The acute inflammatory Response

In a classical acute anti-inflammatory response, such as occurs as a result of streptococcal invasion of the lung airspaces in the evolution of labor streptococcal pneumonia , a stereotyped sequence of cellular and mediator events is usually provoked (see fig. 1.22):

·         Neutrophils sequester in the local lung capillaries, emigrate through the vascular endothelium, the basement membrane and the alveolar epithelial layer, and begin to appear in the alveolar spaces within 2 hours, with a peak of emigration at 4 – 6 hours.

·         Neutrophils become activated, phagocytose and destroy opsonised bacteria by secreting reactive oxygen species (ROS) and granule enzymes into the phagosome.

·         Monocytes begin to emigrate from capillaries into tissues at about 6 hours, reaching a peak at 18-24 hours. Monocytes rapidly mature into inflammatory macrophages which kill and scavenge dead organisms and debris.

In most inflammatory reactions there is vascular dilatation and leakage of fluid and proteins during the early stage of neutrophil emigration. This exudates contains an array of proteins and other mediators, e.g. members of the complement and coagulation cascades, immunoglobulins and other factors that may aid host defense and later repair. In a ‘successful’ beneficial inflammatory response, such as occurs in most cases of lobar pneumonia, inflammatory cells rapidly disappear as the lesion resolves. It is likely that extravasated granulocytes undergo apoptosis locally and are phagocytosed by macrophages; tissue numbers of macrophages then return to normal. Even in ‘beneficial inflammation’ like lobar pneumonia, there is often ‘bystander’ injury to local endothelial cells and epithelial cells; these must be repaired/replaced before tissue homeostasis is re-established.

Much has been learned about the cellular and mediator events involved in the initiation of acute inflammation; some of these mechanisms may provide new targets for therapy in inflammatory disease. Local tissue perturbation, e.g. bacterial invasion, causes the release of inflammatory mediators. Some of these act as chemotaxins, attracting neutrophils then monocytes to the site; others (e.g. TNF-α, IL-1) act on local vascular endothelial cells to promote their adhesion to the surface of activated inflammatory cells (see table. 1.3). Bacteria can generate neutrophil chemotaxins in several ways; some of there own products (e.g. Formylated peptides) are chemotactic; activation of the complement system will generate C5a, an important neutrophil chemotaxin; but perhaps the most important mechanism is the induction of chemokine generation by resident macrophages and other tissue cells. The chemokines (e.g. IL-8, RANTES and eotaxin) are a large family of small, but potent, peptides which attract and activate different inflammatory cells via specific surface receptors. The arrest of neutrophils in a local microvessels is a necessary prelude to their transmigration through the endothelial and epithelial layers and it involves a two-steps process. The first phase is one of transient adhesion which is mediated by adhesion molecules of the selectin family; the second phase of tight adhesion and transmigration is medicated by adhesion molecules of the integrins family (see table 1.3). It is now clear that just as there are many neutrophils chemotaxins, there are also many adhesion molecules that can mediate neutrophil adhesion to microvescular endothelial cells. The importance of the integrin mechanisms in host defense is well illustrated by LAD ,which is caused by an inherited defect in the β chain of the leucocyte integrins.  

although eosenophils and monocytes sequester and emigrate by very similar mechanisms, it is likely that selective accumulation is achieved by differential secretion and expression of the different members of the chemokine and adhesion molecule repertoire (e.g. IL-8 is chemotactic specifically for neutrophils, whereas RANTES and eotaxin specifically attract eosinophils).