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Inflammatory cascade

Brief

  1. Initiation phase
  • Stimulus:
    • Infection (bacteria, viruses, fungi).
  • Activation of Innate immune cells
    • Mainly macrophages
    • Host immune cells have pattern recognition receptors
      • PAMPs and DAMPs
    • Release of proinflammatory mediators
      • Cytokines - TNF alpha, Interferon- gama, IL-1, IL- 6, IL-8
      • Prostaglandins and leukotrienes
      • Histamine (from mast cells): Increases vascular permeability and vasodilation.
  1. Amplification phase
  • Vascular
    • Vasodilation: Increased blood flow (hyperemia) leads to redness and warmth.
    • Increased Vascular Permeability: Leakage of protein-rich fluid (exudate) into the interstitial space causes swelling (edema).
    • Stasis: Slowing of blood flow in capillaries facilitates leukocyte recruitment.
  • Cellular
    • Leukocyte Recruitment: Margination, adhesion, transmigration and chemotaxis
    • Leukocyte Activation: Neutrophils and macrophages become activated, enhancing their ability to phagocytose pathogens and secrete inflammatory mediators (e.g., IL-1, IL-6, TNF-α)
  • Systemic effects
    • Fever - IL-1, TNF-alpha
    • Stress hormones - cytokines
    • RAAS system
    • Activation of Complement cascade
    • Acute phase reactants - CRP, fibrinogen amyloid A
    • Metabolic - hyperglycaemia and insulin resistance
  1. Resolution
  • CARS - compensatory anti-inflammatory response
  • Inflammation subsides after the threat is neutralized:
  • Anti-inflammatory mediators (e.g., IL-4, IL-10, TGF-β) dampen the immune response.
  1. Transition to Sepsis
  • Proinflammatory mediators exceed the boundaries of the local environment
  • This is due to:
    • Endothelial damage and dysfunction
    • Microcirculatory Dysfunction
    • Cellular Energy Failure
    • Proinflammatory factors
    • Translocation of gut bacteria
  • This leads to
    • Progressive Organ Failure
      • Initial damage to one organ increases the risk of dysfunction in others through systemic effects

More detail

1. Initiation phase

  • Stimulus:
    • Infection (bacteria, viruses, fungi).
    • Tissue injury (trauma, ischemia, toxins).
    • Immune reactions (allergies, autoimmune conditions)
  • Activation of Innate immune cells
    • Mainly macrophages - recognise and bind microbial parts or injured tissue
      • Host immune cells have pattern recognition receptors - PRR
        • Pathogen associated molecular patterns (PAMPs) on pathogenic toxins, pathogenic DNA etc
        • Danger associated molecular patterns (DAMPs) on injured tissues E.g heat shock protein
  • Release of proinflammatory mediators
    • Cytokines - TNF alpha, Interferon- gama, IL-1, IL- 6, IL-8
    • Prostaglandins and leukotrienes - Amplify inflammation.
    • Histamine (from mast cells): Increases vascular permeability and vasodilation.

2. Amplification phase

  • Vascular Phase
    • Vasodilation: Increased blood flow (hyperemia) leads to redness and warmth.
    • Increased Vascular Permeability: Leakage of protein-rich fluid (exudate) into the interstitial space causes swelling (edema).
    • Stasis: Slowing of blood flow in capillaries facilitates leukocyte recruitment.
  • Cellular Phase
    • Leukocyte Recruitment: Margination, adhesion, transmigration and chemotaxis
    • Leukocyte Activation: Neutrophils and macrophages become activated, enhancing their ability to phagocytose pathogens and secrete inflammatory mediators (e.g., IL-1, IL-6, TNF-α)
  • Systemic effects
    • Fever - IL-1, TNF-alpha
    • Stress hormones - cytokines
    • RAAS system
    • Activation of Complement cascade
    • Bone marrow response - increased WBC
    • Acute phase reactants - CRP, fibrinogen amyloid A
    • Metabolic - hyperglycaemia and insulin resistance

3. Resolution

  • CARS - compensatory anti-inflammatory response
  • Inflammation subsides after the threat is neutralized:
    • Anti-inflammatory mediators (e.g., IL-4, IL-10, TGF-β) dampen the immune response.
  • Repair processes (angiogenesis, fibroblast activity) restore tissue integrity

4. Transition to Sepsis

  • Proinflammatory mediators exceed the boundaries of the local environment
    • Concepts → malignant intravascular inflammation
      • Malignant - uncontrolled, unregulated and self sustaining
      • Intravascular - haematogenous mediator spread
      • Inflammatory - exaggerated normal inflammatory response
  • This is due to:
    • Endothelial damage and dysfunction
      • Increased vascular permeability, edema, and impaired blood flow.
      • Leads to fluid loss and decreased oxygen delivery
    • Microcirculatory Dysfunction
      • Inflammatory mediators disrupt the balance between oxygen delivery and consumption.
      • Leads to tissue ischemia, hypoxia, and cellular injury.
    • Cellular Energy Failure
      • Mitochondrial dysfunction impairs ATP production, leading to cellular apoptosis or necrosis.
    • Proinflammatory factors
      • Cause direct damage to tissue
    • Translocation of gut bacteria
  • This leads to
    • Progressive Organ Failure
      • Initial damage to one organ increases the risk of dysfunction in others through systemic effects

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