Key words : Lung preservation, Lung transplant, Graft conditioning, Graft dysfunction

Dear Editor:

The addressed study reports the significant ability of ascorbic acid supplementation during ex vivo lung perfusion (EVLP) to increase lung viability by 80% and to improve the mitochondrial functionality toward the oxidative phosphorylation.¹ While ascorbic acid is the main water-soluble antioxidant in human plasma, the study refers its beneficial effects to the ability to interact with electron transport chain rather than to its antioxidant actions.¹

The ischemic reperfusion injury (IRI) during lung transplant results in inhibition of sodium (Na+) potassium-(K+) ATPase and various K+ channels, leading to Na+ influx and persistant cell memberane depolarization. Under physiological conditions, active K+ channels are responsible to antagonize Na+ influx and to establish memberane hyperpo­larization. However, IRI is associated with inhibition of various K+ channels. That leads to enhanced activity of reactive oxygen species (ROS)-producing enzymes, such as nicotinamide adenine dinucleotide phosphate-oxidase and xanthine oxidase, and increased ROS production.² In addition, the increased level of K+ in the mitochondrial matrix leads to increased reactive oxygen species (ROS) production by the respiratory chain.

Reactive oxygen species activate protein kinase C zeta (PKC-ζ), which starts a sequence of phos­phorylation-ubiquitination-recognition-endocytosis-degradation of Na+/K+ ATPase.³ Reactive oxygen species also inhibit pyruvate dehydrogenase complex in a dose-dependent manner¹ and prime graft inflammasomes. Primed inflammasomes are then triggered in action by the simultaneous drop of K+ levels, leading to increased production of inflammatory cytokines. Accordingly, antioxidants, per se, are expected to provide a relatively limited degree of attenuation of the IRI; however, antagonizing the reasons of the increased production of ROS would be more effective.

Several studies have reported the ability of ascorbic acid to activate the K+ channels and Na+/K+ ATPase, establishing hyperpolarization in various cells.4 In addition, ascorbic acid increases the level of cGMP, which was reported to enhance mitochondrial KATP channels.⁵

The activated K+ channels antagonize the persistant membrane depolarization, abort inflam­masome activation, and attenuate ROS production, and provide other protective effects, which lead to the fact that K+ channel activators can protect against various forms of IRI.² Moreover, mitochondrial KATP channels were reported to be in cross-talk with complex II of the respiratory chain, which may contribute to the reported effect of ascorbic acid on the mitochondrial respiration.⁶

Taken together, it seems that the significant effects of ascorbic acid supplementation during EVLP result from combined antioxidant and K+ channels enhancing activities (Figure 1). Accordingly, sup­plementation of the preservation solution with a combination of antioxidants and K+ channel agonists is expected to be, at least, as protective as vitamin C; the notion that was introduced for the first time within Shehata EVLP technique.

Further studies should be conducted to assess the cytokine production of the lung graft during EVLP with ascorbic acid supplementation, and to determine the precise K+ channels that respond to vitamin C. Studies should also be conducted to compare ascorbic acid supplementation during EVLP with the notions of Shehata's technique.

References:

1. Shaghaghi H, Kadlecek S, Siddiqui S, et al. Ascorbic acid prolongs the viability and stability of isolated perfused lungs: A mechanistic study using (31)P and hyperpolarized (13)C nuclear magnetic resonance. Free Radic Biol Med. 2015;89:62-71.
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2. Chatterjee S, Nieman GF, Christie JD, Fisher AB. Shear stress-related mechanosignaling with lung ischemia: lessons from basic research can inform lung transplantation. Am J Physiol Lung Cell Mol Physiol. 2014;307(9):L668-L680.
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3. Helenius IT, Dada LA, Sznajder JI. Role of ubiquitination in Na,K-ATPase regulation during lung injury. Proc Am Thorac Soc. 2010;7(1):65-70.
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4. Grossmann M, Dobrev D, Himmel HM, Ravens U, Kirch W. Ascorbic acid-induced modulation of venous tone in humans. Hypertension. 2001;37(3):949-954.
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5. Wang X, Li J, Liu J, He W, Bi Y. Nitric oxide increases mitochondrial respiration in a cGMP-dependent manner in the callus from Arabidopsis thaliana. Nitric Oxide. 2010;23(3):242-250.
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6. Testai L, Rapposelli S, Martelli A, Breschi MC, Calderone V. Mitochondrial potassium channels as pharmacological target for cardioprotective drugs. Med Res Rev. 2015;35(3):520-553.
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