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A6223 - Club Cell Secretory Protein-16 Protects Against Mycoplasma Pneumoniae-Induced Airway Remodeling.
Author Block: M. Insel1, W. Pederson1, K. J. Addison1, C. A. Owen2, A. Dy3, S. Guerra3, F. D. Martinez3, M. Kraft1, J. G. Ledford1; 1Department of Medicine, University of Arizona, Tucson, AZ, United States, 2Brigham and Womens Hosp, Boston, MA, United States, 3University of Arizona, Tucson, AZ, United States.
RATIONALE: Club cell secretory protein-16 (CC16) is a member of the secretoglobin family of proteins and is one of the most abundant proteins in normal airway secretions. While CC16 has been described as a serum biomarker for progression of lung disease, a distinct mechanism of action has remained elusive. In previous studies, we found CC16 knockout mice have markedly enhanced airway colonization and lung inflammation when challenged with Mycoplasma pneumoniae, an atypical bacterium linked to severe, persistent asthma and asthma/COPD exacerbations. We therefore hypothesized that CC16 plays an important protective role during M. pneumoniae infection and may protect against airway remodeling which is a driver of airflow limitation.
METHODS: We developed a novel mouse model of early life exposure to M. pneumoniae (Mp) in which WT or CC16 deficient mice are infected pre-weaning (equivalent to a ~2-5 year-old child) one time and assessed for lung inflammation and remodeling at 8 weeks of age (equivalent of ~20-30 year old adult). Additionally, mouse tracheal epithelial cells (MTECS) from WT and CC16-/- mice were cultured at an air-liquid interface and infected with Mp or vehicle for 48 hrs. Gene expression was assessed for a panel of inflammatory and remodeling factors by RT-PCR.
RESULTS: Histological sections revealed large areas of thickened basement membrane, including more pronounced elastin fibers and subepithelial enlargement of the lamina propria and smooth muscle in CC16-/- mice infected with M. pneumoniae as compared to saline CC16-/- and WT infected mice. RT-PCR of lung tissue revealed that factors associated with lung remodeling, including pro-collagen type I (Col1A1), pro-collagen type III (Col3A1), TGF-β and α-smooth muscle actin (α-SMA), were significantly elevated in the lungs of CC16-/- mice infected with M. pneumoniae as compared to WT infected mice. As compared to MTECs from WT mice, MTECs from CC16-/- mice had elevated expression of Pro-Col1A1 and Pro-Col3A1 in both vehicle and Mp-infected conditions. α-SMA increased only in the Mp-infected conditions and only in CC16-/- MTECs.
CONCLUSIONS: Mice lacking CC16 have increased airways remodeling in adulthood after a one-time exposure to M. pneumoniae as weanlings. Our findings highlight a previously unidentified role for CC16 in protection against a common asthma-exacerbating agent, M. pneumoniae, and provide mechanistic insight into a possible role of CC16 in fixed airway obstruction.