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Several studies have confirmed the role of hydrogen to scavenge reactive oxygen species (ROSs) and to protect against ischaemic reperfusion injury (IRI) in the lung and the heart [1–4]. In a study, where rabbit lungs were exposed to ex vivo lung perfusion (EVLP), the infusion of H2S significantly reduced ROS activity within the grafts [4]. This resulted in a significant decrease of lipid peroxidation, epithelial apoptosis, airway smooth muscle cell (ASMC) proliferation and (interleukin) IL8 production [3, 4]. On the other hand, graft physiological parameters were improved in response to 2% hydrogen inhalation, while the graft is exposed to EVLP [1, 2]. During graft ischaemia and cold preservation, Na/K adenosine 5’-triphosphatase is inhibited, leading to increased Na intracellular influx and K extracellular efflux. The inhibited activity of K channels leads to the failure to re-establish cell membrane hyperpolarization, leading to sustained cell membrane depolarization, impaired mitochondrial activity, enhanced activity of nicotinamide adenine dinucleotide phosphate hydrogen and Xanthine oxidases, leading to a significant increase in ROS production [5]. ROS stimulate ASMC proliferation, which may contribute to the development of pulmonary hypertension, and prime graft inflammasomes. The drop of the intracellular K levels activates the primed inflammasomes to activate caspase 1, which activates pro-IL1β and pro-IL18. While IL1β stimulates ASMC proliferation, both cytokines induce IL6. Through ROS scavenging by hydrogen, inflammasomes activation is attenuated, levels of IL1β, IL6 and IL8 are decreased, the graft oxygenation capacity and vascular resistance are improved [1, 2]. However, in the experiments of George et al. [4] the graft oxygenation capacity and vascular resistance did not differ between the hydrogen-treated and the non-hydrogen-treated groups. This apparent contradiction between the results of hydrogen therapy might be related to the administration of Na (as a bolus and infusion) during the EVLP model of George et al. [4], where donor blood was used as a perfusate. This might have potentiated the Na influx and the subsequent sustained membrane depolarization. On the contrary, the experiments conducted by Haam et al. [1] utilized a model of EVLP that follows the Toronto technique, using Perfadex and Steen solutions that contain physiological Na and K levels. This may highlight that the reconditioning of the lung graft is a complex procedure that requires multiple effectors that target various aspects simultaneously, where hydrogen therapy targets the reduction of ROS to eliminate their hazardous effects, and the effective EVLP technique improves other graft functional parameters. Nevertheless, hydrogen protects the lung graft against IRI as a potent antioxidant and through the up-regulation of heme-oxygenase-1 (HO-1) [1, 2]. HO-1 catalyzes carbon monoxide production, which is a potent antioxidant, activates guanylyl cyclase (which may explain the trend of increased cGMP observed by George et al.), and activates ATP-sensitive K channels and big conductance calcium-sensitive K channels [6]. The improved activity of K channels has been shown to recondition the graft, antagonize cell membrane depolarization, antagonize the opening of mitochondrial permeability transition pore during reperfusion, decrease ROS production and attenuate the inflammatory cytokine production. All of these would protect the graft against IRI and graft dysfunction [5]. Accordingly, a combination of antioxidants and K channel agonists may achieve at least a similar level of protection and may exhibit more significantly protective effects than those of the hydrogen therapy (future studies should be conducted to investigate this hypothesis). While hydrogen inhalation is applied together with an effective EVLP, in order to provide a ‘multitarget’ graft reconditioning procedure, a recent, theoretically described, EVLP protocol (Shehata protocol) introduced the notion of supplementing Steen solutionTM with a combination of antioxidants and K channel agonists based on the above-discussed principles.

Antioxidants and K+channel agonists versus hydrogen therapy duringex vivolung perfusion

Antioxidants and K⁺channel agonists versus hydrogen therapy duringex vivolung perfusion