Cellular Injury and Hypoxia Basics

Cellular Injury

• Cellular injury occurs when a stress is too much for a cell to adapt to.
• Factors determining injury severity:
  • Type of stress
  • Severity of stress
  • Type of cell affected
  • Examples: Neurons are highly susceptible to ischemic injury, while skeletal muscle is more resistant; Slowly developing ischemia (e.g., renal artery atherosclerosis) causes atrophy, while acute ischemia (e.g., renal artery embolus) causes injury
• Common causes of cellular injury:
  • Inflammation
  • Nutritional deficiency or excess
  • Hypoxia
  • Trauma
  • Genetic mutations

Hypoxia

• Definition: Low oxygen delivery to tissue, a major cause of cellular injury.

• Mechanism of cellular injury:

  • Oxygen is the final electron acceptor in the electron transport chain of oxidative phosphorylation.
  • Decreased oxygen impairs oxidative phosphorylation, leading to decreased ATP production.
  • Lack of ATP (the cell's energy source) causes cellular damage.

• Causes of hypoxia:

  • Ischemia: Decreased blood flow through an organ
    • Can arise from:
      • Decreased arterial perfusion (e.g., atherosclerosis)
      • Decreased venous drainage (e.g., Budd-Chiari syndrome)
      • Shock (generalized hypotension leading to poor tissue perfusion)
  • Hypoxemia: Low partial pressure of oxygen in the blood (PaO2 < 60 mm Hg, SaO2 < 90%)
    • Can arise from:
      • High altitude (decreased barometric pressure leads to lower partial pressure of oxygen in the air)
      • Hypoventilation (increased partial pressure of carbon dioxide in the air leads to lower partial pressure of oxygen in the air)
      • Diffusion defect (a thicker diffusion barrier, like interstitial pulmonary fibrosis, prevents oxygen from moving from the air into the blood as efficiently)
      • Ventilation/perfusion mismatch (blood bypasses oxygenated lung, or oxygenated air cannot reach blood)
  • Decreased oxygen-carrying capacity of blood: Hemoglobin (Hb) loss or dysfunction
    • Examples:
      • Anemia (decrease in red blood cell mass) - PaO2 and SaO2 normal
      • Carbon monoxide poisoning
        • Carbon monoxide binds hemoglobin more avidly than oxygen, PaO2 normal, SaO2 decreased
        • Exposure sources: smoke from fires, exhaust from cars or gas heaters
        • Early sign: headache, more severe exposure: coma and death
        • Classic finding: cherry-red appearance of skin
      • Methemoglobinemia
        • Iron in heme is oxidized to Fe3+, which cannot bind oxygen, PaO2 normal, SaO2 decreased.
        • Seen with oxidant stress (e.g., sulfa and nitrate drugs) or in newborns
        • Classic finding: cyanosis with chocolate-colored blood
        • Treatment: intravenous methylene blue (helps reduce Fe3+ back to Fe2+)

Reversible and Irreversible Cellular Injury

• Hypoxia disrupts cellular functions:

  • Na+-K+ pump: Sodium and water build up inside the cell
  • Ca2+ pump: Calcium builds up in the cytosol of the cell
  • Aerobic glycolysis: Switches to anaerobic glycolysis, lactic acid production results in low pH, protein denaturation, and DNA precipitation

• Initial phase of injury (reversible):

  • Hallmark: Cellular swelling
    • Cytosol swelling: loss of microvilli and membrane blebbing
    • Rough endoplasmic reticulum (RER) swelling: dissociation of ribosomes, decreased protein synthesis

• Irreversible phase of injury:

  • Hallmark: Membrane damage
    • Plasma membrane damage:
      • Cytosolic enzymes leak into the serum (e.g., cardiac troponin)
      • Increase in calcium entry into the cell
    • Mitochondrial membrane damage:
      • Loss of the electron transport chain (inner mitochondrial membrane)
      • Cytochrome c leaks into cytosol (activates apoptosis)
    • Lysosome membrane damage:
      • Hydrolytic enzymes leak into the cytosol, activated by high intracellular calcium

• End result of irreversible injury: Cell death.

