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Modification of surfactant protein D by reactive oxygen-nitrogen intermediates is accompanied by loss of aggregating activity, in vitro and in vivo

Sadis Matalon^*,, Kedar Shrestha^*, Marion Kirk, Stephanie Waldheuser, Barbara McDonald, Kelly Smith, Zhiqian Gao^*, Abderrazzak Belaaouaj^|| and Erika C. Crouch^,1

^* Department of Anesthesiology,

Department of Environmental Health Sciences, and

Comprehensive Cancer Center Mass Spectrometry Facility, Schools of Medicine and Public Health, University of Alabama, Birmingham, Alabama, USA;

Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA; and

^|| UMRS-INSERM 514, Maison Blanche, Reims, France

¹ Correspondence: Washington University School of Medicine, Campus Box 8118, 660 S. Euclid, St. Louis, MO 63110, USA. E-mail: crouch{at}path.wustl.edu

Surfactant protein D (SP-D) is an important effector of innate immunity. We have previously shown that SP-D accumulates at sites of acute bacterial infection and neutrophil infiltration, a setting associated with the release of reactive species such as peroxynitrite. Incubation of native SP-D or trimeric SP-D lectin domains (NCRDs) with peroxynitrite resulted in nitration and nondisulfide cross-linking. Modifications were blocked by peroxynitrite scavengers or pH inactivation of peroxynitrite, and mass spectroscopy confirmed nitration of conserved tyrosine residues within the C-terminal neck and lectin domains. Mutant NCRDs lacking one or more of the tyrosines allowed us to demonstrate preferential nitration of Tyr314 and the formation of Tyr228-dependent cross-links. Although there was no effect of peroxynitrite or tyrosine mutations on lectin activity, incubation of SP-D dodecamers or murine lavage with peroxynitrite decreased the SP-D-dependent aggregation of lipopolysaccharide-coated beads, supporting our hypothesis that defective aggregation results from abnormal cross-linking. We also observed nitration, cross-linking of SP-D, and a significant decrease in SP-D-dependent aggregating activity in the lavage of mice acutely exposed to nitrogen dioxide. Thus, modification of SP-D by reactive oxygen-nitrogen species could contribute to alterations in the structure and function of SP-D at sites of inflammation in vivo.—Matalon, S., Shrestha, K., Kirk, M., Waldheuser, S., McDonald, B., Smith, K., Gao, Z., Belaaouaj, A., Crouch, E. C. Modification of surfactant protein D by reactive oxygen-nitrogen intermediates is accompanied by loss of aggregating activity, in vitro and in vivo.

Key Words: collectin • covalent cross-linking • free radicals • nitrogen dioxide • peroxynitrite