What is the pathology of inflammation?

Inflammation Pathology: Mechanisms, Types, and Clinical Significance

Inflammation is a complex biological response to harmful stimuli that involves immune cells, blood vessels, and molecular mediators working together to eliminate the initial cause of injury, clear damaged tissues, and initiate tissue repair. 1 This fundamental process is essential for host defense against infection and injury but can also contribute to the pathophysiology of many chronic diseases when dysregulated.

Acute vs. Chronic Inflammation

Acute Inflammation

• Definition: Immediate and early response to injury that lasts for hours to days
• Key features:
  • Cardinal signs: Redness (rubor), heat (calor), swelling (tumor), pain (dolor), and loss of function (functio laesa)
  • Vascular changes: Vasodilation and increased permeability
  • Cellular infiltration: Predominantly neutrophils
  • Resolution phase: Once the stimulus is eliminated, inflammation resolves through active processes

Chronic Inflammation

• Definition: Prolonged inflammatory response lasting weeks to years
• Key features:
  • Persistent stimulus or dysregulated immune response
  • Cellular infiltration: Predominantly lymphocytes, plasma cells, and macrophages
  • Tissue destruction and attempts at repair occurring simultaneously
  • Associated with fibrosis and tissue remodeling 2

Cellular Components of Inflammation

Neutrophils

• First responders to acute inflammation
• Contain granules with antimicrobial peptides and proteolytic enzymes
• Phagocytose pathogens and release neutrophil extracellular traps (NETs)
• Key marker of active inflammation in tissue biopsies 3

Macrophages

• Derived from blood monocytes
• Phagocytose pathogens and debris
• Release cytokines and growth factors
• Can polarize to pro-inflammatory (M1) or anti-inflammatory/repair (M2) phenotypes

Lymphocytes

• T cells: Coordinate adaptive immune response
• B cells: Produce antibodies
• Predominate in chronic inflammation
• Can form tertiary lymphoid structures in chronically inflamed tissues

Other cells

• Mast cells: Release histamine and other mediators
• Eosinophils: Important in allergic and parasitic responses
• Dendritic cells: Present antigens to T cells

Molecular Mediators of Inflammation

Cytokines

• Small proteins that regulate immune responses
• Pro-inflammatory cytokines:
  • TNF-α, IL-1β, IL-6: Induce acute phase response
  • IL-8: Neutrophil chemotaxis
• Anti-inflammatory cytokines:
  • IL-10, TGF-β: Limit and resolve inflammation

Chemokines

• Direct leukocyte migration to sites of inflammation
• Examples: CXCL8 (IL-8), CCL2 (MCP-1)

Acute Phase Proteins

• Produced by liver in response to inflammation
• C-reactive protein (CRP): Binds to pathogens and damaged cells
• Fibrinogen: Promotes blood clotting
• Serum amyloid A (SAA): Recruits immune cells 3

Lipid Mediators

• Prostaglandins: Vasodilation, pain, fever
• Leukotrienes: Increase vascular permeability, attract leukocytes
• Pro-resolving mediators: Lipoxins, resolvins, maresins 4

Complement System

• Cascade of proteins that enhance phagocytosis and lysis of pathogens
• Generates inflammatory mediators (C3a, C5a)

Vascular Events in Inflammation

1. Vasodilation: Increased blood flow causing redness and heat
2. Increased vascular permeability: Allows plasma proteins and leukocytes to exit vessels
3. Leukocyte recruitment:
   • Margination: Leukocytes move to vessel periphery
   • Rolling: Mediated by selectins
   • Adhesion: Mediated by integrins
   • Transmigration: Leukocytes cross endothelium into tissues

Histological Features of Inflammation

Acute Inflammation

• Vascular congestion and edema
• Neutrophil infiltration
• Fibrin deposition
• Tissue necrosis in severe cases

Chronic Inflammation

• Mononuclear cell infiltration (lymphocytes, plasma cells, macrophages)
• Tissue destruction
• Attempts at healing with angiogenesis and fibrosis
• Granuloma formation in specific types 3

Histological Scoring Systems

For inflammatory bowel disease and other conditions, standardized scoring systems assess:

• Architectural distortion
• Inflammatory cell infiltrates
• Epithelial damage
• Presence of neutrophils (cryptitis, crypt abscesses)
• Erosions/ulcerations 3

Resolution of Inflammation

• Active process, not passive cessation
• Involves specialized pro-resolving mediators (SPMs)
• Clearance of inflammatory cells through apoptosis and efferocytosis
• Restoration of tissue homeostasis
• Failure of resolution contributes to chronic inflammation 4

Inflammation in Disease Pathogenesis

Infectious Diseases

• Protective response to eliminate pathogens
• Can cause tissue damage if excessive

Autoimmune Diseases

• Inappropriate immune response against self-antigens
• Examples: Rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease

Metabolic Disorders

• Low-grade chronic inflammation in obesity, diabetes
• Adipose tissue inflammation contributes to insulin resistance

Cardiovascular Diseases

• Atherosclerosis involves inflammatory mechanisms
• Recruitment of leukocytes to vessel wall
• Inflammatory mediators contribute to plaque formation and rupture 3, 2

Neurodegenerative Diseases

• Neuroinflammation contributes to Alzheimer's, Parkinson's disease
• Microglial activation and inflammatory cytokines 3

Cancer

• Inflammation can promote tumor initiation and progression
• Tumor-associated macrophages often have pro-tumor functions

Inflammatory Markers in Clinical Practice

Laboratory Markers

• Acute phase reactants: CRP, ESR, fibrinogen
• Cytokines: IL-6, TNF-α
• Complete blood count: Leukocytosis, neutrophilia

Histopathological Markers

• Neutrophils in tissue indicate active inflammation
• One intraepithelial neutrophil is sufficient to define cryptitis
• At least two neutrophils in crypt lumen define crypt abscess 3
• Granulomas suggest specific inflammatory conditions 3

Therapeutic Approaches to Inflammation

Anti-inflammatory Drugs

• NSAIDs: Inhibit prostaglandin synthesis
• Corticosteroids: Broad anti-inflammatory effects
• Targeted biologics: Anti-TNF, anti-IL-6, etc.

Pro-resolving Approaches

• Emerging therapies targeting resolution pathways
• Synthetic analogs of lipoxins, resolvins, and maresins 4

Cell-based Therapies

• Stem cells and tissue engineering for chronic inflammatory conditions
• Promote resolution and tissue regeneration 4

Conclusion

Understanding inflammation pathology is crucial for diagnosing and treating numerous diseases. While inflammation is essential for host defense, its dysregulation contributes to many chronic conditions. Modern approaches to managing inflammatory diseases focus not only on suppressing inflammation but also on promoting its resolution to restore tissue homeostasis.