2.2 Mechanisms of Cellular Injury

Cellular injury is a fundamental concept in understanding disease processes. From hypoxia to chemical agents, various factors can disrupt cellular function, leading to cascading effects throughout the body. These mechanisms of injury form the basis for many pathological conditions.

Exploring cellular injury reveals how cells respond to stress and damage. Understanding these processes is crucial for grasping how diseases develop and progress, as well as for developing targeted therapeutic approaches to prevent or mitigate cellular damage.

Causes and Mechanisms of Cellular Injury

Causes of cellular injury

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• Hypoxia starves cells of oxygen disrupts aerobic metabolism often stems from reduced blood flow (ischemia), anemia, or respiratory disorders (COPD)

• Physical agents damage cells through mechanical force (blunt trauma), extreme temperatures (burns, frostbite), or ionizing radiation (X-rays, gamma rays)

• Chemical agents disrupt cellular processes include environmental toxins (mercury), therapeutic drugs (chemotherapy agents), and pollutants (air particulates)

• Biological agents invade and harm cells encompass viruses (influenza), bacteria (Streptococcus), parasites (malaria), and fungi (Candida)

Pathophysiology of hypoxic injury

• Reduced oxygen availability impairs aerobic respiration decreases ATP production forces cells to rely on less efficient anaerobic metabolism

• Anaerobic metabolism activation increases lactic acid production leads to cellular acidosis disrupts enzyme function and protein structure

• Ion pump dysfunction occurs as sodium-potassium ATPase fails causes intracellular sodium accumulation results in cell swelling (cytotoxic edema)

• Mitochondrial damage disrupts electron transport chain further reduces ATP synthesis compromises cellular energy supply

• Calcium homeostasis disruption increases intracellular calcium levels activates degradative enzymes (phospholipases, proteases) damages cellular structures

• Cellular death pathways activate:

  1. Apoptosis initiates in less severe cases controlled cell death
  2. Necrosis occurs in severe hypoxia uncontrolled cell rupture triggers inflammation

Cellular Injury Mechanisms and Consequences

Free radicals and oxidative stress

• Free radicals highly reactive molecules with unpaired electrons produced by normal metabolism (mitochondrial respiration) and environmental factors (UV radiation)

• Oxidative stress occurs when free radical production overwhelms antioxidant defenses damages lipids (cell membranes), DNA (mutations), and proteins (enzyme dysfunction)

• Antioxidant defense mechanisms protect against oxidative damage:

  • Enzymatic antioxidants neutralize specific free radicals (superoxide dismutase, catalase, glutathione peroxidase)
  • Non-enzymatic antioxidants scavenge various free radicals (vitamin C, vitamin E, glutathione)

• Cellular adaptations to oxidative stress include upregulating antioxidant enzymes (Nrf2 pathway) and increasing synthesis of protective proteins (heat shock proteins)

Consequences of cellular damage

• Membrane damage through lipid peroxidation increases permeability disrupts selective ion transport alters cellular homeostasis

• Mitochondrial dysfunction impairs ATP production releases pro-apoptotic factors (cytochrome c) disrupts calcium homeostasis triggers cell death pathways

• Protein denaturation alters structure and function inactivates enzymes forms toxic protein aggregates (amyloid fibrils in Alzheimer's disease)

• DNA damage induces mutations (point mutations, deletions) causes strand breaks impairs gene expression affects cell division and protein synthesis

• Cellular organelle dysfunction:

  • Endoplasmic reticulum stress leads to unfolded protein response
  • Lysosomal membrane permeabilization releases hydrolytic enzymes into cytoplasm

• Cell death mechanisms activate based on injury severity:

  1. Apoptosis programmed cell death orderly cellular disassembly
  2. Necrosis uncontrolled cell death releases cellular contents triggers inflammation
  3. Autophagy cellular self-digestion can promote survival or lead to cell death

• Tissue-level consequences manifest as inflammation (acute or chronic), fibrosis (excessive scarring), and organ dysfunction (reduced functional capacity)