The Role of Protein Kinase-C in Sensitization and Antigen Response of Airway Smooth Muscle

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Abstract
Recently, we reported the characteristic electrical and contractile changes of airway smooth muscle (ASM) preparations after administration of highly purified antiovalbumin immunoglobin G1(IgG1). Because these changes are comparable to those we observed after administration of several phorbol esters, we theorized that sensitization of ASM with IgG1 leads to the activation of protein kinase-C. Therefore, in this study we examined the effect of two inhibitors of protein kinase-C on the sensitization-induced changes of ASM cells. ASM preparations were obtained from adult male guinea pigs (Camm-Hartley strain). Changes in both the resting membrane potential, as measured by a glass microelectrode technique, and changes in the isometric force, measured by a copper-beryillum strain gauge, were continuously monitored. Experiments were conducted at the optimal length of ASM preparations and a temperature of 37%C. The preparations were pretreated with H-7 (1-(5-isoquinoillnyl-sulfonyl)-2-methyl piperazine) or NA-0345 (N,N-dimethylamine-methyl-SF2370) both protein kinase-C inhibitors, passively sensitized with IgG1, and consequently exposed to a specific antigen. We found that pretreatment inhibited the initial depolarization and the increase in the isometric force, usually observed after administration of IgG1 and that it attenuated ovalbumin-induced depolarization and sustained increase in the isometric force. These effects were concentration-dependent and were observed only when protein kinase-C inhibitors preceded administration of IgG1. Finally, H-7 pretreatment had no effect on KCl- or substance-P-induced physiologic changes but partially attenuated response to histamine. It is apparent that sensitization of ASM with specific IgG1, leads to the activation of protein kinase-C, which is critical for the response of ASM to IgG1, and specific antigen challenge.