Introduction & Cell Injury Lecture Notes PDF

Introduction & Cell Injury ‫ فرع االمراض‬/ ‫كلية طب نينوى‬ ‫ اروى البرهاوي‬. ‫د‬ IRREVERSIBLE CELL INJURY:  Definition: Irreversible cell injury occurs when the damage to cells is so...

Introduction & Cell Injury ‫ فرع االمراض‬/ ‫كلية طب نينوى‬ ‫ اروى البرهاوي‬. ‫د‬ IRREVERSIBLE CELL INJURY:  Definition: Irreversible cell injury occurs when the damage to cells is so severe that they cannot recover, leading to cell death. The two principal types of cell death are necrosis and apoptosis, each with distinct mechanisms, morphology, and roles in physiology and disease. NECROSIS:  Necrosis: o Pathologic Process: Necrosis is a consequence of severe injury and is characterized by the death of cells in a tissue. o Causes: Common causes include ischemia (loss of blood supply), exposure to microbial toxins, chemical and physical injury (e.g., burns), and conditions like pancreatitis where active proteases leak out and damage surrounding tissues. o Characteristics:  Denaturation of Proteins: Cellular proteins become denatured.  Membrane Damage: Cellular contents leak through damaged membranes, triggering local inflammation.  Enzymatic Digestion: Enzymes digest the lethally injured cell.  Eosinophilia: Necrotic cells show increased eosinophilia (pink staining) due to loss of cytoplasmic RNA and accumulation of denatured proteins.  Nuclear Changes:  Karyolysis: Fading of the nucleus due to DNA degradation.  Pyknosis: Shrinkage and increased basophilia of the nucleus.  Karyorrhexis: Fragmentation of the nucleus. o Outcomes: Necrotic cells may be replaced by myelin figures (phagocytosed or degraded into fatty acids) or calcified, leading to calcium-rich precipitates. Patterns of Tissue Necrosis: 1. Coagulative Necrosis: o Definition: The architecture of dead tissue is preserved for a few days after the injury. o Appearance: Affected tissue is firm, with eosinophilic cells that persist due to the denaturation of structural proteins and enzymes. o Cause: Typically caused by ischemia due to vessel obstruction, leading to tissue infarction (except in the brain). 2. Liquefactive Necrosis: o Definition: Characterized by the digestion of dead cells, transforming tissue into a viscous liquid.  o Associated Conditions: Common in bacterial or fungal infections, as well as hypoxic death of brain cells. o Appearance: Necrotic material often appears as pus due to the presence of leukocytes. 3. Gangrenous Necrosis: o Definition: A clinical term used to describe tissue (often a limb) that undergoes necrosis, usually due to loss of blood supply. o Types:  Dry Gangrene: Coagulative necrosis affecting multiple tissue planes.  Wet Gangrene: Occurs when a bacterial infection superimposes, leading to liquefactive necrosis. 4. Caseous Necrosis: o Definition: Often seen in tuberculous infections, characterized by a cheese-like appearance of necrotic tissue. o Microscopic Appearance: Necrotic areas consist of fragmented or lysed cells within a granuloma, a distinctive inflammatory border. 5. Fat Necrosis: o Definition: Focal areas of fat destruction, typically due to the release of pancreatic lipases during acute pancreatitis. o Appearance: Chalky-white areas of fat saponification are visible grossly, while histologically, necrotic fat cells show calcium deposits and an inflammatory reaction. 6. Fibrinoid Necrosis: o Definition: A special form of necrosis seen in immune reactions involving blood vessels. o Appearance: Antigen-antibody complexes and plasma proteins leak into the vessel walls, creating a bright pink, fibrin-like appearance in H&E stains. Sequelae (Outcomes) of Necrosis: 1. Complete Resolution: Some tissues, like the liver and kidney, can regenerate and repair the injury completely. 2. Repair by Fibrous Scarring: In organs like the heart, dead tissue is removed by phagocytes and replaced by fibrous scar tissue. 3. Resorption of Necrotic Tissue: In the brain, necrotic tissue is removed by macrophages, leaving a fluid-filled cyst (pseudocyst). 4. Calcification: Dystrophic calcification can occur in necrotic tissues, leading to calcium deposits. APOPTOSIS :  Definition: Apoptosis is a programmed cell death process in which cells destined to die activate intrinsic enzymes that degrade their genomic DNA and nuclear and cytoplasmic  proteins. This process is tightly regulated and essential for maintaining tissue homeostasis.  