Acute inflammation mechanisms

Acute Inflammation - The First Responders

• Triggers: Microbial Pathogen-Associated Molecular Patterns (PAMPs) or host-derived Damage-Associated Molecular Patterns (DAMPs).
• Sensors: Sentinel cells like macrophages and mast cells use Pattern Recognition Receptors (e.g., Toll-like receptors - TLRs).
• Amplification: The inflammasome, a cytosolic complex, activates caspase-1, leading to the maturation and release of IL-1β.

⭐ The inflammasome-driven production of IL-1β is a critical step, making IL-1 a key therapeutic target in several autoinflammatory syndromes.

Vascular Changes - The Floodgates Open

• Vasodilation: Arterioles expand, causing ↑ blood flow.
  • Mediators: Histamine, bradykinin, Nitric Oxide.
  • Cardinal Signs: Rubor (redness) & Calor (heat).
• ↑ Vascular Permeability: Endothelial cell contraction opens gaps, allowing protein-rich exudate to leak into tissues.
  • Result: Tumor (swelling/edema) & ↑ interstitial fluid.
  • Dolor (pain) is mediated by bradykinin and prostaglandins.

Fluid movement is governed by Starling forces: $P_{net} = [(P_c - P_i) - \sigma(\pi_c - \pi_i)]$

⭐ Exudate (inflammatory) is protein-rich (sp. gr. > 1.020) and cellular, unlike transudate (hydrostatic), which is a protein-poor ultrafiltrate.

Cellular Events - Leukocyte Invasion

Leukocytes journey from the vessel lumen to the interstitial tissue in a defined sequence to fight infection and clear debris. This multi-step process is mediated by specific adhesion molecules and chemokines.

• Margination & Rolling: Slow blood flow pushes leukocytes to the periphery. Endothelial E/P-selectins loosely bind to leukocytes.
• Adhesion: Integrins on leukocytes bind firmly to endothelial ICAM-1. 📌 Mnemonic: Selectins for Slowing/rolling; Integrins for Immobile adhesion.
• Transmigration (Diapedesis): Leukocytes squeeze between endothelial cells, mediated by PECAM-1 (CD31).
• Chemotaxis: Cells migrate toward inflammatory stimuli like $C5a$, $LTB_4$, and IL-8.

⭐ In Leukocyte Adhesion Deficiency (LAD), defective integrins lead to recurrent bacterial infections without pus formation and delayed separation of the umbilical cord.

Phagocytosis - The Clean-Up Crew

• Opsonization: Pathogens are tagged for destruction by opsonins, primarily IgG and C3b.
• Engulfment & Destruction: Phagocytes engulf tagged pathogens into a phagosome. This fuses with a lysosome to form a phagolysosome, where destruction occurs.
• Killing Mechanisms:
  • Respiratory Burst: The primary method. Utilizes oxygen to create reactive oxygen species. $O_2 \xrightarrow{NADPH \text{ oxidase}} O_2^{\cdot-} \xrightarrow{SOD} H_2O_2 \xrightarrow{MPO} HOCl$ (bleach)
  • NETs: Neutrophil Extracellular Traps are webs of DNA and proteins released to trap and kill pathogens.

⭐ Chronic Granulomatous Disease (CGD) results from a defective NADPH oxidase, leading to recurrent infections by catalase-positive organisms.

Chemical Mediators - The Conductors

Orchestrate inflammation from two sources:

• Cell-Derived (Ready or made on demand):

  • Histamine: Vasodilation, ↑ vascular permeability.
  • Arachidonic Acid Metabolites:
    • Prostaglandins (via COX): Pain, fever.
    • Leukotrienes (via Lipoxygenase): Chemotaxis, bronchospasm.
  • Cytokines: TNF, IL-1, IL-6 drive systemic effects (fever).

• Plasma-Derived (From liver):

  • Complement: C3a/C5a (inflammation), C3b (opsonization).
  • Kinin System: Bradykinin (pain, vasodilation).

⭐ The cytokine triad of TNF, IL-1, and IL-6 drives the systemic acute-phase response, causing fever and hepatic synthesis of proteins like C-reactive protein (CRP).

High‑Yield Points - ⚡ Biggest Takeaways

• Key vascular changes are vasodilation (redness, heat) and increased permeability (swelling), driven by histamine and bradykinin.
• Neutrophil extravasation is a cascade: rolling (selectins), adhesion (integrins), and transmigration (PECAM-1).
• Chemotaxis is crucial for recruitment, guided by potent chemoattractants like C5a, LTB4, and IL-8.
• Pain is mediated by bradykinin and PGE₂; fever is driven by cytokines like TNF and IL-1.
• Phagocytosis relies on opsonization by IgG and C3b to clear pathogens and debris effectively.