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 lung host defense against inhaled challenges—be they environmental particulates, pathogens or allergens.
A recent focus is the problem of bacterial pneumonia, especially the secondary bacterial pneumonias that follow influenza. To identify new approaches to enhance innate immunity to bacterial pneumonia, we have investigated the natural experiment of gender differences in resistance to infections. Female and estrogen-treated male mice show greater resistance to pneumococcal pneumonia, seen as greater bacterial clearance, diminished lung inflammation, and better survival. Inhibitors and genetically altered mice identify a critical role for estrogen-mediated activation of lung macrophage nitric oxide synthase-3 (NOS3). Epidemiologic data show decreased hospitalization for pneumonia in women receiving estrogen or statins (known to activate NOS3). Pharmacologic targeting of NOS3 with statins or another small-molecule compound (AVE3085) enhanced macrophage bacterial killing, improved bacterial clearance, and increased host survival in both primary and secondary (post-influenza) pneumonia. The data identify a novel mechanism for host defense via NOS3 and suggest a potential therapeutic strategy to reduce secondary bacterial pneumonia after influenza.
Another project is investigating the potential benefit of plasma gelsolin. Plasma gelsolin (pGSN) functions as part of the ‘extracellular actin scavenging system’ but its potential to improve host defense against infection has not been studied. In a mouse model of primary pneumococcal pneumonia, rhu-pGSN causes enhanced bacterial clearance, reduced acute inflammation and improved survival. pGSN also triggers activating phosphorylation (ser1177) of macrophage nitric oxide synthase type III (NOS3). Prophylaxis with immunomodulators may be especially relevant for patients at risk for secondary bacterial pneumonia, e.g. after influenza. Treatment of mice with pGSN challenged with pneumococci on day 7 after influenza (peak of enhanced susceptibility to secondary infection) caused ~15-fold improvement in bacterial clearance, reduced acute neutrophilic inflammation, and markedly improved survival even without antibiotic therapy. These studies identify plasma gelsolin is a potential immunomodulator for improving lung host defense against primary and secondary bacterial pneumonia.
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 epigenetic changes in dendritic cells in transgenerational transmission of asthma risk is our current project. The goal is to provide new insights into the mechanisms for allergic or ‘tolerance’ responses to inhaled allergens in early life.