Process: o Formation of Apoptotic Bodies: The cell breaks up into plasma membrane- bound fragments called apoptotic bodies, which contain portions of the cytoplasm and nucleus. o Membrane Integrity: While the plasma membrane remains intact, its surface components are altered to produce "find me" and "eat me" signals that attract phagocytes. o Phagocytosis: These signals ensure that apoptotic bodies are rapidly engulfed and digested by phagocytes, preventing the release of intracellular contents and avoiding an inflammatory response.  Historical Context: Apoptosis was first recognized in 1972 and named after the Greek term for "falling off," reflecting the orderly and contained nature of this cell death process. Causes of Apoptosis: Apoptosis occurs in two broad contexts: physiological processes and pathological conditions. 1. Apoptosis in Physiologic Situations:  Role: Apoptosis is a normal phenomenon crucial for eliminating cells that are no longer needed and for maintaining the proper number of cells in tissues. It is estimated that humans turn over nearly 1 million cells per second through apoptosis.  Key Physiologic Situations: o Developmental Cell Removal: Apoptosis removes supernumerary cells during development, helping in the involution of primordial structures and the remodeling of maturing tissues. This is referred to as programmed cell death during development. o Involution of Hormone-Dependent Tissues: Apoptosis is involved in the breakdown of endometrial cells during the menstrual cycle, ovarian follicular atresia during menopause, and regression of the lactating breast after weaning. o Cell Turnover in Proliferating Populations: Apoptosis helps maintain constant cell numbers in tissues with high turnover rates, such as immature lymphocytes in the bone marrow and thymus, B lymphocytes in germinal centers, and epithelial cells in intestinal crypts. o Elimination of Self-Reactive Lymphocytes: Apoptosis eliminates potentially harmful self-reactive lymphocytes, preventing autoimmune reactions.  In all of these situations, 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. 2. APOPTOSIS IN PATHOLOGIC CONDITIONS:  Purpose: In pathological states, apoptosis serves to eliminate cells that are damaged beyond repair without triggering an inflammatory response. This minimizes collateral damage to surrounding tissues.  Key Pathologic Conditions Involving Apoptosis: o DNA Damage:  Causes: DNA damage can result from radiation, cytotoxic anticancer drugs, or the production of free radicals.  Protective Role: Apoptosis prevents the survival of cells with DNA mutations that could potentially lead to cancerous transformation. o Accumulation of Misfolded Proteins:  ER Stress: Misfolded intracellular proteins can trigger cell death via the endoplasmic reticulum (ER) stress response, a protective mechanism to prevent the accumulation of potentially harmful proteins. o Infections:  Viral Infections: Apoptosis can be induced by viral infections, either directly by the virus (e.g., adenovirus, HIV) or by the host immune response (e.g., in viral hepatitis). Cytotoxic T lymphocytes play a crucial role in targeting and killing virus-infected cells through apoptosis. o Pathologic Atrophy:  Duct Obstruction: Apoptosis contributes to the atrophy of parenchymal organs after duct obstruction, as seen in the pancreas, parotid gland, and kidney. The blockage leads to cell loss through apoptosis, resulting in tissue shrinkage. Morphologic and Biochemical Changes in Apoptosis:  Cell Shrinkage: o The cell becomes smaller, with the cytoplasm more tightly packed, contrasting with the cell swelling seen in necrosis.  Chromatin Condensation: o Characteristic Feature: The most distinctive morphological feature of apoptosis is chromatin condensation. The chromatin aggregates under the nuclear membrane into dense masses of various shapes and sizes.  o Nuclear Fragmentation: The nucleus may break into two or more fragments as apoptosis progresses.  Formation of Cytoplasmic Blebs and Apoptotic Bodies: o Apoptotic Bodies: The cell membrane forms blebs, which break off into membrane-bound apoptotic bodies containing cytoplasmic and nuclear material. o Eosinophilic Appearance: In H&E-stained tissue, apoptotic cells appear as round or oval masses with intensely eosinophilic (pink) cytoplasm and dense nuclear chromatin fragments.  