Inflammation - Overview

1. Recognition of the injurious agent
2. Recruitment of leukocytes
3. Removal of the agent
4. Regulation (control) of the response
5. Repair (resolution)

• Robbins, Cotran & Kumar Pathologic Basis of Disease, p. 2564-2566

Types of Inflammation

1. Acute Inflammation

Cardinal Signs (Latin)

• Rubor (redness) - vasodilation
• Calor (heat) - increased blood flow
• Tumor (swelling) - fluid exudation
• Dolor (pain) - mediators acting on nerves
• Functio laesa (loss of function) - combined effect

Vascular Events

1. Vasodilation of small vessels (especially postcapillary venules), increasing blood flow. Histamine is the principal early mediator. This causes heat and redness.
2. Increased vascular permeability, allowing protein-rich fluid (exudate) to escape into extravascular tissue. Unlike a transudate (a low-protein ultrafiltrate due to hydrostatic/osmotic imbalance), an exudate signals active vascular permeability change.
3. Leukocyte emigration - neutrophils accumulate along the endothelium, adhere, then transmigrate into tissues.

• Exudate = high protein, high cells, inflammatory cause
• Transudate = low protein, osmotic/hydrostatic imbalance (e.g., heart failure, cirrhosis)
• Pus = purulent exudate rich in neutrophils + cell debris

Serous inflammation: skin blister with serous effusion between epidermis and dermis (H&E). - Robbins, Cotran & Kumar Pathologic Basis of Disease

Cellular Events (Leukocyte Recruitment)

1. Margination - leukocytes move to the vessel periphery as blood flow slows
2. Rolling - mediated by selectins (L-, E-, P-selectin)
3. Firm adhesion - mediated by integrins (e.g., LFA-1, Mac-1) binding to endothelial ICAMs (upregulated by TNF, IL-1)
4. Transmigration (diapedesis) - through interendothelial junctions via CD31 (PECAM-1)
5. Chemotaxis - migration along a chemical gradient toward the injury site

• Bacterial products (N-formylmethionine peptides)
• C5a (complement)
• LTB4 (leukotriene B4)
• IL-8/CXCL8 (chemokine)

Morphologic Patterns of Acute Inflammation

2. Chemical Mediators of Inflammation

• Vasodilation: Histamine, prostaglandins
• Increased permeability: Histamine, C3a/C5a, leukotrienes LTC4/D4/E4
• Chemotaxis: TNF, IL-1, chemokines, C5a, LTB4
• Fever: IL-1, TNF, prostaglandins
• Pain: Prostaglandins, bradykinin, substance P
• Tissue damage: Lysosomal enzymes, reactive oxygen species (ROS)
• Robbins, Cotran & Kumar Pathologic Basis of Disease, p. 2906-2909

3. Outcomes of Acute Inflammation

1. Complete resolution - the ideal outcome. The injurious agent is eliminated, edema is resorbed via lymphatics, macrophages clear debris, and the tissue regenerates. Seen when injury is limited and parenchymal cells can regenerate.
2. Scarring (fibrosis) - occurs when tissue destruction is substantial, tissue cannot regenerate, or abundant fibrin cannot be cleared. Connective tissue replaces the damaged area ("organization").
3. Progression to chronic inflammation - when the acute response cannot resolve the injurious agent or normal healing is disrupted.

4. Chronic Inflammation

• Ongoing leukocyte infiltration (predominantly mononuclear - macrophages, lymphocytes, plasma cells)
• Tissue destruction (by leukocyte products)
• Healing attempts (fibrosis, angiogenesis)

Causes

• Persistent infections (e.g., Mycobacterium tuberculosis, H. pylori, certain fungi, viruses) that resist clearance
• Immune-mediated diseases (autoimmune diseases, prolonged immune reactions to environmental antigens)
• Prolonged toxic exposure (e.g., silica - silicosis; atherosclerosis)

Principal Cells

• Phagocytose microbes and dead tissue
• Secrete pro-inflammatory cytokines (TNF, IL-1, chemokines, eicosanoids)
• Initiate tissue repair (growth factors)
• Activate T lymphocytes by antigen presentation + costimulation

• CD4+ T cells:
  • Th1 subset: produces IFN-γ (activates macrophages) - involved in defense against bacteria/viruses and autoimmunity
  • Th17 subset: produces IL-17 - recruits neutrophils; also involved in autoimmunity
  • Th2 subset: produces IL-4, IL-5, IL-13 - important in parasitic infections and allergic inflammation
• T cells and macrophages interact bidirectionally, creating a self-amplifying cycle that sustains chronic inflammation
• Plasma cells produce antibodies against persistent antigens or self-antigens

• Eosinophils - prominent in Th2-mediated reactions (parasites, allergies); contain major basic protein (toxic to helminths but damages host tissue)
• Mast cells - bridge acute and chronic inflammation; express FcεRI for IgE binding; degranulate in immediate hypersensitivity

Granulomatous Inflammation

• Langhans giant cell - nuclei at the periphery in a horseshoe pattern (classic for TB)
• Foreign body giant cell - nuclei randomly distributed

Tertiary Lymphoid Structures

5. Systemic Effects - Acute Phase Response

Summary Diagram (Conceptual)

Injury/Infection
       |
       v
Recognition by sentinel cells (macrophages, mast cells, dendritic cells)
       |
       v
Release of mediators (histamine, cytokines, eicosanoids, complement)
       |
   ┌───┴────────────────────────────────┐
   v                                    v
Vascular events                   Cellular events
(vasodilation,                     (leukocyte rolling,
 increased permeability,            adhesion, diapedesis,
 exudate formation)                 chemotaxis, phagocytosis)
   │
   └──────────────── Outcomes ──────────────────┐
           |                   |                |
     Resolution             Fibrosis      Chronic inflammation