BIOL 4680 Pathophysiology: Cell Injury and Accidental Cell Death

Definition of Pathophysiology:
- The study of the causes and mechanisms of disease.
Definition of Disease:
- The loss of homeostasis due to failure of cells or tissues to perform their normal functions.
Stages of Disease Development:
- Etiology: The cause of disease.
- Pathogenesis: The mechanism of cellular damage or injury.
- Pathological Changes: Changes to cells and tissues.
- Evidence of Cell Injury: Clinical signs and symptoms.

Causes Include:
- Ischemia/reperfusion injury.
- Toxic agents such as lung impairments, anemia, pollutants, heavy metals, drugs, household or agricultural chemicals, cellular invasion, immune responses.
- Changes in quantity or activity of proteins.
- Deficiencies: inadequate vitamins or calories; overindulgences in calories, fats, or sugar.
- Physical trauma, radiation, temperature extremes, electric shock.
Specific Terms:
- Ischemia: Inadequate blood supply to tissues.
- Hypoxia: Inadequate oxygen supply.
- Toxic Insult: Damage from reactive chemicals.
- Infectious Pathogens: Include bacteria, viruses, fungi, and parasitic protozoa.
- Immune Responses: Autoimmune disorders and chronic inflammation.
- Genetic Mutations: Can be inborn or acquired.
- Nutritional Issues: Deficiencies or overindulgences.
- Physical Events or Exposures: Various physical conditions leading to injury.

Mechanism of Cellular Damage:
- Identifying cellular targets of the injurious agent.
- Understanding affected functions and their impacts.
Cellular Response to Damage:
- Adaptation and Repair: Can lead to reversible injury.
- Cell Death: Indicates irreversible injury.
Factors Influencing Outcomes:
- The specific cause of cell injury.
- The intensity and duration of the injurious assault.
- The type of cell affected.

Reversible Injury:
- May be accompanied by a decrease in normal function.
- Adaptation by injured cells could temporarily restore function.
- Prolonged adaptive responses might lead to additional injury.
- Repair can restore function permanently if timely removal of the injurious agent occurs.
Irreversible Injury:
- Leads to cell death.

Initial Evidence:
- Decrease in normal function often presents as specific signs and symptoms relative to the tissue injured.
- Examples include localized pain, labored breathing, headache, and muscle weakness.
Secondary Evidence:
- Presence of proteins or enzymes from damaged cells in bodily fluids.
- Examples:
  - Troponin from cardiac muscle cells in blood post-heart attack.
  - Alkaline phosphatase or transglutaminases from liver post-liver damage.
  - Changes in urine volume and composition (protein, RBCs, creatinine) in kidney damage.
Morphological Evidence:
- Late-stage observation may reveal dead cells through urine or tissue examination.
- Gross or microscopic examination during post-mortem analysis can reveal changes consistent with cell death.

Forms of Cell Death:
- Historically categorized as necrosis and apoptosis.
- The type of cell death depends on the specific cause of injury, severity, duration, and cell type affected.
Nomenclature of Cell Death:
- Each type has a unique name based on specific etiology or pathogenesis.
- Most forms are regulated forms of necrosis, but some display morphological characteristics of apoptosis.
- Accidental Cell Death:
- Acute cell injury resulting in rapid uncontrolled necrosis.
- Regulated Cell Death:
- Triggered by less severe or chronic injury showing traits of both apoptosis and necrosis.

Key Features of Necrosis Include:
- Loss of ATP synthesis.
- Loss of osmotic control, leading to cell swelling.
- Loss of calcium (Ca++) homeostasis.
- Activation of proteases and other degradative enzymes.
- Organelle swelling and fragmentation.
- Chromatin changes: clumping, condensation (pyknosis), fragmentation (karyorrhexis), and dissolution (karyolysis).
- Membrane blebbing and cell lysis.
- Associated inflammation.
Nature of Necrosis:
- Characterized as an uncontrolled and rapid series of events.

Common Causes Include:
- Ischemia.
- Toxic insult.
- Infectious pathogens.
- Physical trauma.
Consequences of These Assaults:
- Damage and dysfunction of mitochondria, leading to decreased ATP production.
- Oxidative stress resulting in damage to cellular macromolecules, notably impacting phospholipids, which affects membrane integrity.

Consequences of Mitochondrial Dysfunction:
- Leads to decreased ATP synthesis impacting cellular functions and transport proteins.
- Impairment results in loss of osmotic control, cell swelling, increased intracellular Ca++, and activation of proteases and phospholipases.
- Highly aerobic cells most affected include brain, heart, and kidneys.
Injurious Agents:
- Most interfere with the electron transport chain, such as:
- Hypoxia/ischemia.
- Carbon monoxide and cyanide inhibit electron transfer to oxygen.
- Heavy metals and various toxic substances bind to components of the transport chain, obstructing electron transfer.

Production of ROS:
- Mitochondria can produce ROS during damage, reperfusion following ischemia, or exposure to toxic/reactive chemicals.
- Chemical Reactions:
- Fenton Reaction:
  - ( ext{Fe}^{3+} + - ext{OH} + ext{.OH}
    ightarrow ext{O}_2 + ext{Fe}^{2+})
- Haber-Weiss Reaction:
  - ( rac{1}{2} ext{O}2 + 2e^{-} + 2 ext{H}^{+} ightarrow ext{H}2 ext{O})
Examples of ROS Produced Include:
- Superoxide ion, hydrogen peroxide (H2O2).

Definition of Oxidative Stress:
- Occurs when reactive oxygen species bind indiscriminately to cellular macromolecules.
Role in Cell Death:
- Oxidative stress often contributes to cell death induced by mitochondrial dysfunction.

Definition:
- A cascade of free radical reactions yielding electrophilic lipid aldehydes, notably malondialdehyde.
Susceptible Components:
- Polyunsaturated fatty acids are highly susceptible to lipid peroxidation, causing membrane damage.
Relevance to Cell Death:
- Because iron is critical in this form of cell death, it is commonly termed ferroptosis.