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(American Journal of Pathology. 2006;169:47-60.)
© 2006 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2006.050975

Obligatory Role for Interleukin-13 in Obstructive Lesion Development in Airway Allografts

Vibha N. Lama^*, Hiroaki Harada, Linda N. Badri^*, Andrew Flint, Cory M. Hogaboam, Andrew McKenzie, Fernando J. Martinez^*, Galen B. Toews^*, Bethany B. Moore^* and David J. Pinsky

From the Division of Pulmonary and Critical Care Medicine,^* Division of Cardiovascular Medicine, and the Department of Pathology, University of Michigan Health System, Ann Arbor, Michigan; and the Laboratory of Molecular Biology, Medical Research Council, Cambridge, United Kingdom

The pathogenesis of bronchiolitis obliterans (BO), a common and devastating obliterative disorder of small airways following lung transplantation, remains poorly understood. Lesions are characterized in their early stages by lymphocyte influx that evolves into dense fibrotic infiltrates. Airway specimens taken from patients with histological BO revealed infiltrating myofibroblasts, which strongly expressed the signaling chain of the high affinity interleukin-13 (IL-13) receptor IL-13R1. Because IL-13 has proinflammatory and profibrotic actions, a contributory role for IL-13 in BO development was examined using murine models of orthotopic and heterotopic tracheal transplantation. Compared with airway isografts, allografts exhibited a significant increase in relative IL-13 mRNA and protein levels. Allogeneic tracheas transplanted into IL-13-deficient mice were protected from BO in both transplant models. Flow cytometric analysis of orthotopic transplant tissue digests revealed markedly fewer infiltrating mononuclear phagocytes and CD3⁺ T lymphocytes in IL-13-deficient recipients. Furthermore, protection from luminal obliteration, collagen deposition, and myofibroblast infiltration was observed in heterotopic airways transplanted into the IL-13^–/– recipients. Transforming growth factor-ß1 expression was significantly decreased in tracheal allografts into IL-13^–/– recipients, compared to wild-type counterparts. These human and murine data implicate IL-13 as a critical effector cytokine driving cellular recruitment and subsequent fibrosis in clinical and ex-perimental BO.

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