The generation of utilization of chlorinated oxidants by human neutrophils

Abstract

The human neutrophil uses the hydrogen peroxide-myeloperoxidase-chloride system to generate a complex mixture of chlorinated oxidants which includes both hypochlorous acid (HOCI) and a wide spectrum of nitrogen-chlorine (N-C1) derivatives. Although these species differ in their reactivity with susceptible target molecules, they are capable of mediating diverse biologic effects. These effects range from the modulation of cellular function and induction of cell lysis to the regulation of neutrophil proteoIytic enzyme activity and enzyme-inhibitor interactions. When chlorinated oxidants are used by neutrophils to mediate ceil injury, HOCI appears to be the toxic species involved. The endogenous, long-lived, N-CI derivatives generated by triggered neutrophils cause little injury to microbial or mammalian targets by virtue of their hydrophilic characteristics. However, the presence of appropriate endogenous or exogenous nitrogenous compounds in the extracellular medium can result in the generation of lipophilic N-C1 oxidants having a heightened cytotoxic potential. Chlorinated oxidants are also able to participate in the regulation of neutrophil elastase and collagenase activity during release of these enzymes from intracellular lysosomal granules. Elastase activity is indirectly up-regulated by the oxidative destruction of its primary inhibitor, α1-proteinase inhibitor, while collagenase is oxidatively converted from a latent, inactive enzyme to a fully proteolytic product. Thus, neutrophils are able to convert the short-lived, nonspecific reactivity of HOCI into highly specific and long-acting effects by modifying cellular or plasma constituents that are critical to the development of the inflammatory response.