Cell Injury Lec1 - Pathophysiology PDF

Introduction & Cell Injury ‫ فرع االمراض‬/ ‫كلية طب نينوى‬ ‫ اروى البرهاوي‬. ‫د‬  Pathology focuses on the study of disease processes, examining structural, biochemical, and functio...

Introduction & Cell Injury ‫ فرع االمراض‬/ ‫كلية طب نينوى‬ ‫ اروى البرهاوي‬. ‫د‬  Pathology focuses on the study of disease processes, examining structural, biochemical, and functional changes in cells and tissues  General Pathology addresses cellular responses to injury, while Systemic Pathology focuses on disease mechanisms in specific organs.  Core aspects include etiology, pathogenesis, morphologic changes, and clinical manifestations.  Etiology involves genetic and environmental factors; pathogenesis explores the sequence of events leading to disease Cell Homeostasis, Adaptation, and Injury: 1. Cell Homeostasis: o Definition: Cells maintain normal homeostasis by keeping their internal environment stable and within a narrow range of physiological parameters. This steady state allows cells to function optimally under normal conditions. 2. Adaptations: o Definition: Adaptations are reversible changes in cell function and structure in response to changes in physiological conditions (e.g., pregnancy) or pathological stimuli. o Purpose: These adaptations allow cells to achieve a new, altered steady state that enables them to survive and continue functioning despite the changes in their environment. 3. Cell Injury: o Definition: Cell injury refers to the set of biological and morphological changes that occur when a cell's equilibrium or homeostasis is disrupted by harmful influences. o Outcome: When the cell can no longer maintain homeostasis, injury occurs, which can be either reversible or irreversible depending on the nature and severity of the stress. KEY CONCEPT:  Loss of Homeostasis = Cell Injury: When a cell's ability to maintain its steady state is compromised, it leads to cell injury, disrupting normal cellular function and potentially leading to cell death if the injury is severe or prolonged. CAUSES OF CELL INJURY: 1. Oxygen Deprivation (Hypoxia): o Definition: Hypoxia is a decrease in the oxygen supply to cells, which can result in cell injury. o Causes:  Ischemia: Loss of blood supply due to blocked arteries.  Inadequate Oxygenation: Conditions like cardiac or respiratory failure that impair oxygen delivery.  Reduced Oxygen-Carrying Capacity: Examples include anemia and carbon monoxide (CO) poisoning. 2. Physical Agents: o Examples: Mechanical trauma, extremes of temperature (e.g., burns, frostbite), sudden atmospheric pressure changes, radiation, and electric shock. 3. Chemical Agents and Drugs: o Simple Chemicals: Hypertonic concentrations of glucose or salt can directly injure cells or disrupt electrolyte and fluid balance. o Toxicity: High concentrations of oxygen can be toxic. o Environmental and Occupational Hazards: Includes pollutants, insecticides, herbicides, carbon monoxide, asbestos, and recreational drugs like alcohol. 4. Infectious Agents: o Examples: Viruses, bacteria, fungi, rickettsiae, worms, and other pathogens. 5. Immunologic Reactions: o Function: While the immune system defends against pathogens, it can also cause cell injury. o Autoimmune Diseases: Injurious immune reactions against self-antigens cause conditions like autoimmune diseases. 6. Genetic Abnormalities: o Examples:  Chromosomal Abnormalities: Such as the extra chromosome in Down syndrome.  Single-Gene Mutations: Like the base pair substitution in sickle cell anemia.  Protein Function Deficiency: Includes enzyme defects in metabolic disorders or the accumulation of damaged DNA/misfolded proteins, leading to cell death. 7. Nutritional Imbalances: o Deficiencies: Protein-calorie deficiencies cause widespread death, especially in low-income populations, and vitamin deficiencies are common globally. o Excesses: Nutritional excess, such as obesity, is also a significant cause of cell injury. 8. Cell Aging: o Aging: As cells age, they become more susceptible to injury, contributing to various age-related diseases and conditions Mechanism of cell injury : The mechanisms of cell injury involve a complex interplay of biochemical processes, influenced by various factors that determine the outcome of cellular damage. Here are the key points regarding the mechanisms of cell injury: 1. Nature, Duration, and Severity of Injury  The cellular response to harmful stimuli is closely tied to the nature of the injury, how long it lasts, and its intensity. Small doses of a toxin or brief ischemia might cause reversible injury, allowing for potential recovery. In contrast, larger doses or prolonged exposure can lead to either rapid cell death or a gradual, irreversible injury. 2. Cell Type, State, and Adaptability  The consequences of cell injury vary depending on the type of cell, its current condition, and its ability to adapt. Factors such as the cell’s nutritional status, hormonal environment, metabolic needs, and specific functions play a significant role in determining how it responds to injury.  Different cell types have different vulnerabilities. For example, skeletal muscle cells can withstand periods of ischemia better than cardiac muscle cells, which are more susceptible to damage from loss of blood supply. 3. Individual Variability  There is significant variability in how different individuals respond to the same injurious agent. This variability can be due to genetic differences, such as polymorphisms in genes  that encode enzymes responsible for metabolizing toxins. For example, exposure to the toxin carbon tetrachloride (CCl₄) may cause cell death in one individual but have no effect on another, depending on differences in their hepatic enzyme profiles. 