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Ann Thorac Surg 1999;67:716-722
© 1999 The Society of Thoracic Surgeons

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Original Article

Time course and cellular localization of inducible nitric oxide synthases expression during cardiac allograft rejection

^a Department of Surgery, Washington University School of Medicine, St. Louis, Missouri, USA
^b Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA
^c Department of Molecular Pharmacology, Searle Research and Development, Monsanto Company, St. Louis, Missouri, USA
^d Department of Molecular and Cellular Biology, Searle Research and Development, Monsanto Company, St. Louis, Missouri, USA

Accepted for publication September 14, 1998.

Address reprint requests to Dr Ferguson, Departments of Surgery and Physiology, Louisiana State University Medical Center, 1542 Tulane Ave, 7th Floor, New Orleans, LA 70112-2822

Background. We have demonstrated that inhibition of inducible nitric oxide synthase (NOS) ameliorated acute cardiac allograft rejection. This study determined the time course and cellular localization of inducible NOS expression during the histologic progression of unmodified acute rat cardiac allograft rejection.

Methods. Tissue from syngeneic (ACI to ACI) and allogeneic (Lewis to ACI) transplants were harvested on postoperative days 3 through 10 and analyzed for inducible NOS mRNA expression (ribonuclease protection assay), inducible NOS enzyme activity (conversion of L-[³H]arginine to nitric oxide and L- [³H]citrulline), and nitric oxide production (serum nitrite/ nitrate levels). Inducible NOS mRNA and protein expression were localized using in situ hybridization and immunohistochemistry.

Results. Inducible NOS mRNA and enzyme activity were expressed in allografts during mild, moderate, and severe acute rejection (postoperative days 4 through 10), but were not detected in normals, isografts, or allografts before histologic changes of mild acute rejection (postoperative day 3). Inducible NOS expression resulted in increased serum nitrite/nitrate levels during mild and moderate rejection (postoperative days 4 through 6). Inducible NOS mRNA and protein expression localized to infiltrating mononuclear inflammatory cells in allograft tissue sections during all stages of rejection but were not detected in allograft parenchymal cells or in normals or isografts.

Conclusions. Inducible NOS expression and increased nitric oxide production occurred during the early stages of acute rejection, persisted throughout the unmodified rejection process, and localized to infiltrating inflammatory cells but not allograft parenchymal cells during all stages of acute rejection.

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