Exaggerated airway narrowing in mice treated with intratracheal cationic protein

Airway hyperresponsiveness in mice with allergic airway inflammation can be attributed entirely to exaggerated closure of peripheral airways ( Wagers S, Lundblad LK, Ekman M, Irvin CG, and Bates JHT. J Appl Physiol 96: 2019 - 2027, 2004). However, clinical asthma can be characterized by hyperresponsiveness of the central airways as well as the lung periphery. We, therefore, sought to establish a complementary model of hyperresponsiveness in the mouse due to excessive narrowing of the airways. We treated mice with a tracheal instillation of the cationic protein poly-L-lysine (PLL), hypothesizing that this would reduce the barrier function of the epithelium and thereby render the underlying airway smooth muscle more accessible to aerosolized methacholine. The PLL-treated animals were hypersensitive to methacholine: they exhibited an exaggerated response to submaximal doses but had a maximal response that was similar to controls. With the aid of a computational model of the mouse lung, we conclude that the methacholine responsiveness of PLL-treated mice is fundamentally different in nature to the hyperresponsiveness that we found previously in mice with allergically inflamed lungs.