Acute Inflammation

Acute Inflammation

Definition
1. Complex reaction of vascularized tissue to injurious agents or necrotic tissue
  1. Aims to get rid of irritants and prepare injured tissue for repair
  2. Consists of vascular, cellular and systemic responses
2. Generally protective but can be harmful
  1. Hypersensitivity (e.g. to insect bite)
  2. Inflammatory diseases
  3. Repair of cell damage leading to fibrosis
3. 2 types
  1. Acute
    1. Rapid onset
    2. Short duration (mins, hours, days)
  2. Chronic
    1. Long duration (months, years)
    2. Different cell types and tissue responses
Causes
1. Infection - bacterial/parasitic
2. Trauma
3. Physical/Chemical agens - burns, irradiation
4. Tissue necrosis (by definition)
5. Foreign bodies (e.g. sutures)
6. Immune reaction
7. Some causes have distinct features but all produce fundamental features
Symptoms
1. Calor (hotness)
2. Rubor (redness)
3. Tumour (swelling)
4. Dolor (pain)
5. Laseofunctio (loss of function)
Vascular Changes
1. Alterations in vascular calibre cause changes in blood flow
  1. Transient constriction then dilation of arterioles, capillaries and venules
    1. Increased blood flow to capillaries
      1. Increased permeability of capillaries
2. Structural changes in small blood vessels allow plasma proteins and cells to leave circulation
  1. Increased vascular permeability
    1. Accumulation of fluid in interstitial tissue - oedema
      1. Protein-rich fluid = exudate
      2. Protein-low fluid = transudate
  2. Migration of leukocytes into tissue
3. Loss of fluid causes blood to become more viscous - moves more slowly (stasis)
  1. Allows cells to come into contact with blood vessel wall
    1. Leukocytes stick to endothelium and migrate out into tissues
4. Changes to Vascular Permeability
  1. Formation of Endothelial Gaps
    1. Rapid, short duration - 30 mins
    2. Caused by histamine, leukotrienes, bradykinin
      1. Cause cell contraction
      2. TNF and IL-1 have similar effects but they are delayed (4-6-hours)
    3. Only affects venules
  2. Direct Endothelial Cell Injury
    1. Rapid, long lasting
    2. Caused by necrotising injuries - burns
    3. Destruction of endothelial cells causes immediate, sustained vascular permeability
    4. Response can be delayed - sunburn
  3. Leukocyte Mediated Endothelial Cell Injury
    1. Leukocytes activated as part of acute inflammatory response
    2. Release toxic oxygen species which kill endothelial cells
  4. Increased Transcytosis
    1. Enhanced by VEGF and histamine
    2. Movement of interconnected vesicles across cytoplasm
      1. Vesicuvacuolar organelle
  5. Angiogenesis
    1. Part of response to acute inflammation
    2. New blood vessels are leaky
    3. Prolonged
Cellular Changes
1. Leukocyte extravasation
  1. Margination, rolling (transient adhesion) and firm adhesion to endothelium
    1. Transmigration across endothelium (diapedesis)
      1. Migration in the tissue towards chemotactic stimulus
        Accumulation in area of injury
        Activation to destroy and engulf injurious agent
    2. Margination - cells occupy periphery of blood vessel (due to stasis)
2. Leukocyte Adhesion and Transmigration
  1. Selectins
    1. E-selectin - endothelial cells
    2. P-selectin - endothelial cells and platelets
    3. L-selectin - leukocytes
    4. Bind to sialyl-Lewis X-modified glycoprotein on leukocytes
    5. Mediate rolling
  2. Immunoglobulins
    1. ICAM-1 - mediates adhesion, arrest and migration
    2. VCAM-1 - mediates adhesion
    3. Found on endothelial cells
    4. CD31 (PECAM) - mediates migration
    5. Ligands for integrins
      1. Transmembrane protein - alpha and beta subunit
      2. Beta2 integrins
        LFA-1 (CD11a/CD18)
        Mac-1 (CD11b/CD18)
3. Chemotaxis
  1. Movement along a chemical gradient
  2. Stimuli
    1. Endogenous
      1. Complement components (C5a) in plasma
      2. Products of the lipoxygenase pathway (LTB4) from damaged tissue
      3. Cytokines (IL-8) from activated macrophages/lymphocytes
    2. Exogenous
      1. Bacterial products
  3. Chemotactic factors bind to 7 g-protein coupled receptors on leukocytes
    1. PLCg and PI3K activation
      1. Actin polymerisation
        Migration
4. Leukocyte Activation
  1. Via 4 receptors on leukocytes
    1. 7 transmembrane G-protein coupled receptors
      1. Recognise microbes, C5a and bacterial products
      2. Initiates release of microbicidal factors
    2. Toll-like receptors
      1. Different TLRs recognise different microbes
      2. Bind to LPS and dsRNA (found in some viruses)
      3. Lead to production of cytokines and ROIs
    3. Mannose receptor
      1. Causes ingesting of microbes
      2. Binds terminal mannose/fucose residues on bacterial wall that aren't present in mammals
    4. Scavenger receptors
      1. Bind to modified LDL/bacterial wall
5. Phagocytosis
  1. 3 stages
    1. Recognition and attachment
      1. Microbes bind to specific receptors - aided by opsonisation (higher affinity)
        Opsonins
        IgG - Fc receptor
        C3 complement fragment - CR1
        Fibrinogen - integrins
        Fibronectin - CR proteins
    2. Engulfment
      1. Cytoplasmicpseudopods flow around particle and form phagosome
        Fuses with lysosomal granule ieukocyte (phagolysosome)
    3. Killing and degradation
      1. Generally via RO species
        H2O2-MPO-Halide system
      2. Bacteriacidal permeability increasing protein (BPI)
      3. Lysozyme - hydrolysis of glycopeptides
      4. Lactoferrin
      5. Major basic protein - cytotoxic to parasites
      6. Defensins - cytotoxic to microbes

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