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(American Journal of Pathology. 2005;166:685-694.)
© 2005 American Society for Investigative Pathology

Relationship of Acute Lung Inflammatory Injury to Fas/FasL System

Thomas A. Neff^*, Ren-Feng Guo^*, Simona B. Neff^*, J. Vidya Sarma^*, Cecilia L. Speyer^*, Hongwei Gao^*, Kurt D. Bernacki^*, Markus Huber-Lang^*, Stephanie McGuire^*, L. Marco Hoesel^*, Niels C. Riedemann^*, Beatrice Beck-Schimmer, Firas S. Zetoune^* and Peter A. Ward^*

From the Department of Pathology,^* The University of Michigan Medical School, Ann Arbor, Michigan; and the Department of Anesthesiology, University Hospital of Zurich Medical School, Zurich, Switzerland

There is mounting evidence that apoptosis plays a significant role in tissue damage during acute lung injury. To evaluate the role of the apoptosis mediators Fas and FasL in acute lung injury, Fas (lpr)- or FasL (gld)-deficient and wild-type mice were challenged with intrapulmonary deposition of IgG immune complexes. Lung injury parameters (¹²⁵I-albumin leak, accumulation of myeloperoxidase, and wet lung weights) were measured and found to be consistently reduced in both lpr and gld mice. In wild-type mice, lung injury was associated with a marked increase in Fas protein in lung. Inflamed lungs of wild-type mice showed striking evidence of activated caspase-3, which was much diminished in inflamed lungs from lpr mice. Intratracheal administration of a monoclonal Fas-activating antibody (Jo2) in wild-type mice induced MIP-2 and KC production in bronchoalveolar lavage fluids, and a murine alveolar macrophage cell line (MH-S) showed significantly increased MIP-2 production after incubation with this antibody. Bronchoalveolar lavage fluid content of MIP-2 and KC was substantially reduced in lpr mice after lung injury when compared to levels in wild-type mice. These data suggest that the Fas/FasL system regulates the acute lung inflammatory response by positively affecting CXC-chemokine production, ultimately leading to enhanced neutrophil influx and tissue damage.

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