AUGMENTED MUSCARINIC RESPONSIVENESS CAUSED BY 5-LIPOXYGENASE PRODUCTSSECRETED FROM ALVEOLAR MACROPHAGES IN ISOLATED-PERFUSED RAT LUNG

We examined the effect of activated alveolar macrophages (AM) on airwa y responsiveness to muscarinic stimulation in 33 adult Sprague-Dawley rats. An isolated-perfused lung preparation was used to ensure precise and uniform delivery of cells into peripheral airways. The bronchocon strictor response to acetylcholine (ACh) delivered into the pulmonary arterial circulation was augmented in 8 rats after infusion of 3 x 10( 6) AM activated with 10(-6) M f-met-leu-phe and 5 mug/ml of cytochalas in B. Lung resistance (RL) caused by 10(-6) mol ACh increased 2.5-fold from 0.10 +/- 0.004 cm H2O/Ml/s before infusion of activated AM to 0. 35 +/-0.05 cm H2O/Ml/s after infusion of activated AM (N = 8; p < 0.05 ); the response to ACh was not augmented after infusion of nonactivate d AM (N = 7) or vehicle control (N = 6). Baseline RL before ACh was si milar in all three groups (p NS). Perfusion with activated AM also sig nificantly increased the wet/dry (W/D) lung weight ratios (7.1 +/- 0.5 ) compared with nonactivated AM (5.2 +/- 0.1) or vehicle control (5.5 +/- 0.3) (p < 0.05 versus either nonactivated AM or vehicle control). A63162, a 5-lipoxygenase inhibitor, but not indomethacin, a cyclooxyge nase inhibitor, completely inhibited augmentation of bronchoconstricto r responses to ACh caused by activated AM and also completely attenuat ed the increase in W/D lung weight ratios. A highly significant (p < 0 .01) correlation (R = 0.76) between W/D lung weight ratios and RL was observed after 10(-6) mol ACh (the greatest dose of ACh administered). Baseline RL was equivalent for all groups before and after infusion o f cells or vehicle. We demonstrate augmented muscarinic responsiveness in isolated-perfused lungs after exposure to activated AM. This augme ntation occurs with the increase in the lung W/D ratio and is correlat ed with the magnitude of airway responsiveness. These effects of activ ated AM depend upon the elaboration of products of the 5-lipoxygenase pathway.