Protective Effects of Necrosulfonamide on Ischemia-Reperfusion Injury in Rat Lung

• Published in: The Journal of heart and lung transplantation Vol. 39; no. 4; p. S353
• Main Authors: Ueda, S., Chen-Yoshikawa, T.F., Mineura, K., Yamanashi, K., Oda, H., Yokoyama, Y., Ikeda, M., Tokuno, J., Kayawake, H., Yamagishi, H., Gochi, F., Okabe, R., Tanaka, S., Yamada, Y., Nakajima, D., Ohsumi, A., Hamaji, M., Date, H.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.04.2020
• ISSN: 1053-2498; 1557-3117
• DOI: 10.1016/j.healun.2020.01.414

In lung transplantation, ischemia-reperfusion injury (IRI) plays a critical role in the development of primary graft dysfunction. Among cell deaths induced by IRI, regulated necrosis has been garnering much attention. Above all, necroptosis is well known, and there are some reports on necroptosis inhibition attenuated IRI improvement in solid organ transplantation. However, there are few reports about mixed lineage kinase domain-like protein (MLKL), which is proposed as a crucial mediator of necroptosis. The purpose of this study was to verify the hypothesis that the MLKL inhibitor necrosulfonamide, (NSA) attenuates IRI. Male Lewis rats were heparinized and subjected to left thoracotomy under the anesthetization. Then, the left hilum was clamped for 90 min, followed by reperfusion for 120 min (rat hilar clamp model). NSA 0.5 mg and the solvent were intraperitoneally administered 30 min before ischemia in the NSA group and the vehicle group, respectively (n = 8, for both). After reperfusion, arterial blood gas analysis, physiological data (dynamic compliance, mean, and peak airway pressure), lung wet-to-dry weight ratio (W/D), and histological findings (extravascular red blood cell and neutrophil count and vascular edema) were evaluated under the right hilum occlusion. The NSA group had higher arterial oxygenation than the vehicle group (p = 0.0009). Dynamic compliance was higher and peak and mean airway pressures were lower in the NSA group than in the vehicle group (p = 0.0356, p = 0.0181, and p = 0.0394, respectively). W/D ratio was also significantly improved in NSA group (p = 0.0136). Histologically, hemorrhage and neutrophil in alveolar or interstitial space were significantly lower in the NSA group (p = 0.0357, p = 0.0157, respectively). Perivascular edema evaluated by vascular cuff was also ameliorated in the NSA group as well W/D ratio (p = 0.000155). Our results suggested that NSA alleviated lung IRI via necroptosis inhibition in rat lung.