Arsenic and Innate Immune Function of the Lung
Bruce A. Stanton, Ph.D.
Director, Toxic Metals
Superfund Research Program
Professor, Department of Microbiology and Immunology
Andrew C. Vail Professor
Geisel School of Medicine at Dartmouth
Other Research Team Members:
Tom Hampton, M.S.
Emily Notch, Ph.D.
Dawoon Jung, Ph.D.
Chronic exposure to arsenic in the drinking water is a worldwide health concern and is associated with an increased risk of lung disease including bacterial infections. Recent studies have demonstrated that arsenic regulates the expression of a number of genes involved in the innate immune response in the lung, and thereby the ability to eliminate bacterial infections. Accordingly, the long-term objective of our research is to elucidate the cellular and molecular mechanisms whereby low, environmentally relevant levels of arsenic adversely affect the immune response of the lung and the ability to eliminate infections by P. aeruginosa.
Arsenic and CFTR. The cystic fibrosis transmembrane conductance regulator (CFTR) is a secretory chloride channel in airway epithelia cells. Chloride secretion by CFTR drives fluid secretion into the airway percillary layer, which enables cilia to beat and eliminate bacteria and other inhaled pathogens from the lung. Recently, we found that very low levels of arsenic dramatically reduces CFTR mediated chloride secretion across human airway cells by a mechanism that involves the increased ubiquitination and enhanced degradation of CFTR in lysosomes.
Arsenic and P. aeruginosa biofilms. P. aeruginosa forms antibiotic resistant biofilms (i.e., communities of bacteria that are resistant to antibiotics) in the lungs of CF patients, which contributes to the development of chronic, pernicious infections in CF. Recently, we developed a new model to study P. aeruginosa biofilms growing on human airway epithelial cells expressing wild-type or mutant CFTR and found that the lack of CFTR and/or mutations in CFTR greatly enhance the development of antibiotic resistant biofilms. Because arsenic also enhances the degradation of CFTR, studies in progress are examining the effect of low, environmentally relevant levels of arsenic on the development of antibiotic resistant P. aeruginosa biofilms growing on human airway cells.
In summary, the long term goal of our studies is to elucidate how low, environmentally relevant levels of arsenic adversely affect the immune response in the lung and to determine if arsenic enhances the ability of P. aeruginosa to chronically infect the lung. We anticipate that this information will lead to the development of novel therapies to reduce and/or eliminate the negative effect of arsenic on chronic P. aeruginosa infections in CF and in other individuals who are infected with P. aeruginosa including those with chronic obstructive pulmonary disease and pneumonia.
Bruce Stanton Pubmed
COBRE Lung Biology website