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A1208 - Cc16: A Novel Potential Therapeutic Target for Airway and Airspace Pathologies in COPD
Author Block: F. Polverino1, J. Rojas-Quintero1, M. Laucho Contreras2, X. Wang1, A. Pilon3, B. Celli1, C. Owen1; 1Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States, 2Medicine, Universidad Central de Venezuela, Caracas, Venezuela, Bolivarian Republic of, 3APCBio Innovations, Inc, Rockville, MD, United States.
Background: Chronic Obstructive Pulmonary Disease (COPD) is a highly heterogeneous disease that includes airway (chronic bronchitis and small airway fibrosis) and airspace (emphysema) pathologies. Current treatments for COPD reduce symptoms, but alter minimally the course of the disease. There is an urgent need to reduce the high morbidity and mortality associated with COPD by identifying new therapeutic targets for COPD. One such potential target is Club cell protein 16 (CC16). We have previously shown that CC16 expression is reduced in in COPD airways and that CC16 has potent anti-inflammatory activities in cigarette smoke (CS)-exposed lungs. We hypothesize that delivering exogenous CC16 to the lungs of mice limits the progression of CS-induced established COPD-like lung pathologies. Methods: C57/BL6 WT and CC16-/- mice were exposed to CS or room air for up to 8 weeks using a Teague device. At the mid-point in the CS exposures, thrice weekly intranasal treatments with recombinant human CC16 (rhCC16) or vehicle were initiated and continued for the second 4 weeks of the 8 week CS exposure. We measured: 1) the number of inflammatory cells in bronchoalveolar lavage (BAL) samples; 2) the number of apoptotic cells in the bronchial and alveolar wall by immunostaining lungs for active caspase 3; 3) airway epithelial mucus cell metaplasia by immunostaining lungs for Muc5ac; and 4) body weights. Results: Compared with CS-exposed mice treated with PBS, CS-exposed WT and CC16-/- mice treated with rhCC16 were protected against CS-induced increases in: 1) total leucocyte and macrophage counts in BAL samples; 2) the number of Muc5ac-positive airway epithelial cells; 3) the number of apoptotic alveolar and bronchial epithelial cells. CC16-treated mice were also protected from CS-induced weight loss. Conclusions: RhCC16 protein delivered to the lungs of mice limits CS-induced COPD-like pathologies including lung inflammation, airway mucus cell metaplasia, alveolar and bronchial epithelial cell apoptosis, and weight loss. Thus, CC16 augmentation strategies have potential to limit the progression of CS-induced airway and airspace injury.