Recipient iNOS but Not eNOS Deficiency Reduces Luminal Narrowing in Tracheal Allografts

Abstract

Chronic airway rejection is characterized by prolonged inflammation, epithelial damage, and eventual luminal obliterative bronchiolitis (OB). In cardiac allografts, the inducible nitric oxide synthase (iNOS) promotes acute rejection but paradoxically reduces neointimal formation, the hallmark of chronic rejection. The specific roles of NOS isoforms in modulating lymphocyte traffic and airway rejection are not known. Using a double lumen mouse tracheal transplant model, tracheal grafts from B10.A (allo) or C57BL/6J (iso) mice were transplanted into cyclosporine-treated wild-type (WT) iNOS−/− or endothelial NOS (eNOS)−/− recipients. OB was observed in WT tracheal allografts at 3 weeks (53 ± 2% luminal occlusion vs. 17 ± 1% for isografts, P < 0.05) with sites of obstructive lesion formation coinciding with areas of CD3+ CD8+ T cell–rich lymphocytic bronchitis. In contrast, allografts in iNOS−/− recipients exhibited reductions in local expression of proinflammatory chemokines and cytokines, graft T cell recruitment and apoptosis, and luminal obliteration (29 ± 2%, P < 0.05 vs. WT allografts). Recipient eNOS deficiency, however, suppressed neither chemokine expression, lymphocyte infiltration, nor airway occlusion (54 ± 2%). These data demonstrate that iNOS exacerbates luminal obliteration of airway allografts in contrast with the known suppression by iNOS of cardiac allograft vasculopathy. Because iNOS−/− airways transplanted into WT allograft hosts are not protected from rejection, these data suggest that iNOS expressed by graft-infiltrating leukocytes exerts the dominant influence on airway rejection.

Working toward immune tolerance in lung transplantation

“…However, like IFN-γ, the role of iNOS in allograft acceptance is probably complex and diverse. For example, pharmacologic inhibition of iNOS and iNOS deficiency in upper airway transplant recipients was actually protective (36), and blocking iNOS prevented injury in a preclinical liver transplant model (37). Once again, the unique site-specific physiology of the lung transplant may explain differences in results among the study by Krupnick and colleagues and studies in other organ transplant models.…”

Obligatory Role for Interleukin-13 in Obstructive Lesion Development in Airway Allografts

“…Tracheal isografts (BALB/c into BALB/c) maintained their normal architecture and demonstrated no significant Figure 3, C and D) secondary to characteristic thickening of the epithelial and subepithelial layer. 28,29 To study the role of IL-13, C57Bl/6 tracheas were transplanted into allogeneic IL-13 Ϫ/Ϫ recipients. These experiments showed a significant decrease in luminal occlusion in allografts transplanted into IL-13…”

“…The first model was the previously described double lumen airway (orthotopic) transplant model for studying chronic airway rejection. 28,29 Briefly, after anesthesia, donor mice were exsanguinated, and whole trachea was harvested by transecting below the cricoid cartilage distal to the carinal bifurcation under sterile conditions. Recipient mice were similarly anesthetized, and the whole trachea was exposed.…”

Simultaneous LFA-1 and CD40 Ligand Antagonism Prevents Airway Remodeling in Orthotopic Airway Transplantation: Implications for the Role of Respiratory Epithelium as a Modulator of Fibrosis

“…Recently, the orthotopic tracheal transplantation (OTT) model has been developed by some groups in which the donor trachea is directly anastamosed to recipient trachea (16,17). The OTT model is distinguished from HTTs in several ways.…”