Role of cationic proteins in the airway: Hyperresponsiveness due to airway inflammation

Major basic protein (MBP) is a highly cationic protein found in the granules of eosinophils. It has been postulated that MBP may participate in the pathogenesis of airway hyperresponsiveness exhibited by asthmatic patients. Accordingly, we have employed a rat system to investigate the effect of human MBP instillation on airway responsiveness and the possible role of cationic charge in the determination of this effect. Major basic protein caused a significant increase in airway responsiveness to inhaled methacholine. Two polycations, poly-L-arginine and poly-L-lysine, also increased airway responsiveness to inhaled methacholine. Moreover, two other very different cationic proteins, platelet factor 4 (PF4) and cathepsin G were also capable of inducing airway hyperresponsiveness. These effects were dependent on their positive charge, since the charge-and, hence the effect- of these proteins was neutralized with low molecular weight heparin. In addition, other polyanions, such as low molecular weight heparin, albumin, or dextran sulfate, were also effective. We investigated whether two synthetic cationic proteins, poly-L-arginine and poly-L-lysine, could modify epithelial-dependent responses using a perfused guinea pig tracheal tube preparation. With an intact epithelium, methacholine was some 150 times less potent when applied intraluminally than when applied extraluminally. Perfusion of the luminal surface with cationic proteins increased the potency of intraluminally applied methacholine without modifying the responses to extraluminally applied methacholine. Cationic proteins also attenuated the relaxant effects of intraluminally applied KCl. These effects occurred in the absence of any overt epithelial cell damage. Our data demonstrates that cationic proteins can modify epithelial-dependent responses in the airways. While the precise mechanisms are unclear, a role is suggested for a charge- mediated interaction with the respiratory epithelium, resulting in airway smooth muscle dysfunction. Lastly, we suggest that it is the total cationic load formed by all of the inflammatory cells that may have importance in the pathogenesis of asthma.