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Surfactant-Associated Protein B Is Critical to Survival in Nickel-Induced Injury in Mice

¹ Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, Pennsylvania; ² Department of Environmental Health, University of Cincinnati, Cincinnati, Ohio; ³ Division of Pulmonary Biology, ⁵ Division of Human Genetics, and ⁶ Division of Pulmonary Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; and ⁴ Department of Surgery, Washington University, St. Louis, Missouri

Correspondence and requests for reprints should be addressed to George D. Leikauf, Ph.D., Environmental and Occupational Health, Graduate School of Public Health, University of Pittsburgh, 100 Technology Dr., Suite 350, Pittsburgh, PA 15219-3130. E-mail: gleikauf{at}pitt.edu

The etiology of acute lung injury is complex and associated with numerous, chemically diverse precipitating factors. During acute lung injury in mice, one key event is epithelial cell injury that leads to reduced surfactant biosynthesis. We have previously reported that transgenic mice that express transforming growth factor (TGFA) in the lung were protected during nickel-induced lung injury. Here, we find that the mechanism by which TGFA imparts protection includes maintenance of surfactant-associated protein B (SFTPB) transcript levels and epidermal growth factor receptor–dependent signaling in distal pulmonary epithelial cells. This protection is complex and not accompanied by a diminution in inflammatory mediator transcripts or additional stimulation of antioxidant transcripts. In mouse lung epithelial (MLE-15) cells, microarray analysis demonstrated that nickel increased transcripts of genes enriched in MTF1, E2F-1, and AP-2 transcription factor–binding sites and decreased transcripts of genes enriched in AP-1–binding sites. Nickel also increased Jun transcript and DNA-binding activity, but decreased SFTPB transcript. Expression of SFTPB under the control of a doxycycline-sensitive promoter increased survival during nickel-induced injury as compared with control mice. Together, these findings support the idea that maintenance of SFTPB expression is critical to survival during acute lung injury.

Key Words: adult respiratory distress syndrome • innate immunity • chemokine • surfactant

CLINICAL RELEVANCE Surfactant-associated protein B biosynthesis was found to be critical to survival during lung injury in mice. Future clinical strategies could be developed to maintain differentiated function of type II alveolar cells.