Inflammation associated with sepsis

When sepsis is present, endothelial damage occurs through at least two different pathways ( Fig 3). A rapid phase of damage occurs with activation of the serum complement system. This is followed by a slower phase of injury due to production of certain tissue cytokines. The rapid phase more closely resembles the acute inflammatory response occurring with ischemia-reperfusion because various components of the serum complement system activate neutrophils and other leukocytes causing generation of oxygen radicals, proteases, and arachidonic acid products. These factors cause acute damage to endothelial cells and increase microvascular pressures, both of which promote rapid tissue edema formation. The slower phase occurs because macrophages become activated and release cytokines, such as tumor necrosis factor-a and interleukin 1 (IL-1). These cytokines can cause up-regulation of neutrophil adherence factors, disruption of the endothelial cell cytoskeleton, and up-regulation of the endothelial-cell-expressed rolling factor E-selectin (ELAM-1). Leukocytes can then adhere to the endothelium and further disrupt the endothelial barrier, which in turn results in tissue edema formation over hours to days. The rapid and slow phases of endothelial damage have been discussed here as if they occur in series, but in practice it is difficult to separate the effects of the two systems in such a fashion.

Fig. 3 Schematic diagram showing the ability of endotoxin to produce lung damage: TNF-a, tumor necrosis factor-a; PKC, protein kinase C; MAC-1, leukocyte integrin CD11b/CD18; ELAM-1 (endothelial-leukocyte adhesion molecule), E-selectin; AA, arachidonic acid.

Because the mechanisms producing endothelial injury during sepsis are so complex, many problems are created for the clinician who must treat sepsis-induced inflammation in patients. Blocking systems which are activated during inflammation have not yet been shown to be particularly beneficial in treating the critically ill patient. Therefore much more research must be conducted using experimental animal models before the roles of all factors involved in the inflammatory process can be elucidated.

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