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Reparative Capacity of Airway Epithelium Impacts Deposition and Remodeling of Extracellular Matrix

¹ Department of Pulmonary, Allergy, and Critical Care Medicine, Duke University Medical Center, Durham, North Carolina; and ² Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, Pennsylvania

Correspondence and requests for reprints should be addressed to Barry R. Stripp, Ph.D., Division of Pulmonary, Allergy and Critical Care, Duke University Medical Center, 2075 MSRBII, 106 Research Drive, DUMC Box 103000, Durham, NC 27710. E-mail: Barry.Stripp{at}Duke.edu

Defective epithelial repair in the setting of chronic lung disease has been suggested to contribute to uncontrolled extracellular matrix (ECM) deposition and development of fibrosis. We sought to directly test this hypothesis through gene expression profiling of total lung RNA isolated from mouse models of selective epithelial cell injury that are associated with either productive or abortive repair. Analysis of gene expression in repairing lungs of naphthalene-exposed mice revealed prominent clusters of up-regulated genes with putative roles in regulation of the extracellular matrix and cellular proliferation. Further analysis of tenascin C (Tnc), a representative matrix protein, in total lung RNA revealed a transient 4.5-fold increase in mRNA abundance 1 day after injury and a return to steady-state levels by Recovery Day 3. Tnc was deposited by the peribronchiolar mesenchyme immediately after injury and was remodeled to basement membrane subtending the bronchiolar epithelium during epithelial repair. Epithelial restitution was accompanied by a decrease in Tnc mRNA and protein expression to steady-state levels. In contrast, abortive repair using a transgenic model allowing ablation of all reparative cells led to a progressive increase in Tnc mRNA within lung tissue and accumulation of its gene product within the subepithelial mesenchyme of both conducting airways and alveoli. These data demonstrate that the ECM is dynamically remodeled in response to selective epithelial cell injury and that this process is activated without resolution in the setting of defective airway epithelial repair.

Key Words: airway epithelium • repair • Clara cell • extracellular matrix • fibrosis

CLINICAL RELEVANCE This study demonstrates in vivo that airway epithelial reparative capacity regulates extracellular matrix (ECM) deposition and turnover. As such, this study suggests that excessive ECM deposition in chronic fibroproliferative lung disease may be a result of defective epithelial repair.

 

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