Claire Duguet
Research Mentor: John Osterholzer
Mentor Department: Internal Medicine, Pulmonary Division, Medicine
Author(s): Claire Duguet, Bennett P. Den Houter, Kayla N. Marinetti, Seagal Teitz-Tennenbaum, John J. Osterholzer.
Session: Session 6 (3:00 PM – 3:50 PM)
Presentation Type: Oral Presentation
Abstract
Background: Deployment-related constrictive bronchiolitis (DRCB), a small airway disease characterized by peribronchiolar fibrosis, has been identified in military personnel returning from Southwest Asia and Afghanistan. Currently, no proven treatment is available. Club cells are local progenitors critical for small airway epithelium repair, but sustained depletion may overwhelm their regenerative capacity, leading to scarring. Using the CC-DTA mouse model, we have shown that sustained club cell injury leads to histopathological features consistent with DRCB. This study evaluated whether azithromycin, effective in other small airway diseases and known to inhibit airway epithelium apoptosis, can prevent constrictive bronchiolitis by attenuating club cell injury. Methods: CC-DTA transgenic mice express diphtheria toxin A only in club cells following doxycycline administration. Doxycycline was delivered to CC-DTA mice for 10 days (0-10) to induce murine constrictive bronchiolitis. Littermate mice served as control groups. Azithromycin (100 mg/kg/dose) or vehicle was given daily by oral gavage on day (-1)-19. Lungs were evaluated on day 20 for peribronchiolar fibrosis using trichrome- and picrosirius red (PSR)- staining. Area of collagen deposition, PSR fluorescence intensity, and number of collagen fibers in small airway walls (SAWs) were quantified using ImageJ and CurveAlign. Percentage of club cell depletion and proliferation were quantified on day 10 and 20 by immunofluorescence targeting club cell secretory protein (CCSP) and Ki-67. Results: Vehicle-treated CC-DTA versus control mice exhibited thickened SAWs due to increased deposition of collagen fibers. Azithromycin versus vehicle administration in CC-DTA mice reduced collagen fiber deposition and the width of SAWs. Unexpectedly, azithromycin did not reduce club cell depletion but decreased club cell proliferation both on day 10 and 20. Conclusions: Azithromycin can prevent the development of peribronchiolar fibrosis in response to sustained club cell injury in mice. Moreover, diminished club cell proliferation may skew injury response towards regeneration and away from fibrogenesis.
