Argon Inhalation Reduces Pulmonary Ischemia-Reperfusion Injury in MHC-inbred CLAWN Miniature Swine

Abstract

<h3>Purpose</h3> Ischemia-reperfusion injury (IRI) remains a major cause of early death in lung transplantation. The cytoprotective effects of chemically inert noble gases such as argon (Ar) have been demonstrated, especially Ar, which is non-anesthetic and the third most abundant gas in the atmosphere, suggesting higher safety levels and lower cost advantages. The inhibitory effect of IRI has been reported in small animal models of various organs, but there are conflicting reports on the effect in large animal models. In this study, we evaluated the beneficial effect and safety of Ar inhalation using a large animal lung IRI model to assess the applicability of Ar's cytoprotective effect to transplantation. <h3>Methods</h3> The Ar inhalation group (n=5) inhaled 30% oxygen plus 70% Ar, and the control group (n=5) inhaled 30% oxygen plus 70% nitrogen for a total of 360 minutes. In each group, the degree of lung damage was evaluated up to 28 days postoperatively using arterial and pulmonary venous (PV) gas analysis, chest X-ray (CXR), and lung biopsy as the main indices, as well as the presence of side effects. <h3>Results</h3> Although the arterial blood P/F ratio significantly decreased from pre-ischemia to 2 hours after reperfusion in the control group (from 568 ± 12 to 272 ± 39 mmHg) after 90 minutes of warm ischemia, it was well maintained in the Ar inhalation group (from 563 ± 18 to 431 ± 49 mmHg). In addition, direct assessment of impaired lung using left PV blood showed a significantly better P/F ratio in the Ar inhalation group (331 ± 40 vs. 186 ± 17 mmHg at 2 hours; 519 ± 19 vs. 292 ± 33 mmHg at 2 days). Early postoperative CXR showed that the infiltrations of the left lung in the control group were reduced by Ar inhalation. In addition, histological scores of lung biopsies (calculated based on four items: cellular infiltration, intralobular edema, fibrin exudation, and hemorrhage) were significantly better in the Ar-inhalation group for both 2-hour and 2-day biopsies after reperfusion. The serum evaluation suggested that anti-oxidant and anti-apoptosis were the main mechanisms of action. <h3>Conclusion</h3> In this study, we demonstrated for the first time the inhibitory effect of perioperative Ar inhalation on pulmonary IRI in large animals. In order to apply this new therapy to clinical practice, further detailed analysis of the mechanism and evaluation using ischemic models including cold storage are required in the future.