The Journal of Experimental Medicine
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Published online 4 December 2000.
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© The Rockefeller University Press, 0022-1007/2000/12/1587/ $5.00
The Journal of Experimental Medicine, Volume 192, Number 11, December 4, 2000 1587-1600

Original Article

Interferon {gamma} Induction of Pulmonary Emphysema in the Adult Murine Lung

Zhongde Wanga, Tao Zhenga, Zhou Zhua, Robert J. Homerb,c, Richard J. Riesed, Harold A. Chapman, Jr.e, Steven D. Shapirof, and Jack A. Eliasa
a Department of Internal Medicine, Section of Pulmonary and Critical Care Medicine,
b Department of Pathology, Yale University School of Medicine, New Haven, Connecticut 06520
c Pathology and Laboratory Medicine Service, VA Connecticut Health Care System, West Haven, Connecticut 06516
d Harvard University, Boston, Massachusetts 02115
e Cardiovascular Research Institute, University of California at San Francisco School of Medicine, San Francisco, California 94163
f Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri 63110

Correspondence to: Jack A. Elias, Department of Internal Medicine, Section of Pulmonary and Critical Care Medicine, Yale University School of Medicine, 333 Cedar St., 105 LCI, New Haven, CT 06520-8057. Tel:203-785-4163 Fax:203-785-3826 E-mail:jack.elias{at}yale.edu.

Chronic inflammation containing CD8+ lymphocytes, neutrophils, and macrophages, and pulmonary emphysema coexist in lungs from patients with chronic obstructive pulmonary disease. Although this inflammatory response is believed to cause the remodeling that is seen in these tissues, the mechanism(s) by which inflammation causes emphysema have not been defined. Here we demonstrate that interferon {gamma} (IFN-{gamma}), a prominent product of CD8+ cells, causes emphysema with alveolar enlargement, enhanced lung volumes, enhanced pulmonary compliance, and macrophage- and neutrophil-rich inflammation when inducibly targeted, in a transgenic fashion, to the adult murine lung. Prominent protease and antiprotease alterations were also noted in these mice. They included the induction and activation of matrix metalloproteinase (MMP)-12 and cathepsins B, H, D, S, and L, the elaboration of MMP-9, and the selective inhibition of secretory leukocyte proteinase inhibitor. IFN-{gamma} causes emphysema and alterations in pulmonary protease/antiprotease balance when expressed in pulmonary tissues.

Key Words: chronic obstructive pulmonary disease, matrix metalloproteinase, cathepsin, neutrophil, secretory leukocyte proteinase inhibitor


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