Growth Adaptations, Cellular Injury, and Cell Death PDF

Www.Medicalstudyzone.com Growth Adaptations, Cellular Injury, and Cell Death 3 CELLULAR INJURY I. BASIC PRINCIPLES A. Cellular injury occurs when a stress e...

Www.Medicalstudyzone.com Growth Adaptations, Cellular Injury, and Cell Death 3 CELLULAR INJURY I. BASIC PRINCIPLES A. Cellular injury occurs when a stress exceeds the cell's ability to adapt. B. The likelihood of injury depends on the type of stress, its severity, and the type of cell affected. 1. Neurons are highly susceptible to ischemic injury; whereas, skeletal muscle is relatively more resistant. 2. Slowly developing ischemia (e.g., renal artery atherosclerosis) results in atrophy; whereas, acute ischemia (e.g., renal artery embolus) results in injury. C. Common causes of cellular injury include inflammation, nutritional deficiency or excess, hypoxia, trauma, and genetic mutations. II. HYPOXIA A. Low oxygen delivery to tissue; important cause of cellular injury 1. Oxygen is the final electron acceptor in the electron transport chain of oxidative phosphorylation. 2. Decreased oxygen impairs oxidative phosphorylation, resulting in decreased ATP production. 3. Lack of ATP (essential energy source) leads to cellular injury. B. Causes of hypoxia include ischemia, hypoxemia, and decreased O2-carrying capacity of blood. C. Ischemia is decreased blood flow through an organ. Arises with 1. Decreased arterial perfusion (e.g., atherosclerosis) 2. Decreased venous drainage (e.g., Budd-Chiari syndrome) 3. Shock - generalized hypotension resulting in poor tissue perfusion D. Hypoxemia is a low partial pressure of oxygen in the blood (Pao2 < 60 mm Hg, Sao2 < 90%). Arises with 1. High altitude - Decreased barometric pressure results in decreased PAo2 2. Hypoventilation - Increased PAco2 results in decreased PAo2 3. Diffusion defect - PAo2 not able to push as much O2 into the blood due to a thicker diffusion barrier (e.g., interstitial pulmonary fibrosis) 4. V/Q mismatch - Blood bypasses oxygenated lung (circulation problem, e.g., right- to-left shunt), or oxygenated air cannot reach blood (ventilation problem, e.g., atelectasis). E. Decreased O2-carrying capacity arises with hemoglobin (Hb) loss or dysfunction. Examples include 1. Anemia (decrease in RBC mass)-Pao2 normal; Sao2 normal 2. Carbon monoxide poisoning Fig. 1.3 Keratomalacia. (Courtesy of Fig.1.4 Myositis Ossificans. (Reprinted with motherchildnutrition.org) permission from orthopaedia.com)  Www.Medicalstudyzone.com 4 FUNDAMENTALS OF PATHOLOGY i. CO binds hemoglobin more avidly than oxygen-Pao2 normal; Sao2 decreased ii. Exposures include smoke from fires and exhaust from cars or gas heaters. iii. Classic finding is cherry-red appearance of skin. iv. Early sign of exposure is headache; significant exposure leads to coma and death. 3. Methemoglobinemia i. Iron in heme is oxidized to Fe3+, which cannot bind oxygen-Pao2 normal; Sao2 decreased ii. Seen with oxidant stress (e.g., sulfa and nitrate drugs) or in newborns iii. Classic finding is cyanosis with chocolate-colored blood. iv. Treatment is intravenous methylene blue, which helps reduce Fe2+ back to Fe2+state. III. REVERSIBLE AND IRREVERSIBLE CELLULAR INJURY A. Hypoxia impairs oxidative phosphorylation resulting in decreased ATP. B. Low ATP disrupts key cellular functions including 1. Na+-K+pump, resulting in sodium and water buildup in the cell 2. Ca 2+pump, resulting in Ca2+ buildup in the cytosol of the cell 3. Aerobic glycolysis, resulting in a switch to anaerobic glycolysis. Lactic acid buildup results in low pH, which denatures proteins and precipitates DNA. C. The initial phase of injury is reversible. The hallmark of reversible injury is cellular swelling. 1. Cytosol swelling results in loss of microvilli and membrane blebbing. 2. Swelling of the rough endoplasmic reticulum (RER) results in dissociation of ribosomes and decreased protein synthesis. D. Eventually, the damage becomes irreversible. The hallmark of irreversible injury is membrane damage. 1. Plasma membrane damage results in i. Cytosolic enzymes leaking into the serum (e.g., cardiac troponin) ii. Additional calcium entering into the cell 2. Mitochondrial membrane damage results in i. Loss of the electron transport chain (inner mitochondrial membrane) ii. Cytochrome c leaking into cytosol (activates apoptosis) 3. Lysosome membrane damage results in hydrolytic enzymes leaking into the cytosol, which, in turn, are activated by the high intracellular calcium. E. The end result of irreversible injury is cell death. Fig. 1.5 Coagulative necrosis of kidney. A, Gross appearance. B, Microscopic appearance. C, Normal kidney histology for comparison. (A, Courtesy of Aliya Husain, MD)