Inducible nitric oxide synthase promotes cytokine expression in cardiac allografts but is not required for efficient rejection.

Journal Article (Journal Article)

BACKGROUND: Inducible nitric oxide synthase (iNOS) is enhanced during acute rejection. Pharmacologic inhibition of nitric oxide synthase (NOS) activity has had variable effects on graft survival in a number of animal models. To further characterize the requirement and effects of iNOS during acute allograft rejection, we examined rejection responses of mice completely deficient of iNOS. METHODS: Heterotopic cardiac allografts were performed using wild-type and iNOS deficient mice (iNOS[-/-]) as recipients. Graft survival was determined by abdominal palpation. At days 3 and 7 following transplantation, grafts were harvested and analyzed histologically. Cytokine messenger RNA (mRNA) expression was measured by ribonuclease protection assay. RESULTS: Mean survival time of cardiac allografts did not differ between wild-type (18 +/- 3 days) and iNOS(-/-) recipients (16 +/- 2 days). At 3 days, findings of moderate acute rejection were seen in both recipients groups, although modestly reduced in iNOS(-/ -) mice. By 7 days, allografts in both groups demonstrated severe rejection. Within grafts at day 3, there was a 3-fold reduction in IL-1beta expression and a 4-fold reduction in IL-1RA in iNOS(-/-) recipients (p = 0.03 andp = 0.04, respectively) compared to wild-type recipients. Expression of other proinflammatory cytokines was detected in the grafts from both recipients, but was not significantly different. Finally, rejection responses to iNOS(-/-) cardiac allografts were nearly identical to wild-type allografts. CONCLUSIONS: Rejection of cardiac allografts by iNOS(-/-) mice occurs in a similar fashion to wild-type recipients, with extensive inflammation and proinflammatory cytokine production. While iNOS may play a role in cytokine induction by macrophages, these studies suggest that iNOS is not required for efficient cardiac graft rejection.

Full Text

Duke Authors

Cited Authors

  • Mannon, RB; Roberts, K; Ruiz, P; Laubach, V; Coffman, TM

Published Date

  • September 1999

Published In

Volume / Issue

  • 18 / 9

Start / End Page

  • 819 - 827

PubMed ID

  • 10528743

International Standard Serial Number (ISSN)

  • 1053-2498

Digital Object Identifier (DOI)

  • 10.1016/s1053-2498(99)00052-2


  • eng

Conference Location

  • United States