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A7206 - Bile Acids Alter the Contractile Responses of Distal Airways to Bronchoconstrictors
Author Block: A. Urso1, F. D'Ovidio1, C. W. Emala2, N. W. Bunnett3, J. F. Perez-Zoghbi2; 1Lung Transplant Program, New York Presbyterian Hospital/ Columbia University Medical Center, New York, NY, United States, 2Anesthesiology, New York Presbyterian Hospital/ Columbia University Medical Center, New York, NY, United States, 3Surgery, New York Presbyterian Hospital/ Columbia University Medical Center, New York, NY, United States.
Introduction: Gastro-esophageal reflux (GER) with bile acids (BAs) aspiration is associated with post lung transplant chronic allograft dysfunction and possibly other lung diseases. However, it is unknown whether BAs affect airway tone. We investigated the contractile responses of distal airways to a comprehensive panel of all primary and secondary BAs that have been previously detected in the bronchial washings from lung transplant patients and investigated the mechanism(s) of their effects. Methods: Studies were approved by the Columbia University IACUC and IRB. Precision-cut lung slices (PCLS) were prepared from humans and wild type or TGR5 KO mice. Dynamic changes in airway lumen area in response to the 13 BAs and bronchoconstrictors (acetylcholine or 5-HT) were studied with video-phase contrast microscopy. Synthesis of inositol triphosphates (InsP3) was measured using a radioactive assay. Cholinergic mediated contractions in response to electrical field stimulation (EFS) were measured in guinea pig tracheal rings. Results: Perfusion of PCLS with 30 µM BAs alone showed no effects on resting airway lumen area. However, in airways pre-contracted with 300 nM ACh, addition of BAs induced an ~50% relaxation. In contrast, in mouse airways pre-contracted with 300 nM 5-HT, BAs induced an ~80% further constriction. Secondary derivatives of lithocholic and deoxycholic acids were the most potent BAs. Perfusion of PCLS with 30 µM TC-G 1005, a potent and selective agonist for a known G protein-coupled bile acid receptor (TGR5), had no effect on airway contraction in airways pre-contracted with either ACh or 5-HT while BAs had similar effects on airways from wild type and TGR5 KO mice. BAs inhibited the InsP3 synthesis induced by 300 nM ACh in human airway smooth muscle cells overexpressing the M3 muscarinic receptor. Furthermore, the BA taurolithocholic acid strongly attenuated airway smooth muscle contractions triggered by cholinergic nerve activation with EFS. Conclusions: Our results demonstrate that BAs alter the contractile responses of the peripheral airways to bronchoconstrictors and suggest that these effects were mediated in part by the interaction of BAs with muscarinic receptors in airway smooth muscle. The mechanism by which BAs potentiate 5-HT mediated airway constriction warrants further investigation. Interaction of BA with the distal airways may be important for the pathophysiology of chronic lung allograft dysfunction and other respiratory diseases associated with GER-mediated aspiration.