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Induction of Mast Cell Activation and CC Chemokine Responses in Remodeling Tracheal Allografts

Cardiovascular Research Institute, and Departments of Medicine, Surgery, and Pathology, University of California, San Francisco, California

Address correspondence to: Dr. Kenneth C. Fang, Box 0911, Cardiovascular Research Institute, University of California, San Francisco, CA 94143-0911. E-mail: kfang{at}itsa.ucsf.edu

Activated mast cells release stored and newly synthesized mediators that influence the caliber and responsiveness of inflamed airways. In this work, we show that alloimmune-mediated mechanisms induce mast cell activation and expression of CC chemokines in remodeling rat tracheal allografts. Decreased expression of rat mast cell protease (RMCP) I and II, in concert with tryptase release in tracheal allografts, identified degranulation of stored serine proteases as an early mast cell response to allotransplantation. Transient upregulation of c-Kit expression occurred in a synchronous manner, suggesting that c-Kit receptor signaling controls mast cell responses. Increased expression of CC chemokine ligand (CCL) 2 and CCL3 by RMCP I–positive cells identified mast cells as epithelial and mesenchymal sources of chemoattractant chemokines in allograft airways. Cyclosporin A immunosuppression both attenuated and delayed these changes in mast cell phenotypes. Incubation of rat basophil leukemia 2H3 cells with CCL2 or CCL3 decreased surface c-Kit expression, an effect blocked by protease inhibitors. By controlling surface receptor availability, CC chemokines may regulate c-Kit signaling via a novel proteolytic mechanism. These data suggest that targeting alloimmune responses and restoring quiescence of mast cells may attenuate the development of fibroproliferative and obstructive distortions of bronchiolar architecture in lung allografts.

Abbreviations: c-Kit receptor tyrosine kinase, c-Kit • CC chemokine ligand, CCL • cyclosporin A, CSA • c-Kit ligand, KL • macrophage/monocyte chemoattractant protein-1, MCP-1 • macrophage inhibitory protein-1, MIP-1 • obliterative bronchiolitis, OB • phosphate-buffered saline, PBS • paraformaldehyde, PFA • rat basophil leukemia, RBL • rat mast cell protease, RMCP • tracheal lavage fluid, TLF