Stat3 is required for cytoprotection of the respiratory epithelium during adenoviral infection

The role of Stat3 in the maintenance of pulmonary homeostasis following adenoviral-mediated lung injury was assessed in vivo. Stat3 was selectively deleted from bronchiolar and alveolar epithelial cells in Stat3 ^ΔΔ mice. Although lung histology and function were unaltered by deletion of Stat3 in vivo, Stat3^ΔΔ mice were highly susceptible to lung injury caused by intratracheal administration of AVl-GFP, an early (E) region 1- and E3-deleted, nonproliferative adenovirus. Severe airspace enlargement, loss of alveolar septae, and sloughing of the bronchiolar epithelium were observed in Stat3^ΔΔ mice as early as 1 day after exposure to the virus. Although surfactant protein A, B, and C content and surfactant protein-B mRNA expression in Stat3 ^ΔΔ mice were similar, TUNEL staining and caspase-3 were increased in alveolar type II epithelial cells of Stat3^ΔΔ mice after exposure to virus. RNA microarray analysis of type II epithelial cells isolated from Stat3^ΔΔ mice demonstrated significant changes in expression of numerous genes, including those genes regulating apoptosis, supporting the concept that the susceptibility of StatS-deficient mice to adenovirus was related to the role of StatS in the regulation of cell survival. AVl-Bcl-x_L, an El- and E3-deleted, nonproliferative adenovirus expressing the antiapoptotic protein Bcl-x_L, protected Stat3^ΔΔ mice from adenoviral-induced lung injury. Adenoviral infection of the lungs of Siat3-deficient mice was associated with severe injury of the alveolar and bronchiolar epithelium. Thus, Stat3 plays a critical cytoprotective role that is required for epithelial cell survival and maintenance of alveolar structures during the early phases of pulmonary adenoviral infection.