Week 2 Pathology

Acute inflammation:

  • Components / Sequence of events.
    • Vascular injury, toxin etc –> transient vasoconstriction then vasodilation –> vascular stasis  (histamine)
    • Oedema formation – leakage of plasma proteins and fibrin  (endothelial contraction, direct trauma, leucocyte mediated, increased trancytosis, angiogenesis)
    • Leucocyte margination – line the vessel wall
    • Adhesion to vessel wall by molecules and receptors (glycoproteins, selectins)
    • Migration – diapedesis and enter extravascular space. (integrins, CD 31, PECAM1)
    • Chemotaxis to site of injury – following bacterial products, cytokines, IL8, C5a, Ag-Ab complexes, products of necrosis
    • Cell activation –>phagocytosis and enzyme release.
    • 6-24 hrs – neutrophils
    • 24-48hrs – macrophages
  • Mechanisms.
    • Serous (thin fluid from plasma or epithelium eg burns, effusions)
    • Fibrinous (vascular permeability leads to fibrin deposition – body cavity inflammation eg pericarditis, meningitis)
    • Suppurative (pus eg appendicitis)
    • Ulcers- local defect in surface of tissue or organ
  • Chemical mediators
Chemical mediator Effect
Histamine Vasodilation, increased vascular permeability, endothelial activation
Seretonin
Kinins Vasodilation, increased vascular permeability, pain, smooth muscle contraction
Nitric oxide Vascular smooth muscle relaxation.
Leukotrienes increased vascular permeability, Chemotaxis, leukocyte adhesion and activation
Platelet activating factor Vasodilation, increased vascular permeability, leukocyte adhesion, chemotaxis, degranulation, oxidative burst
Complement Classic, Alternative and lectin pathway, C3 – opsonises, C5- chemotaxis, Membrane attack complex, vasodilation
Clotting factors Exp to ECM or inflammation leads to activation –> thrombin –> further acute inflammation

Cytokines:

  • Terms & definitions – cytokines are proteins produced by cells that modulate functions of other cell types
  • General properties and functional classes – immune response, acute and chronic inflammation.
  • IL-1 & TNF – mediate inflammation and produced by activated macrophages, secretion is stimulated by microbial products, immune complexes, physical injury etc.
  • IL-1 and TNFa Effects – Endothelium – leukocyte adherence, prostaglandin production, procoagulant, increase cytokines, interleukins
    • Fibroblasts – increased proliferation, collagen synthesis, collagenase, protease, PGE synthesis
    • Leukocytes – priming, increased cytokine secretion
    • Acute phase reaction – systemic: fever, annorexia, sleepy, neutrophilia, corticotrophins and steroids, shock(hypotension, tachycardia, decreased peripheral resistance)
  • TNFa – controls body mass by promoting protein and lipid mobilisation and appetite suppression(eg cachexia in cancer)

 

Outcomes of Acute Inflamation

  •  Complete resolution
  • Scarring
  • Fibrosis
  • Abscess formation
  • Chronic inflammation

 

Chronic inflammation

Definition / examples.

  • Inflammation for a prolonged period of time(week or more) characterised by macrophage predominance where there is simultaneous active inflammation, tissue destruction, and attempts at repair.
  •  Examples
    • Peristent infection (TB, syphillis)
    • Persistent irritant/toxic agents (silica/FB)
    • Autoimmune (RA, lupus)

Histologic features

  • Collection of macrophages
  • Destruction of parenchyma
  • Replacement by connective tissue (fibrosis)
  • Macrophages and the mononuclear phagocyte system.

Persistent accumulation of macrophages in chronic inflammation is mediated by continued recruitment of monocytes, local proliferation of Macrophages and immobilisation of macrophages.

 

Products released by macrophages in chronic inflammation

  • Toxic O2 metabolites, proteases, AA metabolites, NO–> mediate tissue injury
  • Growth factors(FGF,PDGF), fibrogenic cytokines, angiogenesis factors –> fibrosis

 

Cell types in chronic inflammation.

  • Macrophages are main
  • Lymphocytes
  • Plasma cells
  • Eosinophils
  • Mast cells
  • Neutrophils
  • Granulomatous inflammation (TB as a popular example)

 

Chronic inflammation characterised by focal accumulation of activated macrophages which often develop an epithelial like appearance. They are surrounded by a collar of mononuclear leukocytes usually lymphocytes and occasionally plasma cells.

Epitheliod cells can fuse to form giant cells.

TB – central caseous necrosis, acid fast bacilli

FB granuloma – giant cell with haphazard cell bodies.

 

 

Morphologic patterns in inflammation

Acute

 Chronic
Vasodilation Tissue destruction
Oedema Attempted healing by connective tissue replacement, angiogenesis
neutrophils

Monocytes – macrophages, lymphocytes, plasma cells.

Systemic effects of inflammation

  • Fever – pyrogens act on hypothalamus(via PG) can be exogenous or endogenous.
  • Raised acute phase proteins – CRP, fibrinogen, serum amyloid A protein–> upregulates TNF a, IL1, IL6
  • Neutrophilia/lymphycytes in viral and eosinophilia in asthma/parasites.
  • Annorexia, sleepy, neutrophilia, corticotrophins and steroids, shock(hypotension, tachycardia, decreased peripheral resistance)
  • High levels of TNFa and IL1 can cause overwhelming levels of cytokines –> DIC, hypoglycaemia(liver dysfunction), cardiovascular failure(too much NO) –> septic shock.

 

Complement

Plasma protein system involved in immunity against microbes. C1-9, normally present in inactive forms. When activated they undergo a cascade of reactions to

  • Form membrane attack complex (C9)
  • C3a and C5a – mediate cell histamine release -> vasodilation and increased permeability
  • C3a – opsonises – assists phagocytosis
  • C5a – chemotaxis – leukocyte adhesion, activation and migration

Classic pathway – stim by Ag-Ab complex

Alternate pathway – stim by microbial surface molecules

Lectin Pathway – stimulated by plasma mannose binding lectin binds to carb on bacterial.

All pathways cleave and activate C3 – most abundant one.