Hemat

• Acute inflammation


  The rapid response of a living vascularised mammalian tissue to an injurious agent. It serves to deliver mediators of host defence (Leukocytes and plasma proteins) to the site of injury, in order to eliminate the offending agent.
• Acute inflammation


  • It is characterized by extracellular fluid and leukocyte accumulation
  • It is a complex dynamic process intended by nature as a protective response, which eliminates noxious agents and paves way for repair of damaged tissues
  • It results from a delicate interplay between several protagonists and antagonists, and therefore trivial to life-threatening effects may result from excessive or inadequate inflammatory reactions
• Without inflammation, infections would go unchecked, wounds would never heal, and injured tissues might remain permanent.
• Ancient Egyptian written documents describing clinical features of inflammation

  2700 BC
• Cardinal signs of inflammation

  • Rubor (redness)
  • Tumor (swelling)
  • Calor (heat)
  • Dolor (pain)
• Virchow added functio laesa (loss of function)
• John Hunter in 1793 noted that inflammation is not a disease
• Julius Cohnheim(1839-1884) described the events of inflammation
• Elie Metchnikoff in 1880 discovered phagocytosis
• Paul Ehrlich developed the humoral theory of inflammation
• Sir Thomas Lewis established the concept of chemical mediators of inflammation
• Causes/stimuli for Acute inflammation


  • Infection (Bacterial, viral, parasitic) and microbial toxins
  • Trauma (blunt and penetrating)
  • Physical and chemical agents(thermal injury e.g. burns, frostbite, irradiation)
  • Tissue necrosis
  • Foreign bodies (splinters, dirt, sutures)
  • Immune reaction (hypersensitivity reaction)
• Events of acute inflammation

  1. Vascular changes

  2. Cellular events
• Vascular changes


  • Vasodilatation
  • Increased blood flow causes redness and heat
  • Increased permeability of the microvasculature with outpouring of protein rich fluid into the extra vascular tissue
  • Loss of fluid causes an increase in the conc. of RBCs in the vessels and increased viscosity and slower blood flow-stasis
  • Leukocytes, principally Neutrophil accumulate along the vascular endothelium and migrate through the vascular wall into the interstitial space
• Exudate


  ECF with high protein conc., high cellular debris and high specific gravity
• Transudate


  ECF with low protein conc., (mostly albumin), little cellular component and low specific gravity
• Edema


  Excess fluid in the interstitium
• Pus


  Purulent exudate, inflammatory exudate (mostly neutrophils), cellular debris and occasional microbes
• How does the endothelium become leaky?

  1. Contraction of endothelial cells, with formation of endothelial gaps

  2. Direct endothelial injury-resulting in endothelial cell necrosis and detachment

  3. Leukocyte mediated endothelial injury

  4. Increased transcytosis across endothelial cytoplasm. Leakage through vesiculovacuolar organelles
• In inflammation, lymph flow is increased and helps drain edema fluid that accumulates because of increased vascular permeability. In addition to fluid, leukocytes and cell debris, as well as microbes, may find their way into lymph. Lymphatic vessels, like blood vessels, proliferate during inflammatory reactions to handle the increased load. The lymphatics may become secondarily inflamed (lymphangitis), as may the draining lymph nodes (lymphadenitis).
• Sequence of events in leukocyte action

  1. Margination

  2. Rolling

  3. Firm adhesion to endothelium

  4. Transmigration across endothelium (Diapedesis)

  5. Migration in interstitial tissue towards a chemotactic stimulus

  6. Activation

  7. Phagocytosis

  8. Killing and Degradation
• Selectins


  A family of three closely related proteins that differ in their cellular distribution, but all function in adhesion of leukocytes to endothelial cells. They are all single chain transmembrane glycoproteins with amino terminal that is related to carbohydrate binding proteins known as C-type lectin.
• Integrins


  Transmembrane heterodimeric glycoproteins, made up of α and β chains that are expressed in many cell types and bind to ligands on endothelial cells. This superfamily consists of 30 structurally homologous protein that promote cell-cell or cell-matrix interaction.
• Transmigration


  1. By the aid of Platelet Endothelial Cell Adhesion Molecule (PECAM-1) or CD31

  2. Leukocytes then accumulate in the site of injury

  3. The type of emigrating leukocyte varies with the age of the inflammatory response and with the type of stimuli

  4. Neutrophils predominate in the first 6-24 hours, then monocytes in 24-48 hours
• Chemotaxis


  Locomotion of leukocytes oriented along a chemical gradient. Chemo attractants may be exogenous or endogenous. Most common exogenous agents are bacterial products e.g. peptides.
• Integrin superfamily


  • Consists of 30 structurally homologous proteins that promote cell-cell or cell-matrix interaction
• Leukocyte adhesion and transmigration

  1. Cytokine-induced (TNF and IL-1) expression of integrin ligands on the endothelium

  2. Increased integrin affinity on the leukocytes

  3. Firm integrin-mediated binding of the leukocytes to the endothelium

  4. Leukocytes stop rolling, cytoskeleton is reorganized, and they spread out on the endothelial surface
• Transmigration


  Leukocytes traverse the endothelium with the aid of Platelet Endothelial Cell Adhesion Molecule (PECAM-1) or CD31
• PECAM-1 or CD31


  • A member of the immunoglobulin family
• Diapedesis


  Leukocyte transmigration that occurs predominantly in the venules (except in the lungs where it occurs in the capillaries)
• Leukocyte transmigration


  1. After traversing the endothelium, leukocytes are transiently retarded by the continuous basement membrane

  2. Leukocytes eventually pierce the basement membrane by secreting collagenase
• Leukocyte accumulation


  1. Leukocytes then accumulate in the site of injury

  2. The type of emigrating leukocyte varies with the age of the inflammatory response and with the type of stimuli

  3. Neutrophils predominate in the first 6-24 hours, then monocytes in 24-48 hours
• Chemotaxis


  Locomotion of leukocytes oriented along a chemical gradient towards the site of injury after extravasation
• Chemoattractants


  • Exogenous agents (e.g. bacterial products with N-formyl-methionine terminal amino acid, lipid in nature)
  • Endogenous agents (components of complement system, lipoxygenase pathway products, cytokines/chemokines)
• Leukocyte activation


  • Changes or responses undergone by leukocytes when in contact with microbes, products of necrotic cells, antigen-antibody complexes, cytokines etc
  • Results from several signalling pathways leading to increase in cytosolic calcium and activation of enzymes such as protein kinase and phospholipase A2
• Functional responses in leukocyte activation

  • Production of Arachidonic acid metabolites from phospholipids
  • Degranulation and secretion of lysosomal enzymes and activation of the oxidative burst
  • Secretion of cytokines which amplify the inflammatory reactions
  • Modulation of leukocyte adhesion molecules
• Opsonization


  The process of coating a particle such as a microbe to target it for phagocytosis
• Opsonins


  • Antibodies like IgG
  • Components of complement system, especially fragments of C3
  • Plasma proteins like Mannose Binding Lectin, fibronectin, fibrinogen, C-reactive protein
• Leukocyte receptors


  • Toll-like receptors
  • Seven-transmembrane G-protein coupled receptors
  • Receptors for cytokines (e.g. IFN-γ)
  • Receptors for opsonins
• Phagocytosis


  The process of engulfment of solid particulate material by cells (cell-eating)