Deposition and accumulation of an abnormal exogenous substance when the cell has neither the enzymatic machinery to degrade the substance nor the ability to transport it to other sites. Accumulation of carbon or silica particles is an example of this type of alteration Fatty Change (Steatosis) : This refers to any abnormal accumulation of triglycerides within parenchymal cells. It is most often seen in the liver, since this is the major organ involved in fat metabolism, but it may also occur in the heart. Causes of fatty change include toxins including : 1.alcohol 2. Diabetes mellitus 3. Obesity 4. Protein malnutrition 5. Anoxia Alcohol abuse and nonalcoholic fatty liver disease associated with obesity& diabetes are the most common causes of fatty change in the liver (fatty liver) in industrialized nations. The significance of fatty change depends on the cause and severity of the accumulation. When mild it may have no effect. More severe fatty change may transiently impair cellular function, but the change is reversible. In the severe form, fatty change may precede cell death. Gross features : Fatty change is most commonly seen in the liver and the heart. In the liver, mild fatty change may not affect the gross appearance. With increasing accumulation, the organ enlarges and becomes progressively yellow until, in extreme cases, it may weigh 5 kg (3 times the normal weight) and appear bright yellow, soft, and greasy. Microscopic features: Early fatty change is seen by light microscopy as small fat vacuoles in the cytoplasm around the nucleus. In later stages, the vacuoles coalesce to create cleared spaces that displace the nucleus to the cell periphery. Cholesterol and Cholesteryl Esters accumulations: Cellular cholesterol metabolism is tightly regulated to ensure normal cell membrane synthesis without significant intracellular accumulation. However, phagocytic cells may become overloaded with lipid (triglycerides, cholesterol, and cholesteryl esters) in several different pathologic processes. 1. Macrophages in contact with the lipid debris of necrotic cells or abnormal (e.g., oxidized) forms of lipoproteins may become stuffed with phagocytosed lipid. These macrophages may be filled with minute, membrane-bound vacuoles of lipid, imparting a foamy appearance to their cytoplasm (foam cells). In atherosclerosis, smooth muscle cells and macrophages are filled with lipid vacuoles composed of cholesterol and cholesteryl esters; these give atherosclerotic plaques their characteristic yellow color and contribute to the pathogenesis of the lesion. 2.In hereditary and acquired hyperlipidemic syndromes, macrophages accumulate intracellular cholesterol; when present in the subepithelial connective tissue of skin or in tendons, clusters of these foamy macrophages form masses called xanthomas. Xanthoma–subepithelial tissue: Glycogen accumulations : Excessive intracellular deposits of glycogen are associated with abnormalities in the metabolism of either glucose or glycogen. In poorly controlled diabetes mellitus, the prime example of abnormal glucose metabolism, glycogen accumulates in renal tubular epithelium, cardiac myocytes, and β cells of the islets of Langerhans. Glycogen also accumulates within cells in a group of closely related genetic disorders collectively referred to as glycogen storage diseases, or glycogenoses. In these diseases, enzymatic defects in the synthesis or breakdown of glycogen result in massive accumulations, with secondary injury and cell death. Pigments: Pigments are colored substances that are exogenous, coming from outside the body, or endogenous, synthesized within the body itself. Exogenous pigments; the most common of these is carbon (an example is coal dust), a ubiquitous air pollutant of urban life. When inhaled, it is phagocytosed by alveolar macrophages and transported through lymphatic channels to the regional tracheobronchial lymph nodes. Aggregates of the pigment blacken the draining lymph nodes and pulmonary parenchyma (anthracosis).Heavy accumulations may induce fibroblastic reaction that can result in a serious lung disease called coal workers' pneumoconiosis. Exogenous pigments: e.g., carbon Endogenous pigments include certain derivatives of hemoglobin. Hemosiderin is a hemoglobin-derived granular pigment that is golden yellow to brown and accumulates in tissues when there is a local or systemic excess of iron. Hemosiderin pigment represents large aggregates of iron, readily visualized by light microscopy; the iron can be identified by the Prussian blue histochemical reaction. Local excesses of iron, and consequently of hemosiderin, result from hemorrhage. Whenever there is systemic overload of iron, hemosiderin is deposited in many organs and tissues including their macrophages. This condition is called hemosiderosis. With progressive accumulation, parenchymal cells throughout the body (but principally the liver, pancreas, heart, and endocrine organs) become "bronzed" with accumulating pigment. Hemosiderosis occurs in the settings of : 1. Increased absorption of dietary iron 2. Impaired utilization of iron 3. Hemolytic anemias, and 4. Transfusions (the transfused red cells constitute an exogenous load of iron). Extensive accumulations of iron are seen in hereditary hemochromatosis, with tissue injuryincluding liver fibrosis, heart failure, and diabetes mellitus. Bilirubin : Bilirubin This is a normal major pigment of bile, which is derived from Hb (but unlike hemosiderincontains no iron). The conversion to bile occurs within hepatocytes. Jaundice results from excess bilirubin pigment that is distributed throughout all tissues and body fluids. In the liver, particularly when there is obstruction to the bile flow (e.g. obstruction of the common bile duct by a stone or atresia) bilirubin is seen within bile canaliculi, kupffer cells and hepatocytes as green-brown globular deposits. This imparts greenish color to the liver grossly. Pathologic Calcification : Deposition of calcium salts dystrophic calcification: in dead or dying tissues: metastatic calcification :in normal tissues. Hypercalcemia is not a prerequisite for dystrophic calcification, it can exacerbate it. Pathologic calcification is a common process in a wide variety of disease states; it implies the abnormal deposition of calcium salts. When the deposition occurs in dead or dying tissues, it is called dystrophic calcification; it occurs in the absence of calcium metabolic derangements (i.e., with normal serum levels of calcium). In contrast, the deposition of calcium salts in normal tissues is known as metastatic calcification and almost always reflects some derangement in calcium metabolism (hypercalcemia). It should be noted that while hypercalcemia is not a prerequisite for dystrophic calcification, it can exacerbate it. Dystrophic calcification is encountered in -Areas of necrosis (of any type as coagulative, caseous, etc.) -Advanced atherosclerosis ( as in the aorta and coronaries) -Aging or damaged heart valves resulting in severely impaired valve motion. Dystrophic calcification of the aortic valves is an important cause of aortic stenosis in the elderly. Regardless of the site, calcium salts are grossly seen as fine white granules or clumps, often felt as gritty deposits. Sometimes a tuberculous lymph node is essentially converted to radiopaque stone. Microscopically, calcification appears as intracellular and/or extracellular basophilic (blusih) deposits. In time, metplastic bone may be formed in the focus of calcification. Dystrophic calcification Metastatic Calcification: This is seen in cases of hypercalcemia of any cause. The four major causes of hypercalcemia are : 1. Increased secretion of parathyroid hormone 2. Destruction of bone (effects of accelerated turnover as in Paget disease, 3. Vitamin D-related disorders including vitamin D intoxication 4. Renal failure, in which phosphate retention leads to secondary hyperparathyroidism. Metastatic calcification can occur widely throughout the body but principally affects the interstitial tissues of the vessels, kidneys, lungs, and gastric mucosa. The calcium deposits morphologically resemble those