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Surfactant Protein A Decreases Nitric Oxide Production by Macrophages in a Tumor Necrosis Factor-–Dependent Mechanism

Department of Medicine, Division of Pulmonary, Allergy, Critical Care and Occupational Medicine, Indiana University Medical Center, Indianapolis, Indiana; and Department of Cell Biology, Duke University Medical Center, Durham, North Carolina

Address correspondence to: William J. Martin II, M.D., College of Medicine, University of Cincinnati, Cincinnati, OH 45267. E-mail: william.martin{at}uc.edu

Surfactant protein A (SP-A) modulates the lung defense system through regulation of cytokines and nitric oxide (NO) production by alveolar macrophages (AMs). Whether SP-A upregulates or downregulates production of proinflammatory cytokines and NO is controversial. This study demonstrates the molecular mechanism(s) by which SP-A suppresses NO production by activated murine AMs. NO production by interferon- (IFN-) and IFN- plus Mycobacterium avium–stimulated AMs was mediated through tumor necrosis factor- (TNF-) production, as addition of neutralizing anti–TNF- antibodies during AMs stimulation resulted in reduced NO production. SP-A suppressed NO production by activated AMs by inhibiting TNF- production. The maximum inhibitory effect of SP-A on NO production was observed at 20 µg/ml of SP-A concentration. Furthermore, SP-A inhibited activation of nuclear factor-B, a transcription factor required for induction of TNF- and inducible NO synthase genes. These findings suggest that SP-A suppresses NO production by activated AMs by inhibiting TNF- secretion and nuclear factor-B activation. This study also highlights the importance of SP-A levels in the lung, as changes in SP-A levels may modulate the local lung defense system.

Abbreviations: alveolar macrophages, AMs • bronchoalveolar lavage fluid, BALF • enzyme-linked immunosorbent assay, ELISA • electrophoretic mobility shift assay, EMSA • interferon-, IFN- • interleukin, IL • inducible nitric oxide synthase, iNOS • interferon regulatory factor-1, IRF-1 • lipopolysaccharide, LPS • nuclear factor-B, NF-B • nitric oxide, NO • peripheral blood mononuclear cells, PBMC • surfactant protein A, SP-A • tumor necrosis factor-, TNF-

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