Bronchiolitis Obliterans and Pulmonary Fibrosis After Sulfur Mustard Inhalation in Rats.

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Abstract

RATIONALE

Inhalation of powerful chemical agents, such as sulfur mustard (SM), can have debilitating pulmonary consequences, such as bronchiolitis obliterans (BO) and parenchymal fibrosis (PF). The underlying pathogenesis of disorders after SM inhalation is not clearly understood, resulting in a paucity of effective therapies.

OBJECTIVE

To evaluate the role of pro-fibrotic pathways involving TGF-β and PDGF in the development of BO and PF after inhalation injury sustained by SM, using a rat model.

METHODS

Adult Sprague-Dawley rats were intubated and exposed to SM (1.0 mg/kg), then monitored daily for respiratory distress, oxygen saturation changes, and weight loss. Rats were euthanized at 7, 14, 21 or 28 days, and markers of injury were determined by histopathology, pulmonary function testing, and assessment for TGF- β, PDGF and PAI-1 levels.

MEASUREMENTS AND MAIN RESULTS

Respiratory distress developed over time after SM inhalation, with progressive hypoxemia, respiratory distress, and weight loss. Histopathology confirmed the presence of both BO and PF, gradually worsening with time. Pulmonary function testing demonstrated a time-dependent increase in lung resistance, and a decrease in lung compliance. Levels of TGF-β, PDGF, and PAI-1 were elevated at 28 days, in lung, bronchoalveolar lavage fluid (BALF), and/or plasma.

CONCLUSION

Time-dependent development of BO and PF occurs in lungs of rats exposed to SM inhalation, and the elevated levels of TGF-β, PDGF and PAI-1 suggest involvement of these pro-fibrotic pathways in the aberrant remodeling after injury.

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