Role of Rho-associated protein kinase and histamine in lysophosphatidic acid-induced airway hyperresponsiveness in guinea pigs

Inhalation of oleoyl lysophosphatidic acid (LPA) induced airway hyperresponsiveness to acetylcholine (ACh). In contrast, palmitoyl and stearoyl LPA exerted minimal effects. Airway hyperresponsiveness was inhibited by inhalation of Y-27632, an inhibitor of Rho-associated protein kinase (ROCK). Mepyramine, an H1 histamine receptor antagonist and ketotifen, an inhibitor of histamine release and H1 histamine receptor antagonist, also inhibited airway hyperresponsiveness induced by LPA; however, aspirin failed to attenuate this response. The incubation of lung fragments with LPA gave rise to releases in histamine. On the other hand, LPA produced no significant changes on the smooth muscle contraction evoked by ACh. These findings suggest that LPA-induced airway hyperresponsiveness is attributable to activation of the Rho/ROCK-mediated pathway via endothelial cell differentiation gene (EDG) receptors, probably EDG 7. Moreover, histamine release may be involved.