22. Noninvasive Measurement of Exhaled Nitric Oxide Correlates with the Degree of Acute Lung Transplant Rejection: Studies using Gene Therapy with Transforming Growth Factor b-1

Bassem N. Mora, Carlos H.R. Boasquevisque, Geoffrey Uy, Timothy J. McCarthy, Michael J. Welch, Mariano Boglione, Jonathan Bromberg, Nelson S. Yew, Ronald K. Scheule and G. Alexander Patterson

Washington University School of Medicine, University of Michigan and Genzyme Corporation

St. Louis, Mo., Ann Arbor, Mich., Framingham, Mass.

Background: Increased nitric oxide (NO) production has been demonstrated during acute lung allograft rejection. Transforming Growth Factor-b 1 (TGF-b 1) is an immunosuppressive cytokine capable of decreasing but not abolishing acute rejection. The purpose of this study was to determine whether exhaled NO measurements correlated with the degree of acute rejection.

Methods: The rat left lung transplant model was used in groups, I-III. In Group I (partial immunosuppression), donor lungs were transfected with TGF-b1before implantation. In Group II (fulminant acute rejection), no immunosuppression was used. In Group III (full immunosuppression), recipients were treated with Cyclosporine. Group IV animals were normal rats. At the time of sacrifice on POD five, the level of NO was measured from both lungs and then selectively from transplanted left lungs.

Results: In Group I (partial immunosuppression), exhale NO levels measured from both lungs and selectively from transplanted left lungs were 4.9 and 8.4 ppb, respectively. In Group II (fulminant acute rejection) exhaled NO levels from both lungs and from transplanted left lungs were 6.7 and 42.1 ppb, respectively. In Groups III (full immunosuppression) and IV (non-transplanted controls), exhaled NO levels obtained from both lungs were 1.1 and 1.5 ppb, respectively. There was a statistically-significant decrease in the level of exhaled NO obtained selectively from left lungs in Group I compared to Groups II, III or IV (p<0.01).

Conclusions: Exhaled NO is elevated in fulminant acute rejection, is reduced following partial immunosuppression using TGF-b1 gene therapy, and is in the normal range in Cyclosporine-treated animals. The measurement of exhaled NO correlates with the degree of acute lung allograft rejection, and may serve as a non-invasive measure of acute lung transplant rejection in the clinical setting.