Characterization of airway and vascular responses in murine lungs

1 We characterized the responses of murine airways and pulmonary vessels to a variety of endogenous mediators in the isolated perfused and ventilated mouse lung (IPL) and compared them with those in precision-cut lung slices. 2 Airways: The EC50 (mu M) for contractions of airways in IPL/slices was methacholine (Mch), 6.1/1.5 > serotonin, 0.7/2.0 > U46619 (TP-receptor agonist), 0.1/0.06 > endothelin-1, 0.1/0.05. In the IPL, maximum increase in airway resistance (R-L) was 0.6, 0.4, 0.8 and 11 cmH(2)O s ml(-1), respectively. Adenosine (less than or equal to 1 mM), bombesin (less than or equal to 100 mu M), histamine (less than or equal to 10 mM), LTC4 (less than or equal to 1 mu M), PAF (0.25 mu M) and substance P (less than or equal to 100 mu M) had only weak effects (<5% of Mch) on R-L. 3 Vessels: The EC50 (mu M) for vasoconstriction in the IPL was LTC4, 0.06 > U46619, 0.05 < endothelin-1, 0.02. The maximum increase in pulmonary artery pressure (PAP) was 11, 41 and 48 cmH(2)O, respectively. At 250 nM, the activity of PAF was comparable to that of LTC4. At 100 mu M only, substance P caused a largely variable increase in PAP. Serotonin, adenosine, bombesin, histamine and Mch had no or only very small effects on PAP. 4 Hyperresponsiveness: In both the IPL and slices, U46619 in subthreshold concentrations (10 nM) reduced the EC50 to 0.6 mu M. In the IPL, U46619 raised the maximum airway response to Mch 5 fold and the maximum PAF-induced vasoconstriction 4 fold. 5 Conclusion: Murine precision-cut lung slices maintain important characteristics of the whole organ. The maximum reagibility of murine airways to endogenous mediators is serotonin < Mch < U46619 < ET-1. The reagibility of the murine pulmonary vasculature is serotonin < LTC4 approximate to PAF < U46619 < ET-1. The airway and vessel hyperreactivity induced by U46619 raises the possibility that thromboxane contributes directly to airway hyperresponsiveness in various experimental and clinical settings.