Ischemia Reperfusion Induces Death Receptor-Independent Necroptosis via Calpain-STAT3 Activation in a Lung Transplant Setting.

In this study, we investigated the role of RN in IR-induced lung injury. To study IR-induced cell-death, we simulated LTx procedure using our cell culture model with human lung epithelial (BEAS-2B) cells. After 18 h of cold ischemic time (CIT) followed by reperfusion, caspase-independent cell-death, mitochondrial-ROS production and mitochondrial-membrane permeability were significantly increased. ALLN (calpain inhibitor) or necrostatin-1 (Nec-1; RIPK1 inhibitor) reduced these changes. ALLN altered RIPK1/RIPK3 expression and MLKL phosphorylation, whereas Nec-1 did not change calpain/calpastatin expression. Furthermore, STAT3 was demonstrated to be downstream of calpain and regulate RIPK3 expression and MLKL phosphorylation during IR. This calpain-STAT3-RIPK axis induces ER-stress and mitochondrial-calcium dysregulation. LTx patients' samples demonstrate that RIPK1, MLKL and STAT3 mRNA expression increased from CIT to reperfusion. Moreover, the expressions of the key proteins are higher in PGD samples than in non-PGD samples. Cell-death associated with prolonged-lung preservation is mediated by calpain-STAT3-RIPK axis. Inhibition of RIPK and/or calpain pathways could be an effective therapy in LTx. PMID: 30024306 [PubMed - as supplied by publisher]
Source: Am J Physiol Lung Ce... - Category: Respiratory Medicine Authors: Tags: Am J Physiol Lung Cell Mol Physiol Source Type: research