Calcium and protein kinase C dependency of lipoxygenase-derived neutrophil chemotactic activity release from bronchial epithelial cells.

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Abstract
In the present investigation, we evaluated the roles of calcium, calcium-calmodulin, inositol turnover, and protein kinase C in the release of lipoxygenase-derived metabolites with neutrophil chemotactic activity (NCA) from bronchial epithelial cells (BECs) in response to endotoxin (ETX) and opsonized zymosan (OZ). Both ETX and OZ stimulated BECs to release NCA [56.9 +/- 5.1 (ETX), 65.2 +/- 5.1 (OZ) versus 15.2 +/- 3.0 (controls) cells/high power field, P < 0.001]. The lipoxygenase inhibitors, nordihydroguaiaretic acid and diethylcarbamazine, and phospholipase A2 inhibitors, mepacrine and dibucaine, blocked the release of NCA in response to ETX, OZ, calcium ionophore A23187 (A23187), and phorbol myristate acetate (PMA). The calcium channel blockers, nifedipine and verapamil, and two putative inhibitors of calcium release from intracellular storage sites, 8-(N,N-diethylamine)-octyl-3,4,5-trimethoxybenzoate hydrochloride and ruthenium red, inhibited the release of NCA induced by ETX but had little effect on the release of NCA induced by OZ. However, depletion of extracellular calcium inhibited the release of NCA in response to both ETX and OZ. Calmodulin inhibitors, compound 48/80 and N-(6-aminohexyl)-1 naphthalenesulfonamide (W-7), inhibited the release of NCA in response to a variety of endotoxin concentrations. Lithium chloride, an inositol turnover inhibitor, inhibited the release of NCA in response to both ETX and OZ, but less attenuation was observed in the response to OZ. A protein kinase C inhibitor, dihydrosphingosine, inhibited the release of NCA in response to both ETX and OZ. Finally, A23187 and PMA stimulated the release of NCA and [3H]arachidonic acid independently and additively. These data suggest that the release of NCA from BECs in response to OZ may be predominantly mediated by inositol turnover and protein kinase C and that the release of NCA in response to ETX may be regulated by calcium influx and calcium release from intracellular storage sites, calcium-calmodulin activation, inositol turnover, and protein kinase C activation. Protein kinase C augmented the release of NCA and [3H]arachidonic acid independent of and in combination with calcium. These results may suggest the calcium and protein kinase C dependency of the release of NCA from BECs.

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