The focus of this AAIDCRC application is on the inflammatory pathogenesis of airway hyperresponsiveness that characterizes human asthma. Particular emphasis will be placed upon the pathogenesis of airway hyperreactivity caused by cellular adhesion and activation of eosinophils. The program consists of 3 related projects that focus upon the l) secretory, 2) neurohumoral and 3) hematopoietic aspects of eosinophil function in airway responsiveness. A fourth project is a Demonstration and Education Project (D&E) that is designed to install and assess the efficacy of an education program for an asthma treatment center in the inner city of Chicago. Project 1 aims to assess the role of specific endothelial and matrix protein adhesion reactions on the upregulation of stimulated secretion from immunomagnetically isolated human blood eosinophils. A second aspect of these investigations determines the role of eosinophil secretion that is augmented by ligand/matrix adhesion in inducing in vitro hypercontractility in human airways. Project 2 assesses bidirectional interactions between sensory c-fibers and eosinophils, which amplify cell recruitment and activation. The physiological relevance to airway hyperresponsiveness of these in vitro interactions is evaluated also in two models of guinea pig inflammation m vivo. Project 3 examines in detail the molecular and cellular aspects of eosinopoiesis using a recently developed method for culturing eosinophils in vitro from the umbilical cord blood of neonates. Since eosinopoiesis is the first step in the translocation of these inflammatory cells to the conducting airways, studies are proposed to assess the essential roles of GM- CSF, interleukin (IL)-3 and IL-5 in the in vitro differentiation of bioactive eosinophils. A second series of studies seeks to identify interactions between extracellular matrix factors and eosinophils that influence cytokine-directed eosinopoiesis. Project 4 is a D and E project that tests the hypothesis that self-management instruction through community health workers significantly decreases morbidity and mortality among inner city children with limited health care resources. This program, conducted through the Department of Pediatrics and the La Rabida Children's Hospital, assesses the efficacy of a targeted co-management approach between physician and community health worker in achieving better asthma treatment by altering patient behavior. Data derived from the basic science component of these investigations will provide a coordinated approach to understanding the role of the eosinophil in caring airway hyperresponsiveness. The D & E project utilizes an experienced clinical teacher to apply pharmacological concepts of asthma therapy to a population facing diminishing health care resources. It is anticipated that the studies proposed in these projects will contribute to a mechanistic understanding of the cellular mechanisms that convert normally responsiveness tissues into asthmatic airways and of applying current therapies effectively.
