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J. Biol. Chem., Vol. 280, Issue 27, 25913-25919, July 8, 2005

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Surfactant Protein A Is a Principal and Oxidation-sensitive Microbial Permeabilizing Factor in the Alveolar Lining Fluid^*

Alexander I. Kuzmenko, Huixing Wu, Sijue Wan, and Francis X. McCormack

From the Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Cincinnati School of Medicine, Cincinnati, Ohio 45267

We have reported that surfactant protein A kills some Gram-negative organisms by increasing membrane permeability. In this study, we investigated the physiologic importance of this activity and the effect of oxidative stress on the antimicrobial functions of SP-A in vitro and in vivo. Concentrated bronchoalveolar lavage fluids from SP-A+/+ mice increased the permeability of the Escherichia coli K12 cell membrane to a greater extent than lavage from SP-A-/- animals. Similarly, calcium-dependent surfactant-binding proteins of SP-A+/+ mice increased membrane permeability more than those from SP-A-/- mice and produced greater zonal killing of agar-embedded bacteria in a radial diffusion assay. Exposure of human SP-A to copper-initiated surfactant phospholipid peroxidation or to free radicals generated by human neutrophils in vitro increased the level of SP-A-associated carbonyl moieties and blocked the permeabilizing function of the protein. We also found that exposure of mice to 90% O₂ for 4 days, sufficient to lead to consumption of glutathione, oxidation of protein thiols, and accumulation of airspace protein-associated carbonyl moieties, blocked the permeabilizing activity of lavage fluid from SP-A+/+ mice. We conclude that SP-A is a major microbial permeablizing factor in lavage fluid and that oxidative stress inhibits the antibacterial activity of SP-A by a mechanism that includes oxidative modification and functional inactivation of the protein.

Received for publication, October 5, 2004 , and in revised form, May 2, 2005.

^* This work was supported by a Merit Grant from the Department of Veterans Affairs and National Institutes of Health Grant HL-68861 (to F. X. M.). 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.

To whom correspondence should be addressed: University of Cincinnati, MSB Rm. 6001, 231 Albert Sabin Way, Cincinnati, OH 45267-0564. Tel.: 513-558-4831; Fax: 513-558-4858; E-mail: frank.mccormack{at}uc.edu.

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