Inhibition of human surfactant protein A function by oxidation intermediates of nitrite.
NitraNitration of protein tyrosine residues by peroxynitrite (ONOO - ) has been implicated in a variety of inflammatory diseases such as acute respiratory distress syndrome (ARDS). Pulmonary surfactant protein A (SP-A) has multiple functions including host defense. We report here that a mixture of hypochlorous acid (HOCl) and nitrite (NO 2 - ) induces nitration, oxidation, and chlorination of tyrosine residues in human SP-A and inhibits SP-A's ability to aggregate lipids and bind mannose. Nitration and oxidation of SP-A was not altered by the presence of lipids, suggesting that proteins are preferred targets in lipid-rich mixtures such as pulmonary surfactant. Moreover, both horseradish peroxidase and myeloperoxidase (MPO) can utilize NO 2 - and hydrogen peroxide (H 2 O 2 ) as substrates to catalyze tyrosine nitration in SP-A and inhibit its lipid aggregation function. SP-A nitration and oxidation by MPO is markedly enhanced in the presence of physiological concentrations of Cl - and the lipid aggregation function of SP-A is completely abolished. Collectively, our results suggest that MPO released by activated neutrophils during inflammation utilizes physiological or pathological levels of NO 2 - to nitrate proteins, and may provide an additional mechanism in addition to ONOO - formation, for tissue injury in ARDS and other inflammatory diseases associated with upregulated *NO and oxidant production.
Davis
Ian C
IC
Department of Anesthesiology, University of Alabama at Birmingham, Birmingham, AL 35205-3703, USA. Sadis.Matalon@cc.uab.edu
Zhu
Sha
S
Sampson
Jacinda B
JB
Crow
John P
JP
Matalon
Sadis
S
D001992:Bronchoalveolar Lavage Fluid; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D006997:Hypochlorous Acid / Q000494:pharmacology; D008358:Mannose / Q000378:metabolism; D009566:Nitrates / Q000378:metabolism; D009573:Nitrites / Q000378:metabolism* / Q000494:pharmacology*; D010084:Oxidation-Reduction; D011485:Protein Binding / Q000187:drug effects; D037662:Pulmonary Surfactant-Associated Protein A / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000378:metabolism
D009566:Nitrates; D009573:Nitrites; D037662:Pulmonary Surfactant-Associated Protein A; D014443:Tyrosine; D006997:Hypochlorous Acid; D006861:Hydrogen Peroxide; C007543:dityrosine; D008358:Mannose