Normal and abnormal inflammatory response

Background

Inflammation is a complex biological response of body tissues to harmful stimuli, including pathogens, damaged cells, toxic compounds, or irritants. It is a protective response involving immune cells, blood vessels, and molecular mediators, designed to eliminate the initial cause of cell injury, clear out necrotic cells and tissues damaged from the original insult and the inflammatory process, and initiate tissue repair.

Initial tissue response to injury - phases of inflammation

1. Vascular Phase (Immediate - Minutes)

• Transient vasoconstriction (seconds) followed by vasodilation
• Increased vascular permeability due to endothelial cell contraction
• Plasma protein extravasation leads to tissue oedema
• Slowing of blood flow facilitates cellular events

2. Cellular/Exudative Phase (Minutes to Hours)

• Neutrophil recruitment: first responders arrive within minutes to hours
• Monocyte/macrophage infiltration: arrive hours to days later
• Lymphocyte recruitment: involved in later phases and chronic inflammation
• Cellular migration occurs through chemotaxis and adhesion molecules

3. Resolution/Repair Phase (Days to Weeks)

• Clearance of inflammatory cells and debris
• Tissue repair and regeneration
• Return to homeostasis or progression to chronic inflammation

Causes of inflammation


Cellular events in inflammation

Chemotaxis
The directed migration of cells along a chemical gradient toward inflammatory sites. Key chemotactic factors include:

• Complement fragments (C5a, C3a)
• Bacterial products (N-formyl peptides)
• Cytokines (IL-8, MCP-1)
• Leukotriene B4

Opsonization
The coating of pathogens or particles with molecules that enhance phagocytosis:

• Complement proteins (C3b, iC3b)
• Antibodies (IgG, IgM)
• Collectins (mannose-binding lectin)
• Acute phase proteins (C-reactive protein)

Phagocytosis
The process by which cells engulf and digest foreign particles:
1. Recognition and binding of opsonized particles
2. Engulfment - formation of phagosome
3. Phagolysosome formation - fusion with lysosomes
4. Intracellular killing and digestion

Intracellular Killing Mechanisms

Oxygen-dependent killing:

• Respiratory burst producing reactive oxygen species (ROS)
• Superoxide, hydrogen peroxide, hydroxyl radicals
• Myeloperoxidase system producing hypochlorous acid

Oxygen-independent killing:

• Lysozyme: breaks down bacterial cell walls
• Lactoferrin: iron sequestration
• Defensins: antimicrobial peptides
• Elastase and other proteases

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Chemical mediators of inflammation

Complement system

• Classical, alternative, and Lectin pathways
• C3a, C4a, C5a: anaphylatoxins causing vasodilation and increased permeability
• C5a (potent chemotactic factor)
• Membrane attack complex (C5b-9) leading to cell lysis

Histamine

• Released from mast cells and basophils
• Causes vasodilation and increased vascular permeability
• Smooth muscle contraction

Cytokines

• TNF-α: fever, acute phase response, endothelial activation
• IL-1: fever, acute phase response, T-cell activation
• IL-6: acute phase response, B-cell differentiation
• Interferons: antiviral activity, macrophage activation
• Chemokines: cellular recruitment (IL-8, MCP-1, RANTES)

Arachidonic acid metabolites

• Prostaglandins (PGE2, PGI2): vasodilation, pain, fever
• Leukotrienes (LTB4): chemotaxis, bronchoconstriction
• Thromboxanes: vasoconstriction, platelet aggregation

Other mediators

• Nitric oxide: vasodilation, antimicrobial activity
• Platelet-activating factor: platelet aggregation, increased permeability
• Kinins (bradykinin): pain, vasodilation, increased permeability
• Coagulation factors: tissue factor, thrombin

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Effects of inflammation

Beneficial effects

• Pathogen elimination: antimicrobial activity
• Toxin dilution: increased blood flow washes out harmful substances
• Barrier formation: fibrin clot prevents spread
• Immune system activation: antigen presentation and adaptive immunity
• Tissue repair initiation: growth factors and repair cells
• Pain response: protective behavior modification

Harmful effects

• Tissue damage: from inflammatory mediators and ROS
• Organ dysfunction: due to edema and cellular infiltration
• Autoimmune reactions: molecular mimicry and epitope spreading
• Chronic inflammation: persistent tissue damage
• Systemic effects: fever, shock, organ failure
• Fibrosis: excessive scar tissue formation

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Systemic signs of inflammation

Acute phase response

• Fever: IL-1, TNF-α, IL-6 acting on hypothalamus
• Leukocytosis
• Increased ESR and CRP
• Altered liver protein synthesis: decreased albumin, increased fibrinogen

Constitutional symptoms

• Malaise and fatigue
• Anorexia
• Sleep disturbances
• Myalgia

Cardiovascular effects

• Tachycardia
• Vasodilation (potential hypotension)
• Increased cardiac output

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Possible outcomes of inflammation

Resolution (Complete Healing)

• Return to normal tissue architecture
• Restoration of function
• Clearance of inflammatory cells
• Ideal outcome with minimal tissue damage

Healing by Repair

• Scar tissue formation: when tissue cannot regenerate
• Fibroblast proliferation and collagen deposition
• May result in loss of function
• Angiogenesis

Suppuration (Pus Formation)

• Neutrophil-rich exudate
• Abscess formation
• May require surgical drainage
• Risk of systemic spread

Chronic inflammation

• Persistent inflammatory stimulus
• Lymphocyte and macrophage predominance
• Tissue destruction and fibrosis
• Granuloma formation in some cases

Fibrosis

• Excessive collagen deposition
• Loss of tissue architecture
• Impaired organ function
• May progress to organ failure

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Abnormal inflammatory responses
Abnormal inflammation occurs when the inflammatory response is inappropriate in intensity, duration, or target, leading to tissue damage rather than protection and healing.