Pulmonary arterial hypertension (PAH) is a progressive disease that ultimately leads to right heart failure and death. Current strategies are ineffective to prevent and cure PAH, especially in those who undergo cardiopulmonary bypass. P2 × 7 receptors (P2 × 7Rs) have been implied to participate in the pathogenesis of PAH and injuries induced by ischemia-reperfusion (IR). In the present study, we aimed to assess the potential therapeutic effects of anti-P2 × 7Rs on PAH and IR-induced lung injuries in rats and explore their underlying cellular and molecular mechanisms. In the present study, we have successfully established rat models with PAH and/or lung IR injuries. Immunohistochemical staining, western blot, and polymerase chain reaction were performed to detect the P2 × 7R expression in these models; P2 × 7R-specific inhibitor, Brilliant Blue G (BBG), was used to antagonize P2 × 7R, and enzyme-linked immunosorbent assay was used to help evaluate the P2 × 7R-mediated function in PAH with or without IR. Moreover, BBG, SB203580 (p38/MAPK inhibitor), and CD39 (adenosine triphosphate hydrolase) were applied to explore the inner signal pathway in vitro and in vivo. Our findings showed that P2 × 7R was involved in the development of PAH. By applying BBG, we have shown that the severity of PAH and IR was ameliorated through reducing the release of proinflammatory cytokines. Moreover, our results in vitro and in vivo indicated that P2 × 7R regulated the release of inflammatory mediators by the p38/MAPK signal pathway. Most important, CD39 showed the most dominant potential in improving inflammation in lung injuries caused by PAH and IR. In conclusion, the inhibition of P2 × 7R could effectively attenuate inflammation in lung injuries caused by PAH and IR in rats by reducing proinflammatory cytokines through regulating the p38/MAPK pathway.