inflammation

definition

· response of body to injury

process

Vascular phase

· redness, heat and swelling of inflammation due to vascular phase

· transient vasoconstriction after injury

· then vasodilatation of arterioles

· followed by increased permeability of microvasculature

· plasma exuded into extravascular space

Cellular phase

· leukocytes adhere to endothelium (margination)

· migrate into extravascular space

inflammatory cells

Granulocytes

Neutrophils

· neutrophils attracted by chemotactic agents

· phagocytose bacteria, immune complexes and particulate matter

· particulate matter may be opsonised (coated with complement or IgG)

· opsonisation facilitates phagocytosis by aiding recognition

· during phagocytosis

· particle encased by vacuole

· lysosomes fuse with vacuole

· released enzymes destroy particle

· released enzymes may also cause cell death and tissue injury

Eosinophils

· involved in host defence from parasitic infections

Mast cells and basophils

· involved in allergic or immediate hypersensitivity reactions

Macrophages

· important in chronic inflammation

· produced as monocytes in bone marrow

· function to

· phagocytose matter

· present antigenic matter to T cells

Lymphocytes

· identify foreign antigens

· participate in responses to eliminate these antigens

· B cells become antibody-producing plasma cells

· T cells mediate cellular immunity

Mediators

Complement

· proteins that circulate in plasma in inactive form

· activated by sequential proteolytic cleavage

· functions

· activation of inflammatory cells

· cytolysis of cells infected with microorganisms

· opsonisation of foreign matter to facilitate phagocytosis

· starts when antigen-antibody complex activates C1

· C3 facilitates phagocytosis of micro-organisms

· C5-9 inserted into cell membranes as pores

· C5a and C9a cause histamine release from mast cells

· C5a is chemotactic for neutrophils

Kinins

· 4 proteins that circulate in plasma in inactive form

· activated by contact with negatively charged surfaces

· cause

· increased vascular permeability

· vasodilatation

· hypotension

· pain

· leukocyte margination

Vasoactive amines

Histamine

· stored in mast cell granules

· released on mast cell activation by IgE

· produces

· increased vascular permeability

· vasodilatation

· bronchospasm

Serotonin

· stored in platelets

· causes

· vasoconstriction

· increased vascular permeability

· fibrogenesis

Arachidonic acid metabolites

· AA is fatty acid found in most tissues

· released by phospholipases

· PL A₂ and PLC

Prostaglandins

· cyclooxygenases catalyse conversion of AA to PGG₂

· PGG₂ converted to PGH₂

· PGH₂ converted to

· PGI₂ (prostacyclin)

· thromboxane A₂

· PGD₂

· PGE₂

· PGF₂

· inflammatory effects of PGE₂ and PGI₂

· vasodilatation

· increase vascular permeability (act with histamine and kinins)

· stimulate osteoclastic bone resorption

· elevate cellular levels of cAMP (mediates effects)

· anti-inflammatory effects

· inhibit T cell activation

· inhibit B cell proliferation

· inhibit IL-2 production

Leukotrienes

· lipoxygenases catalyse conversion of AA to leukotrienes

· leukotrienes are important mediators

· chemotactic for leukocytes

· activate enzyme secretion by neutrophils

· increase vascular permeability

· cause bronchospasm

Regulation

NSAIDs

· NSAIDs inhibit cyclooxygenase activity

· explains many of its effects

· inhibits PG synthesis

· eliminates cytoprotective effect of PGE₂ on gastric mucosa

Glucocorticoids

· inhibit release of AA from phospholipids

Platelet activating factor

· phospholipid

· produced by

· neutrophils

· macrophages

· platelets

· causes

· platelet aggregation

· granule secretion by neutrophils and macrophages

· smooth muscle stimulation in lung and gut

· mediates immediate hypersensitivity reactions

Growth factors or cytokines

· polypeptides that regulate inflammatory cells

· several called interleukins

IL-1, IL-6 and TNF

· similar actions

· produced by monocytes

· effects

· pyrogenic

· stimulate synthesis of acute phase proteins by liver

· facilitates B and T cell proliferation

· stimulate stem cell growth for neutrophils and monocytes

· stimulate production of PGE₂

IL-2 and IL-4

· stimulate proliferation of T cells

· stimulate Ig production by B cells

· stimulates fusion of macrophages to form giant cells

IL-3, IL-5 and IL-7

· promote growth and differentiation of haemopoietic stem cells

Interferons

· interferon-gamma

· produced by activated T cells

· induces expression of type II MHC antigens on several cell types

· activates macrophages for antigen presentation

Proteinases

· potent mediators

· most stored in lysosomes of leukocytes

Acid proteinases

· degrade bacteria and cell debris at low pH within phagolysosomes

Neutral proteinases

· degrade extracellular proteins in connective tissue at neutral pH

· two important enzymes

Metalloenzymes

· require metal ions (eg Zn) as cofactor

Serine proteinases

· collagenase

· degrades extracellular collagen

· gelatinase

· degrades gelatin (denatured collagen)

· proteoglycanase

· degrades proteoglycans