4. Multiple Interconnected Mechanisms  Injurious stimuli often activate multiple, interconnected pathways that contribute to cell damage. This complexity makes it challenging to pinpoint a single dominant biochemical mechanism responsible for the injury in a given situation. Instead, multiple factors often work together to cause cellular damage. MITOCHONDRIAL DAMAGE AND ITS ROLE IN CELL INJURY Mitochondria are essential for cell survival because they produce ATP, the energy currency required for numerous cellular processes. However, they are also highly susceptible to various injurious stimuli, making them critical determinants of cell fate—whether the cell survives, undergoes apoptosis, or experiences necrosis. Major Consequences Of Mitochondrial Damage: 1. ATP Depletion: o ATP Production Pathways: ATP is primarily produced through oxidative phosphorylation in mitochondria. Under normal conditions, oxygen is reduced by the mitochondrial electron transport chain to generate ATP. An alternative, less efficient pathway is glycolysis, which can produce ATP anaerobically from glucose. o Causes of ATP Depletion: ATP depletion can occur due to mitochondrial damage, reduced oxygen and nutrient supply (as seen in ischemia and hypoxia), and exposure to toxins (e.g., cyanide). o When ATP levels fall below 5-10% of normal, critical cellular functions are compromised. 2. Disruption of Cellular Functions: o Sodium-Potassium Pump Failure: The energy-dependent sodium-potassium (Na⁺/K⁺-ATPase) pump relies on ATP to maintain ion gradients across the cell membrane. ATP depletion reduces the activity of this pump, causing sodium to accumulate inside the cell while potassium levels drop. This ionic imbalance leads to water influx, causing cell swelling and endoplasmic reticulum (ER) dilation. o Altered Metabolism: In response to reduced oxygen supply, cells shift from oxidative phosphorylation to glycolysis to generate ATP. This leads to rapid depletion of glycogen stores and accumulation of lactic acid and inorganic phosphates, lowering intracellular pH. The acidification inhibits many cytosolic enzymes, further disrupting cellular metabolism.  o Protein Synthesis Impairment: Prolonged ATP depletion causes structural disruption of the protein synthesis machinery, particularly detachment of ribosomes from the rough ER and dissociation of polysomes. This results in reduced protein synthesis and increased protein misfolding, which can further damage the cell. 3. Irreversible Cell Damage and Death: o Necrosis: Severe or prolonged mitochondrial damage leads to irreversible injury to mitochondrial and lysosomal membranes, culminating in necrosis, a form of uncontrolled cell death. o Reactive Oxygen Species (ROS) Generation: Incomplete oxidative phosphorylation during mitochondrial damage increases the production of ROS, which can damage lipids, proteins, and DNA, exacerbating cell injury. o Apoptosis Initiation: Mitochondrial damage can also trigger apoptosis, particularly through the MEMBRANE DAMAGE AND ITS ROLE IN CELL INJURY Membrane damage is a critical and consistent feature of cell injury. Mechanisms of Membrane Damage: 1. ATP Depletion and Calcium-Mediated Phospholipase Activation: o In ischemic cells, ATP depletion and increased cytosolic calcium activate phospholipases, leading to the breakdown of membrane phospholipids. 2. Direct Damage by External Agents: o The plasma membrane can be directly damaged by bacterial toxins, viral proteins, lytic complement components, and various physical and chemical agents. 3. Reactive Oxygen Species (ROS): o ROS cause oxidative damage to cell membranes through lipid peroxidation, and attack the lipid bilayer, leading to loss of membrane integrity. 4. Decreased Phospholipid Synthesis: o Phospholipid production may be reduced due to defective mitochondrial function or hypoxia, which decrease ATP availability and impair energy-dependent biosynthetic pathways. This reduction affects all cellular membranes, including those of mitochondria. 5. Increased Phospholipid Breakdown: o Severe cell injury leads to increased degradation of membrane phospholipids due to activation of calcium-dependent phospholipases. This breakdown produces lipid degradation products like free fatty acids, acyl carnitine, and lysophospholipids, which can act as detergents, disrupting the membrane structure and altering permeability and electrophysiological properties. 6. Cytoskeletal Abnormalities: o Cytoskeletal filaments anchor the plasma membrane to the cell interior. Proteases activated by increased cytosolic calcium can damage these tethers. In conditions  like myocardial cell swelling, this damage leads to membrane detachment from the cytoskeleton, making the membrane more prone to stretching and rupture. Consequences of Membrane Damage: 1. Mitochondrial Membrane Damage: o Damage to the mitochondrial membrane results in decreased ATP production. And mitochondrial damage which also causes the release of proteins that can trigger apoptotic cell death. 2. Plasma Membrane Damage: o Plasma membrane damage disrupts osmotic balance, leading to the influx of fluids and ions, and the loss of cellular contents. This also includes the leakage of metabolites essential for ATP production, further depleting cellular energy stores. 3. Lysosomal Membrane Damage: o Injury to lysosomal membranes causes the release of digestive enzymes into the cytoplasm. These enzymes, including RNases, DNases, proteases, phosphatases, and glucosidases, become active in the acidic environment of an injured cell, leading to the degradation of RNA, DNA, proteins, phosphoproteins, and glycogen, pushing the cell toward necrosis DNA DAMAGE AND ITS CONSEQUENCES IN CELL INJURY DNA damage is a critical factor in cell injury, activating cellular responses aimed at preserving genomic integrity or eliminating cells with irreparable damage to prevent malignancy. Here’s a detailed summary of how DNA damage impacts cellular processes: Causes of DNA Damage:  External Factors: DNA can be damaged by radiation, chemotherapeutic (anticancer) drugs, and reactive oxygen species (ROS).  Spontaneous and Aging-Related Damage: Over time, DNA damage can occur spontaneously as part of the aging process Cellular Response to DNA Damage:  Activation of p53: When DNA damage is detected, the cell activates p53, a crucial tumor suppressor protein. p53 is responsible for maintaining genomic stability by controlling the cell cycle and initiating DNA repair.  G1 Phase Arrest: p53 halts the cell cycle in the G1 phase, preventing the cell from progressing to DNA replication. This arrest gives the cell time to repair the damaged DNA before it continues through the cell cycle.