Abstract
The number of organ and tissue transplants has increased worldwide in recent decades. However, graft rejection, infections due to the use of immunosuppressive drugs and a shortage of graft donors remain major concerns. Carbon monoxide (CO) had long been regarded solely as a poisonous gas. Ultimately, physiological studies unveiled the endogenous production of CO, particularly by the heme oxygenase (HO)-1 enzyme, recognizing CO as a beneficial gas when used at therapeutic doses. The protective properties of CO led researchers to develop uses for it, resulting in devices and molecules that can deliver CO in vitro and in vivo. The resulting interest in clinical investigations was immediate. Studies regarding the CO/HO-1 modulation of immune responses and their effects on various immune disorders gave rise to transplantation research, where CO was shown to be essential in the protection against organ rejection in animal models. This review provides a perspective of how CO modulates the immune system to improve transplantation and suggests its use as a therapy in the field.
Highlights
The number of organ and tissue transplants has increased worldwide in recent decades
A third concern is the shortage of organs that has forced the donor pool to include extended criteria and non-heart beating donors, which are more susceptible to delayed graft function (DGF) [4]
The increase in TLR4 following Ischemia and reperfusion (IR) was accompanied by an upregulation of HMGB-1, hyaluronan and brevican [27], which suggested that these ligands could be responsible for the downstream activation of Toll-like receptors (TLRs), thereby improving the inflammatory response and contributing to IR injury
Summary
↑graft survival, ↑graft function, ↑tissue preservation, ↓ischemia/reperfusion injury, ↓cell proliferation, ↓inflammation, ↓apoptosis, ↓cell infiltration, ↓cell activation, ↑Tregs. Recipients treated with CO gas presented improved graft function in a liver transplantation model due to the inhibition of proinflammatory molecules, such as TNF, ICAM-1 and iNOS, leading to decreased neutrophil accumulation and diminished necrosis [196]. Similar results were obtained when recipient rats were treated by methylene chloride in a liver transplant model; the recipients displayed increased survival, impaired CD95/FasLmediated apoptosis and preserved hepatic architecture and function [197]. The transplanted heart with inhibited HO-1 was rapidly rejected from the recipient rat in comparison with the wild-type graft, suggesting the importance of HO-1 production by the graft Treatment of both the donor and the recipient with CO prolonged the graft survival independently of HO-1 inhibition by blocking platelet aggregation and endothelial cell apoptosis [198]. CO is a good candidate for potential changes in the clinical setting
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