Inhibition of neutrophil oxidative metabolism by nimesulide

Abstract

Oxygen derived free radical release from activated neutrophils may be in part responsible of tissue damage in the acute phase of inflammation. We have shown that the methane sulfonanilide antiinflammatory agent nimesulide inhibits the respiratory burst of phagocytosing neutrophils without affecting their phagocytic or chemotactic responsiveness. In fact, chemiluminescence and superoxide anion generation by polymorphonuclear leukocytes (PMN) stimulated with zymosan particles or with the synthetic peptide FMLP are inhibited by nimesulide and its 4-OH metabolite in a dose dependent fashion without affecting cell viability. The control of the extracellular flux of radical species by pharmacological compounds may affect the course of inflammation reducing tissue damage. Our data suggest that the inhibition of superoxide anion production by neutrophils is an additional mechanism of action of the antiinflammatory agent nimesulide.

The Anti-Inflammatory Drug Nimesulide Rescues Alpha-1-Proteinase Inhibitor from Oxidative Inactivation by Phagocytosing Neutrophils

“…Owing to the neutrophil's capacity to oxidatively in activate AlPI [4][5][6], elastase can escape regulation by AlPI and digest key connective tissue elements. These include elastin, type III and IV collagen, fibronectin, laminin and this end, we studied the anti-inflammatory drug nimesulide (NMS) [14], previously proved to reduce the neutro phil's oxidative potential by down-regulating the cell's capacity to handle oxygen [15,16] and by inactivating hypochlorous acid (HOC1) produced by the neutrophil myeloperoxidase system [17].…”

Pharmacological properties of nimesulide

“…14) appear to be 50-fold higher than those expected in plasma in vivo, but these are within the range observed in cellular uptake studies by Bevilacqua. Two major observations concerning the relevance of in vitro effects to what may occur in vitro should be taken into consideration. First, consistent with the ability of nimesulide to inhibit in vitro neutrophil respiratory burst [139,[142][143][144], it was found that the oral administration of 200 mg nimesulide taken by healthy volunteers results in a reduced capacity of circulating neutrophils to generate superoxide anions in response to a soluble stimulus, such as formyl-peptides, as well as in response to phagocytosis of opsonised targets [167]. Percent reductions of superoxide generation were 67.62% ± 7.57 (mean ± 1SEM, n = 8) and 36.75% ± 7.92 (mean ± 1SEM, n = 8) in response to formyl peptides and particle phagocytosis, respectively [167].…”

“…These cell activities are susceptible to inhibition by nimesulide as well. Indeed, the drug is able to inhibit neutrophil respiratory burst in a concentration-dependent manner, as detected by measuring both the production of superoxide anions [139,142] and cellular chemiluminescence [143,144,223]. The generation of oxidative derivatives of superoxide anions are also prevented by nimesulide [145,224].…”

Neutrophil Oxidative Responses

“…The capacity of neutrophils to respond to major chemotactic factors (FMLP, C5a) is unaffected by nimesulide (Capsoni et al 1987). Thus, cell recruitment at inflamed tissue sites will probably occur normally in the presence of the drug.…”