Cell Injury and Pathology

• Pathology involves studying the causes and mechanisms of disease at a cellular level.
• Cell injury can lead to cell death and pathology in different organ systems.

Causes of Cell Injury

• Hypoxia: Lack of oxygen to cells can be due to ischemia, heart failure, or decreased oxygen-carrying capacity (anemia).
• Pathogens: Infectious agents that cause cell damage.
• Immunologic Dysfunctions: Immune system disorders lead to cell injury.
• Genetic Mutations: Mutations in genes lead to various diseases, including cancer.
• Chemical Toxins: Exposure to harmful chemicals damages cells.
• Physical Injury: Trauma causes cell damage.
• Nutritional Imbalances: Deficiencies or excesses of nutrients (vitamins) can harm cells.
• Aging: Reduced ability of cells to respond to stress, making them more prone to injury.

Mechanisms of Cell Injury

• Damage to DNA, proteins, and lipid membranes can result in the formation of oxygen-derived free radicals.
• Focus on oxygen-derived free radicals like reactive oxygen species (ROS) that are always high yield on any examination. - Damage to DNA can be caused by ionizing radiation and/or inflammation.
• Protective factors against free radicals include antioxidants (vitamins A, C, and E), glucose-6-phosphate dehydrogenase, glutathione, superoxide dismutase, and catalase.
• ATP depletion from ischemia and hypoxia leads to ADP dependency and ion pump disruptions, causing imbalances.
• Hypoxia shifts cells from aerobic to anaerobic metabolism, decreasing cell pH, increasing lactic acid, and reducing ATP production.
• Increased cell membrane permeability allows influx of calcium. - Calcium activates enzymes, including proteases (break down proteins), ATPases (deplete ATP), phospholipases (injure the cell membrane), and endonucleases (damage DNA).
• Mitochondrial dysfunction decreases ATP production and releases cytochrome c, triggering apoptosis (cell suicide).

Free Radicals

• Molecules with an unpaired electron in their outer orbital that steal electrons from other molecules to become stable.
• Free radicals are formed physiologically as part of normal metabolic processes or pathologically due to disease.
  • Physiological Sources: - Cellular respiration (oxidative phosphorylation) in mitochondria. - Reactive oxygen species (ROS) are formed when oxygen does not receive all four electrons. - Superoxide: Oxygen gains one electron. - Hydrogen peroxide (H2O2): Oxygen gains two electrons. - Hydroxyl radical: Oxygen gains three electrons.
  • Pathological Sources: - Inflammation: Phagocytes (macrophages, neutrophils) generate free radicals to destroy pathogens. - Respiratory Burst: NADPH oxidase is activated by lysosomal enzymes, causing NADPH to oxidize and produce superoxide ions. - Nitric oxide synthase produces nitric oxide, which reacts with superoxide ions to form peroxynitrite. - Ionizing Radiation: Radiation (UV light, X-rays) converts water in tissues into hydroxyl radicals. - Metals (Copper/Iron): Excess iron (e.g., hemochromatosis) reacts with hydrogen peroxide to produce hydroxyl radicals via the Fenton reaction. - Ischemia/Reperfusion Injury: Reintroduction of blood flow to ischemic tissue results in more free radical production and cell damage. - Chemical Metabolism: Metabolism of drugs (e.g., acetaminophen) by the liver generates free radicals.

Defense Mechanisms Against Free Radicals

• Antioxidants: - Vitamins A, C, and E neutralize free radicals by donating electrons. - Glutathione: Neutralizes hydrogen peroxide and requires NADPH to function. - Glucose-6-Phosphate Dehydrogenase (G6PD): Reduces NADP+ back to NADPH to regenerate glutathione.
• Metal Carrier Proteins: - Bind metal ions to prevent free radical formation (e.g., transferrin for iron, ceruloplasmin for copper).
• Free Radical Scavenging Enzymes: - Superoxide Dismutase: Converts superoxide into hydrogen peroxide. - Catalase: Converts hydrogen peroxide into water in peroxisomes. - Glutathione Peroxidase: Converts hydrogen peroxide into water in the cytoplasm.

Consequences of Free Radical Damage

• Lipid Peroxidation: Free radicals damage lipids in the cell membrane, causing membrane instability and cell leakage.
  • Hydroxyl radicals ( OH) can attack lipids in the cell membrane.
  • PUFAs (polyunsaturated fatty acids) are most susceptible because they contain double bonds.
  • Lipid peroxidation leads to: - Membrane instability - Disrupted cell signaling - Cell leakage
  • Can contribute to inflammatory processes.
  • Role in diseases such as atherosclerosis, neurodegenerative diseases like Alzheimer's, and liver diseases.
• Protein Oxidation: Free radicals cause oxidative modification of proteins, affecting the function of enzymes and structural proteins.
• DNA Oxidation: Free radicals damage DNA, causing strand breaks and mutations that increase the risk of cancer. - Common form of oxidative DNA damage is the modification of bases, such as guanine, into 8-oxoguanine, which results in errors during DNA replication. - DNA oxidation is mutagenic and can lead to cancer - Mutations accumulate over time, especially if they are not repaired properly by the cell’s DNA repair machinery. - DNA damage can also lead to accelerated aging

How Damage to Cell Structures contribute to disease

• Lipid Peroxidation: Damage to the cell membrane causes weakens the cell's function and structural integrity, and it can also contribute to inflammatory processes,

• DNA Oxidation: When the DNA is oxidized, mutations can accumulate and if they affect critical genes, they can lead to diseases like cancer.

• Protective Mechanisms: - Antioxidant enzymes like superoxide dismutase, catalase, and glutathione peroxidase neutralize free radicals. - Antioxidants like vitamins A, C, and E play important roles in scavenging ROS and preventing lipid peroxidation and DNA oxidation - DNA Repair: Cells have DNA repair systems, like base excision repair (BER) and nucleotide excision repair (NER), that recognize and fix oxidative DNA damage before it leads to mutations.

• Antioxidant enzymes work against free radicals to prevent cellular damage.

• Understanding these mechanisms helps in understanding the pathogenesis of many diseases.