Takashi Kanou1, Akihiro Ohsumi1, Hyunhee Kim1, Manyin Chen1, Xiaohui Bai1, Zehong Guan1, David Hwang1, Marcelo Cypel1, Shaf Keshavjee1, Mingyao Liu2. 1. Latner Thoracic Surgery Research Laboratories, Toronto General Hospital Research Institute, University Health Network and Department of Surgery and Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada. 2. Latner Thoracic Surgery Research Laboratories, Toronto General Hospital Research Institute, University Health Network and Department of Surgery and Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada. Electronic address: mingyao.liu@utoronto.ca.
Abstract
BACKGROUND: Increasing evidence indicates that regulated necrosis plays a critical role during cell death caused by ischemia-reperfusion (IR) injury. Necroptosis is one form of regulated necrosis. Necrostatin-1 (Nec-1), an inhibitor of receptor-interacting protein kinase 1 (RIPK1), is known to reduce necroptosis. We investigated the effect of Nec-1 treatment on IR-induced lung injury in a rat lung transplant model. METHODS: Lewis rats were divided into 4 groups (n = 6 each): (1) Control (no treatment), (2) Donor treatment (D), (3) Recipient treatment (R), and (4) Donor plus Recipient treatment (D+R) groups. Donor lungs were flushed and preserved for 18 hours at 4ºC before transplantation. Recipient animals underwent a left single lung transplant. After 2 hours of reperfusion, we assessed the physiologic function, cytokine expression, pathway activation, and the extent of necrosis. RESULTS: Pulmonary gas exchange in D+R group was significantly better than in the other 3 groups (p = 0.003). Lung edema was significantly lower in the D+R group compared with the Control group (p = 0.006). The expression of interleukin-6 in lung tissue and plasma was significantly reduced in the D+R group compared with the Control group (p = 0.036). The percentage of necrotic cells in D+R group was significantly lower than in the Control and D groups (p = 0.01), indicating Nec-1inhibited regulated necrosis. CONCLUSIONS: The administration of Nec-1 to both donor and recipient improved graft function after lung transplantation through the reduction of necroptosis. The inhibition of regulated necrosis appears to be a promising strategy to attenuate IR lung injury after lung transplantation.
BACKGROUND: Increasing evidence indicates that regulated necrosis plays a critical role during cell death caused by ischemia-reperfusion (IR) injury. Necroptosis is one form of regulated necrosis. Necrostatin-1 (Nec-1), an inhibitor of receptor-interacting protein kinase 1 (RIPK1), is known to reduce necroptosis. We investigated the effect of Nec-1 treatment on IR-induced lung injury in a rat lung transplant model. METHODS: Lewis rats were divided into 4 groups (n = 6 each): (1) Control (no treatment), (2) Donor treatment (D), (3) Recipient treatment (R), and (4) Donor plus Recipient treatment (D+R) groups. Donor lungs were flushed and preserved for 18 hours at 4ºC before transplantation. Recipient animals underwent a left single lung transplant. After 2 hours of reperfusion, we assessed the physiologic function, cytokine expression, pathway activation, and the extent of necrosis. RESULTS: Pulmonary gas exchange in D+R group was significantly better than in the other 3 groups (p = 0.003). Lung edema was significantly lower in the D+R group compared with the Control group (p = 0.006). The expression of interleukin-6 in lung tissue and plasma was significantly reduced in the D+R group compared with the Control group (p = 0.036). The percentage of necrotic cells in D+R group was significantly lower than in the Control and D groups (p = 0.01), indicating Nec-1inhibited regulated necrosis. CONCLUSIONS: The administration of Nec-1 to both donor and recipient improved graft function after lung transplantation through the reduction of necroptosis. The inhibition of regulated necrosis appears to be a promising strategy to attenuate IR lung injury after lung transplantation.
Authors: Wenjun Li; Guoshuai Feng; Jason M Gauthier; Inessa Lokshina; Ryuji Higashikubo; Sarah Evans; Xinping Liu; Adil Hassan; Satona Tanaka; Markus Cicka; Hsi-Min Hsiao; Daniel Ruiz-Perez; Andrea Bredemeyer; Richard W Gross; Douglas L Mann; Yulia Y Tyurina; Andrew E Gelman; Valerian E Kagan; Andreas Linkermann; Kory J Lavine; Daniel Kreisel Journal: J Clin Invest Date: 2019-02-26 Impact factor: 14.808
Authors: Davide Scozzi; Mohsen Ibrahim; Fuyi Liao; Xue Lin; Hsi-Min Hsiao; Ramsey Hachem; Laneshia K Tague; Alberto Ricci; Hrishikesh S Kulkarni; Howard J Huang; Seiichiro Sugimoto; Alexander S Krupnick; Daniel Kreisel; Andrew E Gelman Journal: Am J Transplant Date: 2019-01-25 Impact factor: 8.086