Professor in the Department of Environmental Health
Director, Molecular and Integrative Physiological Sciences Program
Professor of Pathology, HMS
Pathologist, Brigham & Women’s Hospital
My main research interest is how the lung interacts with inhaled particles—be they environmental particulates, pathogens or allergens. One focus is the role of the lung macrophage in lung defense mechanisms and pulmonary inflammation, especially in relationship to environmental lung disease.
A fascinating aspect of lung macrophages is their selective interaction with inhaled particles. They respond with simple ingestion and clearance to some particles (the harmless, ‘inert’ dusts). In contrast, encounters of lung macrophages with pathogenic particles result in release of mediators that initiate inflammation and injury. These mysteriously regulated responses are central to the public health problems caused by air pollution in urban areas, by dusts in certain occupations, and by certain inhaled pathogenic organisms.
My lab is approaching the problem at a number of levels. I have used in vitro analysis of macrophage-particle interactions to identify features of both host (e.g., inflammatory priming) and particle (e.g., solid vs. soluble phases, trace endotoxin) important in pathogenesis. To identify the structure(s) that mediate particle binding, my lab has used monoclonal antibodies and expression cloning to implicate scavenger-type receptors on the cell surface of the lung macrophage as the molecules that allow this cell to bind a diverse range of inert particles. Recently, we have found that a surprising member of this family of receptors (MARCO) is responsible for this important macrophage function.
Current studies using ‘knockout’ mice deficient in scavenger receptors confirm their critical importance in defense of the lung against environmental particles and infectious bacteria. My research program is also targeting another problem caused by inhaled particles (allergens)—asthma. Specifically, these studies have developed a novel mouse model of the maternal transmission of asthma risk. The role of maternal lymphocytes and cytokines is being investigated using adoptive transfer and cytokine blockade technologies. The goal is to provide new insights into the mechanisms for allergic or ‘tolerance’ responses to inhaled allergens in early life.