Mucosal Immunology Laboratories
http://www.massgeneral.org/mucosalimmunology/fellows/fellow_hurley.html
Summary of Research
During my thesis studies in the Program of Immunology at Tufts University Sackler School of Biomedical Science, I became interested in mechanisms of innate mucosal immunity. Particularly, I wanted to better understand how pathogenic bacteria stimulate the process of neutrophil migration through epithelial surfaces. Upon completion of my thesis I joined the lab of Dr. Beth A. McCormick at the Mucosal Immunology Laboratories at Massachusetts General Hospital to further pursue this important area of innate immunity. Dr. McCormick has developed a novel in vitro assay to study pathogen-induced neutrophil migration across intestinal epithelial cell barriers. Studies using this model have uncovered a previously unrecognized inflammatory signaling pathway involving Protein Kinase C (PKC) and the production and secretion of an eicosanoid neutrophil chemo-attractant known as hepoxilin A3. As a member of Dr. McCormick’s lab, I have participated in studies mapping this novel pathway in intestinal cells and have adapted this in vitro assay to assess pathogen / epithelial interactions at the lung epithelial surface. We have recently made the observation that the lung pathogen Pseudomonas aeruginosa stimulates neutrophil migration across lung epithelial monolayers in a manner independent of the well-studied protein neutrophil chemokine, IL-8. Similar to intestinal cells, lung epithelial cells are capable of producing the eicosanoid, hepoxilin A3, in a PKC-dependant manner. Production of hepoxilin A3 occurs in response to infection with Pseudomonas aeruginosa and serves to direct neutrophils across the lung epithelial monolayers. More recently, we have uncovered an important role for phospholipase A2 in bacterial induced neutrophil migration across lung epithelial cells. Phospholipase A2 is the enzyme mainly responsible for the conversion of membrane phospholipids into arachidonic acid, which serves as the precursor for eicosinoids such as hepoxilin A3. In addition, I am investigating whether infection with Pseudomonas aeruginosa induces the production of other eicosinoids such as prostaglandins and how the epithelial cell partitions arachidonic acid into specific eicosinoids upon encountering infectious stimuli. Another important component of my studies includes executing strategies to identify the Pseudomonas aeruginosa factor(s) responsible for stimulating the signaling pathway leading to the production of hepoxilin A3. Evaluating the relevance of the process in animal models of lung inflammation and assessing the prevalence of this inflammatory pathway in primary human lung tissue will be important extensions of my current studies. This novel observation may have direct relevance to the design of therapy geared towards dampening lung inflammation and clearing Pseudomonas aeruginosa infections in patients with Cystic Fibrosis. Of consideration, molecular mechanisms involved in neutrophil trans-epithelial migration uncovered from studies proposed herein, may have broader implications in terms of non-bacterial lung pathologies involving PMN recruitment such as chronic obstructive pulmonary disease (COPD) and acute respiratory distress syndrome (ARDS).
Contact Information
Phone: 617-726-7991
Fax: 617-726-4172
E-mail: bphurley@partners.org
