Abstract: Objective To observe the effect of up-regulation of protein kinase D2 (PKD2) expression on lung ischemia-reperfusion injury (LIRI). Methods 20 C57BL/6J wild-type (WT) mice and 40 PKD2 gene overexpression (PKD2+/+) mice were randomly divided into sham operation group (WS and PS groups), LIRI group (WIR and PIR groups, the left hilum was first clamped for 1 h, then reperfused for 2 h) and the hypoxia inducible factor-1α (HIF-1α) inhibitor (2-methoxyestradiol, 2-ME) group (WIR+2ME and PIR+2ME groups, 20 mg/kg?d 2ME was injected intraperitoneally 2 days before modeling). After 2 hours of reperfusion, the wet/dry weight ratio (W/D) of lung tissues was detected, the pathological changes of lung tissues were observed by HE staining, and the content of inflammatory factors TNF-α, IL-1β and IL-6 in lung tissues were detected by ELISA. RT-qPCR and Western blot were used to detect the expression of HIF-1α and VEGFA mRNA and protein in lung tissues. Results Compared with WS group, the W/D value of the WIR group increased, the lung tissues were damaged, the content of inflammatory factors increased, and the expression of HIF-1α and VEGFA mRNA and protein increased (P<0.05). Compared with the WIR group, the PIR group W/D value decreased, lung tissue damage was reduced, inflammatory factor content decreased, HIF-1α and VEGFA mRNA and protein expression increased (P<0.05). Compared with WIR and PIR groups, W/D values of WIR+2ME and PIR+2ME groups increased, lung tissue damage worsened, inflammatory factor content increased, HIF-1α and VEGFA mRNA and protein expression decreased (P<0.05). Compared with WIR+2ME group, there was no significant difference in the changes of the above indicators in PIR+2ME group (P>0.05). Conclusions Up-regulation of PKD2 gene can improve LIRI, and its mechanism may be related to increasing the expression of HIF-1α/VEGFA signaling pathway.