Cationic Proteins Induce Airway Hyperresponsiveness Dependent on Charge Interactions

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Abstract
It has previously been demonstrated that human eosinophil-derived granule major basic protein (MBP) can increase airway responsiveness after intratracheal administration in the rat. This effect was mimicked by synthetic polycations, suggesting that charge interactions may be important in the development of airway hyperresponsiveness (AHR). To support this hypothesis, we investigated whether two other cationic proteins, platelet factor 4 (PF4) and cathepsin G, were capable of inducing AHR. Furthermore, to determine whether these effects were dependent on their positive charge, the charge of these proteins was neutralized with low molecular weight heparin. In addition, we have examined whether the effect of a synthetic polycation, poly-L-lysine could be inhibited by low molecular weight heparin, albumin, or dextran sulphate. MBP, PF4, or cathepsin G induced a 2- to 3-fold increase in airway responsiveness 1 h after instillation, as assessed by the dose of inhaled methacholine required to increase total lung resistance by 100%. Admixing these native cationic proteins with low molecular weight heparin inhibited the development of AHR. Similarly, poly-L-lysine increased airway responsiveness that was inhibited not only by low molecular weight heparin but also by two other anionically charged molecules, albumin and dextran sulphate. These findings suggest that charge interactions in the airways are important not only in alterations in airway responsiveness induced by eosinophil-derived MBP, but also because they underlie altered airway responsiveness after treatment with other cationic proteins. The precise mechanisms involved in this phenomenon remain to be determined.