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Surfactant Protein-D, a Mediator of Innate Lung Immunity, Alters the Products of Nitric Oxide Metabolism

Pulmonary and Critical Care Division, University of Pennsylvania School of Medicine, Philadelphia; Children's Hospital of Philadelphia, Division of Neonatology, Philadelphia, Pennsylvania; and Cardiovascular Research Institute and Department of Pediatrics, University of California at San Francisco, San Francisco, California

Address correspondence to: Andrew J. Gow, Ph.D., Children's Hospital of Philadelphia, Abramson Research Center, Rm. 416A, 34th & Civic Center Blvd., Philadelphia, PA 19104. E-mail: Gow{at}email.chop.edu

Surfactant protein (SP)-D, a 43-kD multifunctional collagen-like lectin, is synthesized and secreted by the airway epithelium. SP-D knockout (SP-D [-/-]) mice exhibit an increase in the number and size of airway macrophages, peribronchiolar inflammation, increases in metalloproteinase activity, and development of emphysema. Nitric oxide (NO) is involved in a variety of signaling processes, and because altered NO metabolism has been observed in inflammation, we hypothesized that alterations in its metabolism would underlie the proinflammatory state observed in SP-D deficiency. Examination of the bronchial alveolar lavage (BAL) from SP-D (-/-) mice reveals a significant increase in protein and phospholipid content and total cell count. NO production and inducible NO synthase expression were increased in the BAL; however, there was a decline in S-nitrosothiol (SNO) content in the BAL and a loss of SNO immunoreactivity within the tissue. This decline in SNO was accompanied by an increase in nitrotyrosine staining. We conclude that inflammation that occurs in SP-D deficiency results in an increase in NO production and a shift in the chemistry and targets of NO. We speculate that the proinflammatory response due to SP-D deficiency results, in part, from a disruption of NO-mediated signaling within the innate immune system.

Abbreviations: bronchiolar alveolar lavage, BAL • enzyme-linked immunosorbent assay, ELISA • inducible nitric oxide synthase, iNOS • large aggregate surfactant, LA • matrix metalloproteinase, MMP • nitric oxide, NO • small aggregate surfactant, SA • S-nitrosothiol, SNO • surfactant protein, SP