Genetically Transmitted Cholinergic Hyperresponsiveness Predisposes to Experimental Asthma

Abstract

The excitatory innervation of the airway smooth muscle is primarily cholinergic in nature. However, the potential neural mechanism(s) underlying airway hyperresponsiveness, one of the hallmarks of asthma, is not fully understood. In this study, cholinergic hyperresponsive Flinders sensitive line (FSL) rats and their control counterparts, Flinders resistant line (FRL) rats, were repeatedly challenged with different doses of nebulized methacholine (0, 4, 16, 64, and 256 mg/ml) for 5 min. Airway responsiveness was assessed in spontaneously breathing, unrestrained animals by means of whole body plethysmography. Increased airway responsiveness of FSL rats was evidenced as a more pronounced increase in Penh value (enhanced pause, an index of bronchoconstriction) across different concentrations of methacholine. In subsequent experiments, FSL and FRL rats were sensitized to ovalbumin and challenged with nebulized antigen. Our results indicate that the genetically transmitted cholinergic hyperresponsiveness of the FSL rat is paralleled by an increased susceptibility to allergen-induced bronchoconstriction and inflammation of the airways. This study provides further evidence that neural factors can play an important role in determining airway responsiveness and thus may be relevant for the expression of asthma. In addition, the FSL rat may be a useful model for studies of airway hyperresponsiveness.