INFLAMMATION: AN ORCHESTRATED CELLULAR RESPONSE

The inflammatory response results from a complex interplay between different mediator cascades (e.g. complement, cytokines and chemokines), the ‘inflammatory’ blood cells (neutrophils, eosinophils and monocytes) that are recruited to the site, and ‘resident’ tissue cells, particularly the micro-vascular cells of the organ or tissue involved. The beneficial nature of the inflammatory response, particularly in host defense against infection, has been recognized for centuries, and has the classical external signs: calor, rubor, dolor and functio laesa-heat, redness, pain and loss of function. However, it has only comparatively recently become clear that these identical processes may, under circumstances that are not fully understood, be centrally involved in the pathogenesis of a wide range of common and important diseases (see the information box). The acute inflammatory response is often restricted to recruitment of neutrophil granulocytes and inflammatory macrophages yet its effectiveness is clearly exemplified in streptococcal lobar pneumonia (see table 4.12). In more complex situations (e.g. some viral diseases), a chronic inflammatory response causes additional local recruitment of lymphocytes, sometimes leading to a fibrotic response, or against some parasites (e.g. in schistosomiasis, see fig2.43) there may be local recruitment of large numbers of eosinophin granulocytes in addition to neutrophils and lymphocytes, thus completing the cellular picture typical of allergic inflammation. Defects in the cellular or mediator components of inflammation can lead to major problems in host deffence against bacterial infections. These can be inherited (e.g. leucocyte adhesion deficiency – LAD – see the information box) or acquired (e.g. drug-induced neutropenia). 

Some functions of Macrophages

Inflammatory Responses

·          Initiation Generation of neutrophil chemokines (e.g. IL-8) Generation of monocyte chemokines (e.g. MIP-1α) Generation of agents (e.g. IL-1, TNF-α) that activate endothelial cells Generation of acute phase response (IL-1, TNF, IL-6) ·          Amplification Secretion of agents that stimulate bone marrow generation of leucocyte (IL-1, TNF- α) ·          Resolution Scavenging of necrotic and apoptotic cells and debris ·          Repair/ Fibrosis Remodeling – elastase, collagenase Scar formation – IL-1, platelet-derived growth factor (PDGF), fibroblast growth factor (FGF)

Immune Response

·          Antigen presentation – lymphocyte activation

Host Defense

·          Phagocytosis and killing of microorganisms by oxygen radicals, nitric oxide-dependent mechanisms and enzymes

Antitumour effects

·          Lysis of tumor cells by TNF- α and nitric oxide-dependent mechanisms

LEUCOCYTE ADHESION DEFICIENCY (LAD)

See Figure 1.19

Mechanism

·          Inherited defect of β2 integrins on the neutrophil surface

Clinical Features

·          Destructive skin ulceration without pus formation (no neutrophil emigration) ·          Chronic neutrophilia ·          Poor wound-healing with dystrophic scars ·          Delayed umbilical cord separation in the neonate ·          Recurrent septicaemia and life-threatening infection.