Acute Inflammation

Acute Inflammation

1. Definition

   • Complex reaction of vascularized tissue to injurious agents or necrotic tissue
     • Aims to get rid of irritants and prepare injured tissue for repair
     • Consists of vascular, cellular and systemic responses
   • Generally protective but can be harmful
     • Hypersensitivity (e.g. to insect bite)
     • Inflammatory diseases
     • Repair of cell damage leading to fibrosis
   • 2 types
     • Acute
       • Rapid onset
       • Short duration (mins, hours, days)
     • Chronic
       • Long duration (months, years)
       • Different cell types and tissue responses

2. Causes

   • Infection - bacterial/parasitic
   • Trauma
   • Physical/Chemical agens - burns, irradiation
   • Tissue necrosis (by definition)
   • Foreign bodies (e.g. sutures)
   • Immune reaction
   • Some causes have distinct features but all produce fundamental features

3. Symptoms

   • Calor (hotness)
   • Rubor (redness)
   • Tumour (swelling)
   • Dolor (pain)
   • Laseofunctio (loss of function)

4. Vascular Changes

   • Alterations in vascular calibre cause changes in blood flow
     • Transient constriction then dilation of arterioles, capillaries and venules
       • Increased blood flow to capillaries
         • Increased permeability of capillaries
   • Structural changes in small blood vessels allow plasma proteins and cells to leave circulation
     • Increased vascular permeability
       • Accumulation of fluid in interstitial tissue - oedema
         • Protein-rich fluid = exudate
         • Protein-low fluid = transudate
     • Migration of leukocytes into tissue
   • Loss of fluid causes blood to become more viscous - moves more slowly (stasis)
     • Allows cells to come into contact with blood vessel wall
       • Leukocytes stick to endothelium and migrate out into tissues
   • Changes to Vascular Permeability
     • Formation of Endothelial Gaps
       • Rapid, short duration - 30 mins
       • Caused by histamine, leukotrienes, bradykinin
         • Cause cell contraction
         • TNF and IL-1 have similar effects but they are delayed (4-6-hours)
       • Only affects venules
     • Direct Endothelial Cell Injury
       • Rapid, long lasting
       • Caused by necrotising injuries - burns
       • Destruction of endothelial cells causes immediate, sustained vascular permeability
       • Response can be delayed - sunburn
     • Leukocyte Mediated Endothelial Cell Injury
       • Leukocytes activated as part of acute inflammatory response
       • Release toxic oxygen species which kill endothelial cells
     • Increased Transcytosis
       • Enhanced by VEGF and histamine
       • Movement of interconnected vesicles across cytoplasm
         • Vesicuvacuolar organelle
     • Angiogenesis
       • Part of response to acute inflammation
       • New blood vessels are leaky
       • Prolonged

5. Cellular Changes

   • Leukocyte extravasation
     • Margination, rolling (transient adhesion) and firm adhesion to endothelium
       • Transmigration across endothelium (diapedesis)
         • Migration in the tissue towards chemotactic stimulus
           • Accumulation in area of injury
             • Activation to destroy and engulf injurious agent
       • Margination - cells occupy periphery of blood vessel (due to stasis)
   • Leukocyte Adhesion and Transmigration
     • Selectins
       • E-selectin - endothelial cells
       • P-selectin - endothelial cells and platelets
       • L-selectin - leukocytes
       • Bind to sialyl-Lewis X-modified glycoprotein on leukocytes
       • Mediate rolling
     • Immunoglobulins
       • ICAM-1 - mediates adhesion, arrest and migration
       • VCAM-1 - mediates adhesion
       • Found on endothelial cells
       • CD31 (PECAM) - mediates migration
       • Ligands for integrins
         • Transmembrane protein - alpha and beta subunit
         • Beta2 integrins
           • LFA-1 (CD11a/CD18)
           • Mac-1 (CD11b/CD18)
   • Chemotaxis
     • Movement along a chemical gradient
     • Stimuli
       • Endogenous
         • Complement components (C5a) in plasma
         • Products of the lipoxygenase pathway (LTB4) from damaged tissue
         • Cytokines (IL-8) from activated macrophages/lymphocytes
       • Exogenous
         • Bacterial products
     • Chemotactic factors bind to 7 g-protein coupled receptors on leukocytes
       • PLCg and PI3K activation
         • Actin polymerisation
           • Migration
   • Leukocyte Activation
     • Via 4 receptors on leukocytes
       • 7 transmembrane G-protein coupled receptors
         • Recognise microbes, C5a and bacterial products
         • Initiates release of microbicidal factors
       • Toll-like receptors
         • Different TLRs recognise different microbes
         • Bind to LPS and dsRNA (found in some viruses)
         • Lead to production of cytokines and ROIs
       • Mannose receptor
         • Causes ingesting of microbes
         • Binds terminal mannose/fucose residues on bacterial wall that aren't present in mammals
       • Scavenger receptors
         • Bind to modified LDL/bacterial wall
   • Phagocytosis
     • 3 stages
       • Recognition and attachment
         • Microbes bind to specific receptors - aided by opsonisation (higher affinity)
           • Opsonins
             • IgG - Fc receptor
             • C3 complement fragment - CR1
             • Fibrinogen - integrins
             • Fibronectin - CR proteins
       • Engulfment
         • Cytoplasmicpseudopods flow around particle and form phagosome
           • Fuses with lysosomal granule ieukocyte (phagolysosome)
       • Killing and degradation
         • Generally via RO species
           • H2O2-MPO-Halide system
         • Bacteriacidal permeability increasing protein (BPI)
         • Lysozyme - hydrolysis of glycopeptides
         • Lactoferrin
         • Major basic protein - cytotoxic to parasites
         • Defensins - cytotoxic to microbes