Regulation of Polymorphonuclear Leukocyte (PMN) Survival and Function by Proinflammatory Agents That Are Released as a Consequence of Sulfur Mustard- Mediated Injury

摘要

The chemical warfare vesicant, sulfur mustard (SM), continues to be an effective weapon of terror more than eighty years after the end of World War I. Exposure of the skin and other epithelial surfaces to this agent leads to a reproducible pattern of histological injury (1). Despite considerable investigation over many years, no effective therapy currently exists for the treatment and/or prevention of SM induced wounds. It is also apparent that SM induces a secondary inflammatory response that may cause extension and prolongation of the initial tissue injury (2-4). PMN are the primary effector cells in the innate immune response against infection (5). When activated, PMN produce reactive oxygen species (ROS) and express a number of antimicrobial agents via exocytosis of preformed granules, all of which can be injurious to host tissue. PMN activation is a two-step process that requires an initial exposure to an agent that 'primes' the PMN, and results in an amplified response to a secondary, or activating, stimulus (6). Priming is important in modulating the activation of PMN, since unprimed circulating PMN do not express the same antimicrobial capacity as primed PMN extravasated at the site of injury or infection (7). In vivo studies have also shown that the response from primed PMN can result in increased damage to host tissue, when compared to unprimed PMN (8, 9). The extent to which a priming agent enhances PMN response to stimulus depends on the concentration of and length of exposure to the priming agent and can vary greatly between different agents (7).