The activation and accumulation of leukocytes during inflammatory processes such as that initiated by
myocardial ischemia and reflow appear to be major determinants of irreversible tissue injury. Myocardial salvage by dual
cyclooxygenase/
lipoxygenase inhibitors and selective
5-lipoxygenase inhibitors has suggested a role for
lipoxygenase (LOX) products, such as the potent
chemotactic factor leukotriene B4, in
ischemia-reflow injury. However, many LOX inhibitors are
antioxidants and several have been shown to directly inhibit neutrophil function in vitro, thereby questioning the role of LOX products in
reperfusion injury. To clarify further the protective mechanism of
lipoxygenase inhibitors, we have examined the effects of two nonantioxidant inhibitors,
SK&F 86002 and
REV-5901, on human neutrophil activation and function in vitro. The
antioxidant LOX inhibitor nordihydroguiaretic
acid, which served as a positive control, exhibited a concentration-dependent inhibition of
N-formyl-methionyl-leucyl-phenylalanine (fMLP) and recombinant C5a-induced neutrophil bipolarization, fMLP-induced upregulation of the adherence
glycoprotein Mac-1 (CD11b/CD18), fMLP-induced aggregation and neutrophil adherence to and migration through interleukin-1-stimulated human endothelial monolayers. In contrast, neither
SK&F 86002 nor
REV-5901 (in concentrations up to 50 microM) had any effect on these functions, nor did they inhibit neutrophil oxidative metabolism (
phorbol myristate acetate-induced chemiluminescence). Inasmuch as both of these agents have been observed to reduce
myocardial ischemia-reflow injury in vivo, their failure to directly inhibit neutrophil function further supports an important role for chemotactic LOX products in the pathogenesis of
reperfusion injury.