Absence of Inflammation: o Rapid Clearance: Apoptotic bodies are rapidly phagocytosed by neighboring cells or macrophages, preventing the release of cellular contents and subsequent inflammation. o Histological Detection: Because of the rapid clearance and lack of inflammation, apoptosis can occur extensively in tissues before becoming apparent in histologic sections, making it challenging to detect with light microscopy. Mechanism of apoptosis Apoptosis is a programmed cell death process orchestrated by caspases, which are activated through two main pathways: the mitochondrial pathway (intrinsic) and the death receptor pathway (extrinsic). These pathways converge on caspase activation, leading to the execution phase where cellular components are fragmented, forming apoptotic bodies that are then cleared by phagocytes, ensuring that apoptosis proceeds without triggering inflammation.  The Mitochondrial (Intrinsic) Pathway of Apoptosis  The Mitochondrial Pathway is crucial for apoptosis in most physiological and pathological situations.  This pathway is initiated by increased permeability of the mitochondrial outer membrane.  Mitochondria contain essential proteins like cytochrome c, which is involved in energy production (e.g., ATP) but also triggers apoptosis when released into the cytoplasm.  The release of pro-apoptotic proteins such as cytochrome c is controlled by the integrity of the mitochondrial outer membrane.  The integrity of the outer mitochondrial membrane is regulated by the BCL2 family of proteins.  Anti-apoptotic proteins: BCL2, BCL-XL, and MCL1 are key members that reside in the outer mitochondrial membrane, cytosol, and ER membranes. They prevent cytochrome c leakage by maintaining the membrane's impermeability.  Pro-apoptotic proteins: BAX and BAK are the primary members of this group. When activated, they oligomerize in the outer mitochondrial membrane, increasing its permeability and allowing cytochrome c to leak into the cytosol.  Regulated apoptosis initiators: Proteins like BAD, BIM, and BID can initiate apoptosis when they are upregulated and activated. The Extrinsic (Death Receptor–Initiated) Pathway of Apoptosis  the Extrinsic Pathway of Apoptosis is initiated by the engagement of death receptors on the plasma membrane.  Death receptors are members of the TNF (Tumor Necrosis Factor) receptor family, which contain a cytoplasmic death domain crucial for protein-protein interactions and delivering apoptotic signals.  The most well-known death receptors include TNFR1 (Type 1 TNF receptor) and Fas (CD95), though several others exist.  The ligand for Fas is called Fas ligand (FasL), which is expressed on T cells that recognize self-antigens and functions to eliminate self-reactive lymphocytes.  FasL is also expressed on some cytotoxic T lymphocytes (CTLs) that kill virus-infected and tumor cells.  Upon binding of FasL to Fas, three or more Fas molecules are brought together, facilitating the formation of a binding site for the adaptor protein FADD (Fas- associated death domain).  FADD binds to this complex and subsequently recruits inactive caspase-8 (or caspase-10), bringing multiple caspase molecules together.  This proximity leads to autocatalytic cleavage of caspase-8, generating active caspase-8.  Active caspase-8 then initiates the activation of executioner caspases, leading to the apoptotic process.  While the extrinsic pathway is distinct from the intrinsic (mitochondrial) pathway of apoptosis, there may be interconnections between the two pathways, indicating potential crosstalk. The Execution Phase of Apoptosis  The intrinsic and extrinsic pathways of apoptosis both lead to the activation of a caspase cascade.  The intrinsic pathway activates caspase-9, while the extrinsic pathway activates caspase-8 and caspase-10.   These initiator caspases then trigger executioner caspases like caspase-3 and caspase-6, which carry out the final steps of apoptosis. Removal of Dead Cells 1. Formation of cytoplasmic buds: During apoptosis, the cell membrane forms small protrusions known as cytoplasmic buds. These buds contain essential cellular components, including nuclear fragments, mitochondria, and condensed protein fragments, indicating the breakdown of the cell's internal structure. 2. Formation of apoptotic bodies: The cytoplasmic buds eventually break off from the cell, forming distinct membrane-bound structures called apoptotic bodies. These apoptotic bodies encapsulate the fragmented cellular contents, preventing the release of potentially harmful substances into the surrounding tissue. 3. Phagocytosis of apoptotic bodies: Neighboring cells or specialized immune cells, such as macrophages, recognize and engulf the apoptotic bodies through a process known as phagocytosis. This step ensures the safe and efficient removal of dying cells, preventing inflammation or damage to surrounding tissues.