Pathology

• During the last two lectures, we have talked about the adaptive mechanisms in response to stress, reversible and irreversible cell injury, and causes of cell injury in general.
• In this lecture, we will talk about the mechanisms, and the molecular basis of cell injury.
• Principles of cellular response, and consequences regarding injurious stimulus

  The cellular response to injury depends on: 1. The type of injury, 2. Its duration, 3. Its severity
• The consequences of an injurious stimulus depend on:

  1. The type of the cell, 2. Its status, 3. Adaptability, and genetic makeup of the injured cell
• Cell injury disrupts cellular homeostasis. Cells are injured by numerous and diverse causes (etiologic agents) from intrinsic and extrinsic sources; however, all of these causes, activate one or more biochemical mechanisms that may act together at the same time cooperating in the same scenario leading to cell injury.
• Ischemia


  Decreased blood flow to the tissue
• Hypoxia


  Decreased oxygen to the tissue
• Hypoxia can be caused by Ischemia
• Several causes can lead to the same mechanism of cell injury, ex: Hypoxia lead to ATP depletion (since oxygen is needed in ATP generation in mitochondria) then, every energy-dependent function, like protein synthesis, plasma membrane pumps, will be decreased, leading to necrosis in the end.
• Also, Immunologic disorders (ex: allergy, autoimmune disease), cause inflammation to the cell, by the high accumulation of leukocytes, generating toxic molecules, and leading to necrosis "mainly" and Apoptosis "some".
• The stimuli of cell injury with the mechanism of cell injury determine whether the cell will die by Apoptosis or by Necrosis.
• Cell


  The basic unit of which our body is made
• Mechanisms of Cell injury

  1. Hypoxia and Ischemia

  2. Oxidative stress

  3. Ischemia-Reperfusion injury

  4. Cell injury caused by Toxins
• Hypoxia


  Defective oxidative phosphorylation, failure of ATP generation, depletion of ATP in cells
• Cell components


  • Cell membrane
  • Nucleus covered with nuclear membrane
  • Mitochondria (energy factory)
  • Ribosomes (for protein production)
  • Lysosomes (contain digestive enzymes)
  • Other organelles
• Cells


  • Interact actively with their surrounding environment
  • Constantly changing to adjust their structure and function to adapt to changing demand and stress
• Depletion of energy source (ATP) in the cell

  Causes failure of energy-dependent pathways such as; plasma membrane transportation (Na+/K+ pump), protein synthesis in ribosomes, lipogenesis (production of lipids) and phospholipid turnover (degradation of phospholipids every 1-2 cell division)
• Homeostasis


  The intracellular compartments of each cell are kept within a normal range and highly regulated to remain constant
• Anaerobic Glycolysis


  A compensatory pathway of generating ATP that can help the cell to withstand hypoxia for a longer period of time, but it is less efficient than Oxidative phosphorylation, since it produces only 2 ATP molecules, and causes muscle fatigue, due to Lactic acid accumulation

  
• Every cell lives in its own homeostasis and will try to keep it
• Cell response to increasing demands or injurious stimuli

  1. Adaptation

  2. Reversible cell injury

  3. Irreversible cell injury (cell death)
• Reversible cell injury


  The cell can go back to normal when the injury disappears
• Irreversible cell injury


  The point of no return, the cell can't go back to normal
• Cell injury is a crucial and basic element in any disease process
• Effects of hypoxia on cells

  • Reduced activity of membrane ATP-dependent sodium pumps, sodium and water accumulation inside the cell, cellular swelling
  • Lactic acid accumulation, decreased PH, failure of enzymes in the cell
  • Disruption of the ribosomes from the RER membrane, decreased protein synthesis
  • Accumulation of ROS, damage to mitochondrial and lysosomal membranes and leakage of destructive lysosomal enzymes to the cytosol of the cell
  • Leading to necrosis

  
• Types of adaptation


  • Physiologic adaptations
  • Pathologic adaptations
• Forms of adaptation


  • Increase in cell size
  • Increase in number of cells
  • Decrease in cell size
  • Change into another type of cell
• Adaptation to stress can progress to cell injury if the stress is not relieved
• Oxidative stress


  Cellular abnormalities induced by ROS (free radicals), which are chemical species with single unpaired electron (extremely unstable, and have high energy), that if the they bind to any organic/inorganic molecule, they will convert them to a free radical too, and they will induce damage to cellular proteins/lipids and nucleic acids

  
• Adaptive mechanisms


  • Hypertrophy
  • Hyperplasia
  • Metaplasia
  • Atrophy
• When are ROS generated

  • Chemical substance injury (CCl4)
  • Radiation injury (UV, Xray)
  • Hypoxia
  • Cellular aging
  • Inflammation
  • Ischemia-reperfusion injury
• Hypertrophy


  Increased in cell size and functional capacity
• Hypochlorite


  Bleaching agent, we use at home as a microbicidal agent that can kill a bacterium and often microbes
• Types of hypertrophy


  • Pure (in organs/cells with limited capacity to divide)
  • Mixed (in cells/tissues that can divide)
• Generation and Production of ROS

  1. Normally produced in small amounts in all cells during the redox reactions, in the mitochondria when oxygen is reduced to produce water

  2. Produced in phagocytic leukocytes (neutrophils and macrophages) during inflammation, in an attempt to kill the microbe or to phagocytose the bacteria by phagosomes and phagolysosomes

  
• Mechanism of hypertrophy


  Increase the production of structural proteins and organelles
• Causes of hypertrophy


  • Hormonal stimulation
  • Growth factor stimulation
  • Increased functional demand
• Pathologic hypertrophy


  • Hypertrophy of cardiac muscles in response to hypertension or aortic valve stenosis
• Mechanisms of removing free radicals

  • Decay spontaneously
  • Superoxide dismutase, (catalyzes the conversion: O2•into H2O2)
  • Glutathione (GSH) peroxidases (mostly GSH type 1), (catalyzes the conversion: H2O2into water)
  • Catalase (one of most active enzymes known, also contributes in catalyzing the previous reaction)
  • Endogenous or Exogenous anti-oxidants (e.g., vitamins E, A and C and β-Carotene), antioxidants either block free radicals' production or scavenge them as soon as they are produced
• Physiologic hypertrophy


  • Smooth muscles of uterus in response to estrogenic stimulation during pregnancy
  • Skeletal muscles of athletes