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This Article Full Text Full Text (PDF) All Versions of this Article: 291/6/L1177    most recent 00142.2006v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via ISI Web of Science (2) Citing Articles via Google Scholar Google Scholar Articles by Liu, C. Articles by Janssen, L. J. Search for Related Content PubMed PubMed Citation Articles by Liu, C. Articles by Janssen, L. J.

Isoprostane-induced airway hyperresponsiveness is dependent on internal Ca²⁺ handling and Rho/ROCK signaling

Firestone Institute for Respiratory Health, St. Joseph's Hospital, and Department of Medicine, McMaster University, Hamilton, Ontario, Canada

Submitted 13 April 2006 ; accepted in final form 26 June 2006

We previously reported the ability of isoprostanes to induce airway hyperresponsiveness (AHR). In this study, we examined the signaling mechanisms underlying that phenomenon with the standard muscle bath technique. Responses to a threshold concentration of carbachol (CCh, 3 x 10^–9 M) were significantly augmented by pretreatment for 20 min with 8-isoprostaglandin E₂ (15-E_2t-IsoP, 10^–6 M): this AHR was obliterated in tissues pretreated with the selective Rho kinase (ROCK) inhibitor Y-27632 added 20 min before isoprostane, but not by cyclopiazonic acid (CPA). Increasing the CCh concentration to 3 x 10^–8 M (still considerably less than the half-maximally effective concentration of CCh) evoked larger contractions that were also augmented significantly by 15-E_2t-IsoP: this AHR was completely abolished in tissues pretreated with CPA as well as those pretreated with Y-27632. We noted, however, that Y-27632 and CPA profoundly effect baseline tone and the cholinergic response per se, which confounds the interpretation of the data summarized above. We therefore modified the protocol by using combinations of CCh and blocker (CPA, Y-27632, or nifedipine) that were equieffective. In this way, we found that AHR could not be demonstrated under conditions in which Rho/ROCK signaling or Ca²⁺ release was abolished (by Y-27632 and CPA, respectively). Likewise, other autacoids that act through G protein-coupled receptors via Rho/ROCK and Ca²⁺ release (serotonin, histamine) mimicked this effect of isoprostane, whereas bradykinin did not. We conclude that isoprostane-induced AHR is mediated in part through an action on Rho/ROCK signaling. This novel finding may contribute to a better understanding of the mechanisms underlying AHR and asthma.

RhoA; Rho kinase; airway smooth muscle; contraction; relaxation; cholinergic responsiveness; sarcoplasmic reticulum