Helen Hicks
Pronouns: She/her
Research Mentor(s): John Osterholzer
Research Mentor School/College/Department: Internal Medicine, Pulmonary Division / Medicine
Program: UROPF
Session: Session 5 (2:40pm – 3:30pm)
Authors: Helen Hicks, Kayla Marinetti, Khadijah Siddiqui, Brian Song, Seagal Teitz-Tennenbaum, John J. Osterholzer
Abstract
Deployment-related constrictive bronchiolitis (DRCB), a medical condition characterized by fibrosis (scarring) of the small airways in the lung, has been identified in a subset of military personnel previously deployed to Afghanistan and/or Iraq. Most patients diagnosed with DRCB suffer from chronic cough, dyspnea, and exercise intolerance and report exposures to airborne hazards such as smoke from the Al-Mishraq sulfur enrichment facility fire and military base open air burn pits, and sandstorms. The defining histologic feature of DRCB is increased thickness of small airway walls due to collagen deposition. No proven treatment for DRCB is currently available. Club cells are local progenitors lining the small airways that are critical for repairing the epithelium integrity after injury. In a previous study, using the CC-DTA inducible transgenic mouse model, continuous club cell injury was found to induce constrictive bronchiolitis consistent with DRCB. The aim of this study was to evaluate whether azithromycin (AZM), a drug known to be effective in other small airway diseases, can prevent the development of DRCB using the CC-DTA model. Four groups of mice, two CC-DTA and two littermates, received doxycycline for ten consecutive days (protocol day 0-10) to induce constrictive bronchiolitis or serve as controls, respectively. One CC-DTA and one control group of mice were treated with AZM (100 mg/kg/dose daily by oral gavage) from protocol day -1 to 19, whereas the other two groups received vehicle (water). Lungs were harvested on protocol day 20 to evaluate fibrosis by histology and hydroxyproline assays. Fibrosis localized to the wall of small airways was quantified in picrosirius red (PSR) stained-lung sections using Image J software. Doxycycline-exposed vehicle treated CC-DTA versus littermate mice had increased PSR fluorescence intensity (p<0.0001, two-way analysis of variance) confirming the induction of constrictive bronchiolitis. Doxycycline-exposed CC-DTA mice treated with AZM versus vehicle showed reduction in PSR fluorescence intensity (p<0.0001). Total lung hydroxyproline assay demonstrated a similar trend but did not reach statistical significance. Our results indicate that AZM was effective in preventing the development of DRCB in this murine model. Identifying AZM as a potential preventive measure against DRCB may form the basis for designing future clinical trials aimed at protecting military personnel from this debilitating disease.