Cell Injury

• Cellular injury occurs when stress exceeds the cell’s ability to adapt.
• The likelihood of injury depends on the type of stress, its severity, and the type of cell affected.
  • Neurons are highly susceptible to ischemic injury, while skeletal muscle is relatively more resistant.
  • Slowly developing ischemia results in atrophy, whereas acute ischemia leads to injury.
• Common causes of cellular injury include inflammation, nutritional deficiency or excess, hypoxia, trauma, and genetic mutations.

Hypoxia

• Low oxygen delivery to tissue, a significant cause of cellular injury.
  • Oxygen is the final electron acceptor in the electron transport chain of oxidative phosphorylation.
  • Decreased oxygen impairs oxidative phosphorylation, resulting in decreased ATP production.
  • Lack of ATP (essential energy source) leads to cellular injury.
• Causes of hypoxia: ischemia, hypoxemia, and decreased O2-carrying capacity of blood.
• Ischemia is decreased blood flow through an organ.
  • Decreased arterial perfusion (e.g., atherosclerosis)
  • Decreased venous drainage (e.g., Budd-Chiari syndrome)
  • Shock - generalized hypotension resulting in poor tissue perfusion.

Hypoxemia

• Low partial pressure of oxygen in the blood (Pao2 < 60 mm Hg, Sao2 < 90%).
  • High altitude - Decreased barometric pressure results in decreased PAo2.
  • Hypoventilation - Increased PAco2 results in decreased PAo2.
  • Diffusion defect - PAo2 not able to push as much O2 into the blood due to a thicker diffusion barrier (e.g., interstitial pulmonary fibrosis).
  • 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).

Decreased O2-carrying capacity

• Arises with hemoglobin (Hb) loss or dysfunction.
  • Anemia (decrease in RBC mass) - Pao2 normal; Sao2 normal.
  • Carbon monoxide poisoning
    • CO binds hemoglobin more avidly than oxygen - Pao2 normal; Sao2 decreased.
    • Exposures include smoke from fires and exhaust from cars or gas heaters.
    • Classic finding is cherry-red appearance of skin.
    • Early sign of exposure is headache; significant exposure leads to coma and death.
  • Methemoglobinemia
    • Iron in heme is oxidized to Fe3+, which cannot bind oxygen - Pao2 normal; Sao2 decreased.
    • Seen with oxidant stress (e.g., sulfa and nitrate drugs) or in newborns.
    • Classic finding is cyanosis with chocolate-colored blood.
    • Treatment is intravenous methylene blue, which helps reduce Fe2+ back to the Fe2+ state.

Reversible and Irreversible Cellular Injury

• Hypoxia impairs oxidative phosphorylation resulting in decreased ATP.

• Low ATP disrupts key cellular functions:

  • Na+-K+ pump, resulting in sodium and water buildup in the cell.
  • Ca2+ pump, resulting in Ca2+ buildup in the cytosol of the cell.
  • Aerobic glycolysis, resulting in a switch to anaerobic glycolysis. Lactic acid buildup results in low pH, which denatures proteins and precipitates DNA.

• The initial phase of injury is reversible.

  • The hallmark of reversible injury is cellular swelling.
    • Cytosol swelling results in loss of microvilli and membrane blebbing.
    • Swelling of the rough endoplasmic reticulum (RER) results in dissociation of ribosomes and decreased protein synthesis.

• Eventually, the damage becomes irreversible.

  • The hallmark of irreversible injury is membrane damage.
    • Plasma membrane damage:
      • Cytosolic enzymes leaking into the serum (e.g., cardiac troponin).
      • Additional calcium entering into the cell.
    • Mitochondrial membrane damage:
      • Loss of the electron transport chain (inner mitochondrial membrane).
      • Cytochrome c leaking into cytosol (activates apoptosis).
    • Lysosome membrane damage results in hydrolytic enzymes leaking into the cytosol, which, in turn, are activated by the high intracellular calcium.

• The end result of irreversible injury is cell death.

