Isoform-specific functions of c-Jun N-terminal kinase 1 and 2 in lung ischemia-reperfusion injury through the c-Jun/activator protein-1 pathway
2020
Abstract Objective JNK1 and JNK2 regulate distinct pathological processes in lung diseases. Here, we discriminated the respective roles of these kinases in lung transplantation-induced ischemia-reperfusion injury. Methods Rat pulmonary microvascular endothelial cells were transfected with JNK1 small-interfering RNA and JNK2 small-interfering RNA and then subjected to in vitro ischemia-reperfusion. For the isoform confirmed to aggravate ischemia-reperfusion injury, the delivery of short-hairpin RNA plasmid was performed by intratracheal administration 48 hours before transplantation into donor rats. After 3-hour reperfusion, the samples were collected. Results JNK1 small-interfering RNA decreased, whereas JNK2 small-interfering RNA increased JNK phosphorylation and activity, phosphorylated and total c-Jun, and activator protein-1 activity. Although JNK1 small-interfering RNA decreased apoptosis and the levels of malondialdehyde, interleukin-1, interleukin-6, and tumor necrosis factor-α, they increased the levels of superoxide dismutase, S-phase percentage, and cyclin D1; JNK2 small-interfering RNA had a converse effect. JNK1 small-interfering RNA decreased the level of lactate dehydrogenase, and increased the levels of VE-cadherin, nitric oxide, phosphorylated nitric oxide synthase, and cell viability; JNK2 small-interfering RNA had a converse effect. Compared with control group, JNK1 short-hairpin RNA group exhibited a higher lung oxygenation index, lower lung apoptosis index, injury score, wet weight-to-dry weight ratio, and the levels of interleukin-1, interleukin-6, and tumor necrosis factor-α. Conclusions JNK1 aggravated, but JNK2 alleviated, ischemia-reperfusion injury through differential regulation of the c-Jun/activator protein-1 pathway in in vitro ischemia-reperfusion. JNK1 silence attenuated lung graft dysfunction by inhibition of inflammation and apoptosis. These provide theoretical basis and therapeutic strategies against ischemia-reperfusion injury after lung transplantation.
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