232: Simvastatin Treatment Inhibits the Development of Obliterative Airway Disease in Rat Tracheal Allografts

Purpose: The molecular mechanisms of BO are not fully understood. Matrix metalloprotease (MMP)-9 broncho-alveolar lavage levels increase in BO. Interleukin (IL)-17 plays a role in lung graft rejection; and azithromycin (AZI) downregulates IL-17 production. This study examined the effect of broad spectrum MMP inhibition and AZI treatment on BO development. Methods and Materials: BO was induced by transplantation of Fisher F344 rat lungs to Wistar Kyoto (WKY) rats. Five groups of n 5 were studied for 8 weeks: 1. WKY-WKY isografts, 2. F344-WKY control allografts, 3. F344-WKY with MMP inhibitor (tanomastat, Bayer) treatment, 4. F344-WKY with AZI treatment, and 5. F344-WKY with tanomastat and AZI combined treatment. Tanomastat was administered daily and orally starting on the first post-transplant day. AZI was administered i.p. daily for the first 3 days following transplantation and thereafter 3 times per week. Explanted lung grafts were analyzed histologically and by Western blotting. Results: Allografts showed BO characteristics histologically, while isografts did not. MMP-9 and IL-17 protein levels increased in allografts versus isografts (P 0.05). Of all treated groups, the tanomastat/ AZI combination had the best histological outcome evidenced by reduced extracellular matrix deposition and better lung parenchymal preservation compared to control allografts. MMP-9 was not significantly changed in treatment groups versus control allografts. IL-17 protein expression was significantly decreased in both groups receiving AZI treatment versus control allografts (P 0.05). Conclusions: Our results indicate that IL-17 is involved in chronic lung allograft rejection, and that AZI reduces IL-17 protein expression in vivo. MMP inhibition is effective in ameliorating BO when combined with AZI.