Cellular Injury

• Cellular injury happens when stress exceeds the cell's ability to adapt.
• The likelihood of injury depends on the type of stress, its severity, and the kind of cell.
• Neurons are highly susceptible to ischemic injury while skeletal muscle is more resistant.
• Slowly developing ischemia leads to atrophy, while acute ischemia results in injury.
• Common causes of cellular injury include inflammation, nutritional deficiencies or excess, hypoxia, trauma, and genetic mutations.

Hypoxia

• Low oxygen delivery to tissue is a critical cause of cellular injury.
• Oxygen is the final electron acceptor in the electron transport chain of oxidative phosphorylation.
• Decreased oxygen impairs oxidative phosphorylation, leading to decreased ATP production.
• Lack of ATP disrupts critical cellular functions, causing cell injury.

Causes of Hypoxia

• Ischemia: Decreased blood flow through an organ.
  • Decreased arterial perfusion (e.g., atherosclerosis).
  • Decreased venous drainage (e.g., Budd-Chiari syndrome).
  • Shock: Generalized hypotension resulting in poor tissue perfusion.
• Hypoxemia: Low partial pressure of oxygen in the blood (Pao2 < 60 mm Hg, Sao2 < 90%).
  • High altitude: Decreased barometric pressure reduces PAo2.
  • Hypoventilation: Increased PAco2 reduces PAo2.
  • Diffusion defect: PAo2 struggles to push oxygen into the blood due to a thicker diffusion barrier (e.g., interstitial pulmonary fibrosis).
  • V/Q mismatch: Blood bypasses oxygenated lung (circulation problem, e.g., right-to-left shunt) or oxygenated air can't reach blood (ventilation problem, e.g., atelectasis).
• Decreased O2-carrying capacity arises with hemoglobin (Hb) loss or dysfunction.
  • Anemia: Decreased red blood cell mass. Pao2 and Sao2 are normal.
  • Carbon monoxide poisoning: Carbon monoxide binds hemoglobin more avidly than oxygen. Pao2 is normal, but Sao2 is decreased.
    • Classic finding is a cherry-red appearance of the skin.
    • Early sign of exposure is headache; significant exposure leads to coma and death.
  • Methemoglobinemia: Iron in heme is oxidized to Fe3+, which cannot bind oxygen. Pao2 is normal, but Sao2 is decreased.
    • Seen with oxidant stress (e.g., sulfa and nitrate drugs) or in newborns.
    • Classic finding is cyanosis with chocolate-colored blood.
    • Treatment is intravenous methylene blue, which helps reduce Fe2+ back to Fe2+ state.

Reversible and Irreversible Cellular Injury

• Hypoxia impairs oxidative phosphorylation, resulting in decreased ATP.
• Low ATP disrupts critical cellular functions.
  • Na+-K+ pump: Leads to sodium and water buildup in the cell.
  • Ca2+ pump: Results in Ca2+ buildup in the cytosol of the cell.
  • Aerobic glycolysis: This shifts to anaerobic glycolysis, leading to lactic acid buildup which lowers pH, denatures proteins, and precipitates DNA.

Reversible Injury

• The initial phase of injury is reversible.
• The hallmark of reversible injury is cellular swelling.
  • Cytosol swelling causes loss of microvilli and membrane blebbing.
  • Swelling of the rough endoplasmic reticulum (RER) results in dissociation of ribosomes and decreased protein synthesis.

Irreversible Injury

• Eventually, the damage becomes irreversible.
• The hallmark of irreversible injury is membrane damage.
  • Plasma membrane damage leads to:
    • Cytosolic enzymes leaking into the serum (e.g., cardiac troponin).
    • Additional calcium entering the cell.
  • Mitochondrial membrane damage results in:
    • Loss of the electron transport chain (inner mitochondrial membrane).
    • Cytochrome c leaking into the cytosol (activates apoptosis).
  • Lysosome membrane damage causes hydrolytic enzymes to leak into the cytosol, which are activated by the high intracellular calcium.

Cell Death

• The end result of irreversible injury is cell death.

