*Purpose: Noble gases, such as xenon and argon (Ar), are chemically inert but have shown to have cytoprotective effect. In contrast to xenon, Ar is the non-anesthetic and the third most abundant gas in the earth’s atmosphere suggesting its higher safety level and economic benefit. The effects of Ar on reducing ischemia-reperfusion injury (IRI) have been reported in a variety of organs in murine models, however, the results from large animal models have been still controversial. In this study, we evaluated the cytoprotective effects of Ar inhalation in in situ porcine lung model of 90-minutes warm IRI.

*Methods: Ten CLAWN miniature swine were evenly divided into two groups (Ar-treated and control group). In both groups, warm ischemia was induced for 90 minutes by clamping the left bronchus, pulmonary artery and veins. Animals were inhaled with either 70% Ar (Ar-treated) or 70% nitrogen (control) in 30% oxygen for 360 minutes throughout the procedure. Lung function and structure were serially assessed via the ratio of partial pressure of oxygen to fractional inspired oxygen (pO₂/FiO₂) measured by both arterial blood and pulmonary vein (PV), chest X-ray and lung biopsy.

*Results: Ar inhalation dramatically decreased lung injury associated with ischemia and reperfusion without apparent adverse effects. In the control group, 90 minutes of warm ischemia resulted in a significant decrease in pO₂/FiO₂ by arterial blood, from 568 +/-12 mmHg before ischemia to 272 +/-39 mmHg 2 hours after reperfusion (p<0.05). In sharp contrast, animals in the Ar-treated group had no significant change in pO₂/FiO₂ by arterial blood despite 90-min ischemia (563 +/-18 mmHg before ischemia to 431 +/-49 mmHg 2 hours after reperfusion). Moreover, pO₂/FiO₂ by PV showed well-maintained lung function in the Ar-treated group (331 +/-40 vs. 186 +/-17 at 2 hours, p<0.05; 519 +/-19 vs. 292 +/-33 at 2 days after reperfusion, p<0.05). Histologic scores of lung biopsy specimens based on light microscopy which was calculated on the basis of the evaluation of cell infiltration, intra-alveolar edema, fibrin exudation and hemorrhage showed significantly better in the Ar-treated group at both 2 hours and 2 days after reperfusion.

*Conclusions: To our knowledge, this is the first demonstration of the beneficial effects of perioperative inhalation of Ar on IRI of the lung in a large animal model. Further studies are required to clarify the exact mechanism of the effect of Ar inhalation including anti-inflammation, anti-apoptotic or anti-oxidation for clinical application of this novel therapy.

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