Reciprocal regulation of airway rejection by the inducible gas-forming enzymes heme oxygenase and nitric oxide synthase

Abstract

Obliterative bronchiolitis (OB) develops insidiously in nearly half of all lung transplant recipients. Although typically preceded by a CD8+ T cell–rich lymphocytic bronchitis, it remains unresponsive to conventional immunosuppression. Using an airflow permissive model to study the role of gases flowing over the transplanted airway, it is shown that prolonged inhalation of sublethal doses of carbon monoxide (CO), but not nitric oxide (NO), obliterate the appearance of the obstructive airway lesion. Induction of the enzyme responsible for the synthesis of CO, heme oxygenase (Hmox) 1, increased carboxyhemoglobin levels and suppressed lymphocytic bronchitis and airway luminal occlusion after transplantation. In contrast, zinc protoporphyrin IX, a competitive inhibitor of Hmox, increased airway luminal occlusion. Compared with wild-type allografts, expression of inducible NO synthase (iNOS), which promotes the influx of cytoeffector leukocytes and airway graft rejection, was strikingly reduced by either enhanced expression of Hmox-1 or exogenous CO. Hmox-1/CO decreased nuclear factor (NF)-κB binding activity to the iNOS promoter region and iNOS expression. Inhibition of soluble guanylate cyclase did not interfere with the ability of CO to suppress OB, implicating a cyclic guanosine 3′,5′-monophosphate–independent mechanism through which CO suppresses NF-κB, iNOS transcription, and OB. Prolonged CO inhalation represents a new immunosuppresive strategy to prevent OB.

Models of Lung Transplant Research: a consensus statement from the National Heart, Lung, and Blood Institute workshop

“…This model has provided useful insights about early events in AR (e.g., see ref. 60) and has been developed as an especially useful model for studying microvascular changes that occur in AR, as described in detail below. The intrapulmonary tracheal transplant model as a model of AR has been useful to show the importance of intrapulmonary de novo lymphoid tissue (61).…”

“…The OTT model is useful for the study of airway microvessels because the tracheal vasculature can be easily visualized in one tissue plane (76). The model is performed through an interposition transplant in which the recipient trachea is transected and a donor trachea is sewn into the space created by the naturally retracted airway; alternatively, the donor trachea can be sewn in parallel to the native airway (60). During AR, this model has revealed that the airways undergo a transient loss of a functional microcirculation accompanied by localized tissue hypoxia and ischemia (77); although a functional microcirculation returns, these grafts cannot be rescued with immunosuppression once the vascular bed is transiently lost, suggesting an anatomic basis for the development of chronic rejection.…”

The Carcinoma-Associated Fibroblast Expressing Fibroblast Activation Protein and Escape from Immune Surveillance

“…This study indicates that yet another enzyme expressed by the innate immune cells that accumulate in tumors has immune-suppressive activity. It is of interest that carbon monoxide, one of the products of the catabolism of heme by HO-1, prevents tracheal allograft rejection (20), and that inflammation in a model of immunologically induced arthritis is more severe in mice lacking HO-1 than in wild-type mice (21). Although the latter two studies did not identify the cellular source of HO-1, their findings support the possibility that the HO-1-expressing FAP þ macrophage may have immune-suppressive functions that are beneficial to the host.…”

Protective effect of carbon monoxide in transplantation

“…In the rat nonvascularized tracheal transplantation model, significant luminal narrowing was observed in allografts at 3 weeks after transplantation. CO exposure to the recipient at 250 ppm for 2 weeks significantly reduces graft luminal occlusion [136]. In vitro cell culture experiments have demonstrated that CO plays an important role in modulating human airway SMC proliferation via inhibition of cyclin D1 expression or G0/G1 arrest mediated by G1-cyclindependent protein kinase inhibitor p21 cip1 [137].…”