Cellular Injury

• Cell injury occurs when stress exceeds the cell's ability to adapt.
• The type and severity of stress and the type of cell determine injury likelihood.
  • Neurons are highly susceptible to ischemic injury, while skeletal muscle is more resistant.
  • Slow ischemia leads to atrophy, while acute ischemia results in injury.
• Common causes of cellular injury include inflammation, nutritional deficiency or excess, hypoxia, trauma, and genetic mutations.

Hypoxia

• Low oxygen delivery to tissue is a significant cause of cellular injury.
  • Oxygen is the final electron acceptor in oxidative phosphorylation.
  • Reduced oxygen impairs oxidative phosphorylation, leading to decreased ATP production.
  • Lack of ATP causes cellular injury.
• Hypoxia can result from ischemia, hypoxemia, or decreased oxygen-carrying capacity of the blood.

Ischemia

• Ischemia is reduced blood flow through an organ.
• It can arise from:
  • Decreased arterial perfusion (e.g., atherosclerosis)
  • Reduced venous drainage (e.g., Budd-Chiari syndrome)
  • Shock - generalized hypotension resulting in poor tissue perfusion

Hypoxemia

• Hypoxemia is a low partial pressure of oxygen in the blood (PaO2 < 60 mm Hg, SaO2 < 90%).
• It can arise from:
  • High altitude - Decreased barometric pressure lowers PAO2
  • Hypoventilation - Increased PAco2 lowers PAO2
  • Diffusion defect - Thicker diffusion barrier (e.g., interstitial pulmonary fibrosis) hinders oxygen transfer from alveoli to blood.
  • V/Q mismatch - Blood bypasses oxygenated lung (circulation problem) or oxygenated air cannot reach blood (ventilation problem).

Decreased O2-carrying Capacity

• Decreased oxygen-carrying capacity occurs with hemoglobin loss or dysfunction.
• Examples include:
  • Anemia (reduced RBC mass) - PaO2 normal; SaO2 normal
  • Carbon monoxide poisoning
    • CO binds to hemoglobin more avidly than oxygen - PaO2 normal; SaO2 decreased.
    • Exposures include smoke from fires and exhaust from cars or gas heaters.
    • Cherry-red skin appearance is a classic finding.
    • Early sign of exposure is headache; significant exposure leads to coma and death.
  • Methemoglobinemia
    • Iron in heme is oxidized to Fe3+, which cannot bind oxygen - PaO2 normal; SaO2 decreased.
    • Seen with oxidant stress (e.g., sulfa and nitrate drugs) or in newborns.
    • Cyanosis with chocolate-colored blood is a classic finding.
    • Treatment is intravenous methylene blue, which helps reduce Fe3+ back to Fe2+ state.

Reversible and Irreversible Cellular Injury

• Hypoxia disrupts oxidative phosphorylation, decreasing ATP production.
• Low ATP affects key cellular functions, leading to:
  • Sodium and water buildup in the cell due to disruption in Na+-K+ pump
  • Calcium buildup in the cytosol of the cell due to Ca2+ pump disruption
  • Switch to anaerobic glycolysis, causing lactic acid buildup and lowering pH, which denatures proteins and precipitates DNA.

Reversible Injury

• The initial phase of injury is reversible.
• Cellular swelling is the hallmark of reversible injury.
  • Cytosol swelling results in loss of microvilli and membrane blebbing
  • Rough endoplasmic reticulum (RER) swelling disrupts ribosomes and decreases protein synthesis.

Irreversible Injury

• Once the damage becomes irreversible, it results in membrane damage.
• The hallmark of irreversible injury is membrane damage:
  • Plasma membrane damage leads to:
    • Cytosolic enzymes leaking into the serum (e.g., cardiac troponin)
    • Additional calcium entering the cell
  • Mitochondrial membrane damage results in:
    • Loss of the electron transport chain (inner mitochondrial membrane)
    • Cytochrome c leaking into cytosol (activates apoptosis)
  • Lysosome membrane damage releases hydrolytic enzymes into the cytosol, which are activated by high intracellular calcium.

