HUMAN EOSINOPHIL GRANULE MAJOR BASIC-PROTEIN AND SYNTHETIC POLYCATIONS INDUCE AIRWAY HYPERRESPONSIVENESS IN-VIVO DEPENDENT ON BRADYKININ GENERATION

In the current series of experiments we investigated the role of brady kinin in airway hyperresponsiveness induced by human eosinophil-granul e major basic protein (MBP), Bronchoalveolar lavage was performed afte r intratracheal instillation of MBP or poly-L-lysine in anesthetized, intubated rats, and levels of immunoreactive kinins and kallikrein-lik e activity were determined, Both MBP and poly-L-lysine induced a three - and eightfold increase in levels of kallikrein-like activity and i-k inins, respectively, To determine whether kinin production is required for the development of airway hyperresponsiveness induced by cationic proteins, dose-response curves to methacholine were constructed befor e and 1 h after intratracheal instillation of either MBP or poly-L-lys ine (100 mu g). MBP and poly-L-lysine induced an increase in airway re sponsiveness, which was inhibited by pretreatment with a selective BK- 2 receptor antagonist, NPC 17713 (250 mu g/ml). Our results demonstrat e that MBP and poly-L-lysine activate kallikrein and stimulate the gen eration of i-kinins in vivo, an effect that may be related to the cati onic charge of these proteins, Furthermore, the ability of these prote ins to increase airway responsiveness appears to be dependent on the g eneration of i-kinins.