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J. Biol. Chem., Vol. 280, Issue 34, 30201-30205, August 26, 2005

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NADPH Oxidase Restrains the Matrix Metalloproteinase Activity of Macrophages^*

Sean Y. Kassim, Xiaoyun Fu, W. Conrad Liles, Steven D. Shapiro¶, William C. Parks||, and Jay W. Heinecke**

From the Department of Medicine, University of Washington, Seattle, Washington 98195, the Departments of Medicine and ^||Pediatrics, Washington University, St. Louis, Missouri 63110, and the ^¶Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02115

Matrix metalloproteinases (MMPs) regulate numerous functions in normal and disease processes; thus, irreversibly blocking their activity is a key step in regulating MMP catalysis. We previously showed in vitro that oxidizing intermediates generated by phagocytes inactivate MMPs by modifying specific amino acids. To assess whether this mechanism operates in vivo, we focused on MMP-12, a macrophage-specific MMP known to mediate emphysema in mouse models. We found that mice lacking gp91^phox, a phagocyte-specific component of the NADPH oxidase, developed extensive, spontaneous emphysematous destruction of their peripheral air spaces, whereas mice deficient in both NADPH oxidase and MMP-12 were protected from spontaneous emphysema. Although gp91^phox-null and wild-type macrophages produced equivalent levels of MMP-12 protein, the oxidant-deficient cells had greater MMP-12 activity than wild-type macrophages. These findings indicate that reactive intermediates provide a physiological mechanism to protect tissues from excessive macrophage-mediated damage during inflammation.

Received for publication, March 25, 2005 , and in revised form, June 3, 2005.

^* This work was supported by National Institutes of Health Grants HL078527, HL075381, AG021191, HL64344, HL62995, HL77555, P01-HL29594, P30-ES07033, and P50-HL073996 and by the Donald W. Reynolds Foundation. 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: Division of Metabolism, Endocrinology, and Nutrition, Box 356426, University of Washington, Seattle, WA 98195. E-mail: heinecke{at}u.washington.edu.

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