Cell Death

• Irreversible injury ultimately leads to cell death.

Cellular Injury

• When stress exceeds a cell's ability to adapt, cellular injury occurs.
• The likelihood of injury depends on the type of stress, its severity, and the cell type.
• Neurons are very vulnerable to ischemic injury, while skeletal muscle is more resistant.
• Slow developing ischemia (e.g., renal artery atherosclerosis) results in atrophy, whereas acute ischemia (e.g., renal artery embolus) results in injury.
• Common causes of cellular injury include inflammation, nutritional deficiency or excess, hypoxia, trauma, and genetic mutations.

Hypoxia

• Low oxygen delivery to tissue is an important cause of cellular injury.
• Oxygen is essential for the electron transport chain in oxidative phosphorylation.
• Decreased oxygen impairs oxidative phosphorylation, leading to decreased ATP production.
• Lack of ATP disrupts cellular function.
• Causes of hypoxia include ischemia, hypoxemia, and decreases oxygen-carrying capacity of blood.

Ischemia

• Ischemia is reduced blood flow to an organ.
• It can arise from decreased arterial perfusion (e.g., atherosclerosis), decreased venous drainage (e.g., Budd-Chiari syndrome), and shock, which is generalized hypotension resulting in poor tissue perfusion.

Hypoxemia

• Hypoxemia is a low partial pressure of oxygen in the blood (Pao2 < 60 mm Hg, Sao2 < 90%).
• It arises from:
  • High altitude - Decreased barometric pressure results in decreased PAo2
  • Hypoventilation - Increased PAco2 results in decreased PAo2
  • Diffusion defect - PAo2 struggles to push O2 into the blood due to a thicker diffusion barrier (e.g., interstitial pulmonary fibrosis)
  • 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).

Decreased O2-Carrying Capacity

• This arises with hemoglobin (Hb) loss or dysfunction.
• Examples include:
  • Anemia (decrease in RBC mass)-Pao2 normal; Sao2 normal
  • Carbon monoxide poisoning
    • CO binds hemoglobin more avidly than oxygen-Pao2 normal; Sao2 decreased
    • Exposures include smoke from fires and exhaust from cars or gas heaters.
    • Classic finding is cherry-red appearance of skin.
    • Early sign of exposure is headache; significant exposure leads to coma and death.
  • Methemoglobinemia
    • Iron in heme is oxidized to Fe3+, which cannot bind oxygen-Pao2 normal; Sao2 decreased
    • Seen with oxidant stress (e.g., sulfa and nitrate drugs) or in newborns
    • Classic finding is cyanosis with chocolate-colored blood.
    • Treatment is intravenous methylene blue, which helps reduce Fe2+ back to Fe2+state.

Reversible and Irreversible Cellular Injury

• Hypoxia impairs oxidative phosphorylation resulting in decreased ATP.
• Low ATP disrupts key cellular functions, including:
  • Na+-K+pump, resulting in cellular sodium and water buildup.
  • Ca 2+pump, resulting in Ca2+ buildup in the cytosol.
  • Aerobic glycolysis, resulting in a switch to anaerobic glycolysis. Lactic acid buildup results in low pH, which denatures proteins and precipitates DNA.
• The initial phase of injury is reversible. The hallmark of reversible injury is cellular swelling.
  • Swelling of the cytosol results in the loss of microvilli and membrane blebbing.
  • Swelling of the rough endoplasmic reticulum (RER) results in dissociation of ribosomes and decreased protein synthesis.
• Eventually, the damage becomes irreversible. The hallmark of irreversible injury is membrane damage.
  • Plasma membrane damage results in:
    • Cytosolic enzymes leaking into the serum (e.g., cardiac troponin)
    • Additional calcium entering the cell
  • Mitochondrial membrane damage results in:
    • Loss of the electron transport chain (inner mitochondrial membrane)
    • Cytochrome c leaking into the cytosol (activates apoptosis).
  • Lysosome membrane damage results in hydrolytic enzymes leaking into the cytosol, which are then activated by the high intracellular calcium.
• The end result of irreversible injury is cell death.