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Key Words complement, C5a receptor, C5L2, inflammation
Abstract The complement system not only represents an effective innate immune mechanism of host defense to eradicate microbial pathogens, but it is also widely involved in many forms of acute and chronic inflammatory diseases including sepsis, acute lung injury, ischemia-reperfusion injury, and asthma, to give just a few examples. The complement-activated product, C5a, displays powerful biological activities that lead to inflammatory sequelae. C5a is a strong chemoattractant and is involved in the recruitment of inflammatory cells such as neutrophils, eosinophils, monocytes, and T lymphocytes, in activation of phagocytic cells and release of granule-based enzymes and generation of oxidants, all of which may contribute to innate immune functions or tissue damage. Accumulating data suggest that C5a provides a vital bridge between innate and adaptive immune functions, extending the roles of C5a in inflammation. Herein, we review human and animal data describing the cellular and molecular mechanisms of C5a in the development of inflammatory disorders, sepsis, acute lung injury, ischemia-reperfusion injury, and asthma.
INTRODUCTION
It has been almost a century since the complement system was discovered. In the past decade, the interest in complement research has been rekindled because of the discovery of complement receptors and new functional aspects of complement activation products. Traditionally, the complement system has been viewed as a central part of the innate immune system in host defenses against invading pathogens and in clearance of potentially damaging cell debris. However, complement activation has recently been implicated in the pathogenesis of many inflammatory and immunological diseases, including sepsis (1), acute respiratory distress syndrome (2), rheumatoid arthritis (3), glomerulonephritis (4), multiple sclerosis (5), ischemia-reperfusion injury (6), and asthma (7). Complement activation exerts its harmful roles through the generation of complement protein split products, especially C3a and C5a. Although these activation products are not necessarily the initiating factors in the inflammatory disorders, they appear to be responsible for promoting and perpetuating inflammatory reactions.
Among the complement activation products, C5a is one of the most potent inflammatory peptides, with a broad spectrum of functions. C5a is a strong chemoattractant (at 1-10 nM) for neutrophils and also has chemotactic activity for monocytes and macrophages (8). C5a causes an oxidative burst (O2 consumption) in neutrophils and enhances phagocytosis and release...