Asthma is a syndrome characterized by airways narrowing and hyperresponsiveness and is frequently associated with inflammation of the airways and/or the sinuses. We have shown that sinusitis in rabbits can cause a granulocyte-dependent increase in lower airways responsiveness caused by the post nasal drip of secreted granulocyte products, an effect also induced by the direct instillation of such products into the airways. Since eosinophil major basic protein has been suggested to play an important role in the hyperresponsiveness, a role for polycations in general, including those from other inflammatory cells, seemed likely. Employing studies with intact animals, isolated-perfused airways and tracheal epithelial cell cultures, the following three hypotheses will be examined: Hypothesis 1: Granulocytes can induce increases in airways responsiveness by the action of liberated cationic proteins. Neutralization of cations with anions such as heparin or albumin will abrogate the effects of these materials and will reduce the hyperresponsiveness seen after inflammation of the sinuses and airways. Hypothesis 2: Granulocyte-derived cations induce airways hyperreactivity in part by an action on the airway epithelium. Likely effects include: a) alterations of the barrier properties of the epithelium, b) induction of epithelial-derived mediators that act on nerves and/or smooth muscle, and c) loss and/or change in epithelial metabolic abilities. The recovery of the epithelium towards normal structure and function will coincide with the return of airways responsiveness to normal. Hypothesis 3: Actions of cationic proteins will render the airways more susceptible to the effects of lipid mediators which can also participate in the induction of airways hyperresponsiveness. Studies will involve the use of synthetic cations as well as those derived from neutrophils and eosinophils and will, in collaboration with project 5, explore the usefulness of anion 'therapy' in the models of IgE-induced hyperreactivity. These studies on the mechanisms of charge-induced airways hyperresponsiveness should help determine the mechanisms by which granulocytes (and other inflammatory cells) alter airways function, and may eventually lead to novel and effective therapy.
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