Polyphosphoinositide metabolism in polymorphonuclear cells from healthy and thermally injured rats: effect of the immunomodulator RU 41740.

Burn trauma is associated with alterations of various components of host defenses, including impaired neutrophil functions. In an animal model of experimental thermal injury, we studied if the modifications of cellular reactivity result from alterations in signalling systems by comparing polyphosphoinositide breakdown, particularly the production of inositol phosphates (IP, IP2 IP3), in healthy and burned rat polymorphonuclear neutrophil leukocytes (PMNs). Neutrophil activators such as N-formyl-methionyl-leucyl-phenylalanine (fMLP) and serum-opsonized zymosan increased in vitro production of inositol phosphates in PMNs from healthy rats. The immunomodulator RU 41740 had no effect by itself, but decreased the stimulating effect of fMLP and zymosan. In PMNs from burned rats, the stimulating effects of fMLP and zymosan were decreased, while RU 41740 stimulated inositol phosphate generation. In vivo treatment with RU 41740 inhibited the activation of phosphoinositide metabolism by fMLP or zymosan in healthy rat PMNs. Similar treatment of burned rats after injury restored the stimulating effect of fMLP and zymosan on inositol phosphate accumulation in PMNs. Thus, RU 41740 can modulate fMLP and zymosan receptor-mediated signal transduction, inducing an attenuation of the phosphatidylinositol hydrolysis response. After burn injury, when the activating effects of fMLP and zymosan are inhibited, RU 41740 can, on the contrary, stimulate phospholipase C-mediated polyphosphoinositide turnover and the formation of intracellular messengers such as IP3. These data show that RU 41740 has different effects on polyphosphoinositide metabolism in rat PMNs, according to the physiological and pathological state of the animals. Interestingly, it has a beneficial action on the post-burn decrease in PMN reactivity.