Lester-Kobzik-orig

Lester Kobzik

Professor in the Department of Environmental Health
Director, Molecular and Integrative Physiological Sciences Program

Department of Environmental Health

Department of Environmental Health

655 Huntington Avenue
Building II Room 221
Boston, Massachusetts 02115
Phone: 617.432.2247

Other Affiliations

Professor of Pathology, HMS
Pathologist, Brigham & Women’s Hospital

Research

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.

A recent 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.