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Selective Inhibition of Inducible NO Synthase Activity In Vivo Reverses Inflammatory Abnormalities in Surfactant Protein D-Deficient Mice¹

Elena N. Atochina-Vasserman^2,*, Michael F. Beers^*, Helchem Kadire^*, Yaniv Tomer^*, Adam Inch^*, Pamela Scott, Chang J. Guo and Andrew J. Gow^2,

^* Pulmonary and Critical Care Division, University of Pennsylvania School of Medicine, Philadelphia, PA 19104; and Department of Pharmacology & Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ 08854

Surfactant protein D (SP-D)-deficient (SP-D^–/–) mice exhibit early development of emphysema. Previously we have shown that SP-D deficiency results in increased production and activity of inducible NO synthase (iNOS). In this study, we examined whether treatment with the iNOS inhibitor 1400W could inhibit the inflammatory phenotype. Mice were treated with 1400W systemically for 7 wk from 3 wk of age. Treatment reduced total lung NO synthase activity to 14.7 ± 6.1% of saline-treated 10-wk-old SP-D^–/– littermates. Long-term administration of 1400W reduced lung inflammation and cellular infiltration; and significantly attenuated the increased levels of matrix metalloproteinases 2 and 9, chemokines (KC, TARC), and cytokines (IFN-) seen in bronchoalveolar lavage (BAL) of SP-D^–/– mice. Abrogation of these levels was associated with decreasing BAL chemotactic activity for RAW cells. Two weeks of treatment with 1400W reduced total lung NO synthase (NOS) activity to 12.7 ± 6.3% of saline-treated SP-D^–/– mice. Short-term iNOS inhibition resulted in attenuation of pulmonary inflammation within SP-D^–/– mice as shown by decreases in total BAL cell count (63 ± 6% of SP-D^–/– control), macrophage size (>25 µm) within the BAL (62 ± 10% of SP-D^–/– control), and a percentage of BAL macrophages producing oxidants (76 ± 9% of SP-D^–/– control). These studies showed that s.c. delivery of 1400W can be achieved in vivo and can attenuate the inflammatory processes within SP-D deficiency. Our results represent the first report linking defects in the innate immune system in the lung with alterations in NO homeostasis.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Grants P50 000428 and HL 64520 (to M.F.B.) and HL 74115 (to A.J.G.) from National Institutes of Health.

² Address correspondence and reprint requests to Dr. Andrew J. Gow, Department of Pharmacology, Ernest Mario School of Pharmacy, Rutgers University, 160 Frelinghysen Road, Piscataway, NJ 08854. E-mail address: gow{at}rci.rutgers.edu. or Dr. Elena N. Atochina-Vasserman, Pulmonary, Allergy & Critical Care Division, Vernon and Shirley Hill Pavilion Room H410C, University of Pennsylvania Medical Center, 380 South University Avenue, Philadelphia, PA 19104. E-mail address: eatochina{at}stelex.com

³ Abbreviations used in this paper: SP-D, surfactant protein D; MMP, matrix metalloproteinase; BAL, bronchoalveolar lavage; DCF, dichlorodihydrofluorescein; NOS, NO synthase; iNOS, inducible NOS; eNOS, endothelial NOS; nNOS, neuronal NOS; WT, wild type.