Cell Injury Mechanisms: Pathology Overview

• Pathology involves studying mechanisms of disease, focusing on cell injury, death, and organ system pathologies.

Causes of Cell Injury

• Hypoxia, pathogen exposure, immunologic dysfunctions, genetic mutations, chemical toxins, physical injury, nutritional imbalances, and aging are all causes of cell injury.
• Hypoxia is the most common cause; it is the lack of oxygen to cells due to ischemia, heart failure, or decreased oxygen-carrying capacity, seen in anemia.
• Pathogens cause cell injury through inherent abilities.
• Immunologic dysfunctions cause cell injury through immune conditions
• Genetic mutations can arise and cause certain conditions, even cancers.
• Aging reduces a cell's ability to respond to stress, making it more susceptible to injury.

Mechanisms of Cell Injury

• Damage to DNA, proteins, and lipid membranes can cause oxygen-derived free radicals.
• DNA damage may result from ionizing radiation and/or inflammation.
• Defense mechanisms against free radicals include antioxidants like vitamins A, C, and E, glucose-6-phosphate dehydrogenase, glutathione, superoxide dismutase, and catalase.
• ATP depletion caused by ischemia and hypoxia results in ADP dependency and disruptions of ion pumps that cause imbalances.
• In hypoxia, cells shift from aerobic to anaerobic states, utilizing anaerobic glycolysis, decreasing pH, increasing lactic acid, and reducing ATP production.
• Increased cell membrane permeability can cause severe cell injury and cell death.
• Influx of calcium via defunct calcium ion channels can enter the cell and activate internal enzymes, leading to the breakdown of cellular components.
• Mitochondrial dysfunction decreases ATP production and the release of cytochrome c, triggering apoptosis.

Free Radicals

• Free radicals are molecules with an unpaired electron in their outer orbital which steals electrons from any molecule to become stable.
• Free radicals are formed when a molecule gains or loses an electron in the body, either physiologically or pathologically.
• Cellular respiration/oxidative phosphorylation is a major physiological source of free radicals.
• Reactive oxygen species (ROS) are formed in the electron transport chain when oxygen doesn't receive all 4 electrons.
• Oxygen given one electron becomes superoxide, two electrons becomes hydrogen peroxide (H2O2), and three electrons becomes the hydroxyl radical.
• During inflammation, phagocytes like macrophages and neutrophils produce free radicals.
• NADPH oxidase in phagocytes generates superoxide ions during a respiratory burst to destroy pathogens.
• Nitric oxide synthase produces nitric oxide, which reacts with superoxide ions to form peroxy nitrite, a free radical.
• Exposure to ionizing radiation, like UV light or X-rays, converts water in tissues into hydroxyl radicals.
• Buildup of metals like copper or iron in the body results in the Fenton reaction producing hydroxyl radicals.
• Ischemia or reduced blood flow contributes to reactive oxygen species production by the mitochondria at a cellular level.
• Reperfusion, the return of blood flow to ischemic tissue, increases free radicals, causing reperfusion injury.

Defensive Mechanisms Against Free Radicals

• Antioxidants, such as vitamins A, C, and E, donate electrons to neutralize free radicals, protecting cells.
• Glutathione neutralizes hydrogen peroxide, requiring NADPH for its function.
• Glutathione reductase requires NADPH as an electron donor to reduce oxidized glutathione back into its working state.
• Glucose-6-phosphate dehydrogenase (G6PD) reduces NADP+ back to NADPH by oxidizing glucose-6-phosphate.
• Metal carrier proteins, such as transferrin (for iron) and ceruloplasmin (for copper), bind to metal ions, preventing free radical generation.
• Free radical scavenging enzymes convert free radicals into harmless substances like water.
• Superoxide dismutase converts superoxide into hydrogen peroxide.
• Catalase and glutathione peroxidase convert hydrogen peroxide into water.

Cellular Damage by Free Radicals

• When free radicals overwhelm defense mechanisms, cell damage starts to occur.
• Free radicals react with lipids in the cell membrane, causing lipid peroxidation in a chain reaction that damages the cell membrane.
• Free radicals can cause oxidative modification of proteins, affecting the function of enzymes and structural proteins.
• Oxidation of DNA can cause breaks in the DNA strands and can also induce mutations, increasing the risk of cancer.