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Endothelial PP2AC prevents endotoxemia‐induced acute lung injury by suppressing STAT3 activity

Acute lung injury (ALI) is a critical hypoxemic respiratory failure characterized by alveolar‐capillary damage, unchecked inflammation, vascular leak, and pulmonary edema secondary to endothelial barrier dysfunction. Identifying the candidate molecules targeting mechanisms for excessive production of proinflammatory cytokines and endothelial dysfunction are warranted for therapeutic intervention. Recent studies show that the signal transducers and activators of transcription 3 (STAT3) phosphorylation in critical for inflammatory cytokines production and systemic inflammation. Protein phosphatase 2A (PP2A) is a hetero‐trimeric, ubiquitously expressed Ser/Thr phosphatase. The phosphatase activity of PP2A is regulated by its catalytic C subunit (PP2AC). PP2A plays an essential role in modulating tissue inflammation by maintaining the phosphorylation/de‐phosphorylation balance of multiple proteins. So far, however, no studies have deciphered PP2AC isoform‐a function in regulating pulmonary vascular endothelial permeability and inflammatory signaling. We hypothesize that PP2AC expression in vascular endothelial cell (EC) protects the lung against sepsis‐induced lung injury. Wild‐type (WT) and endothelial specific PP2AC‐deficient mice (PP2ACCKO) were challenged with lipopolysaccharide. We found that lipopolysaccharide‐induced inflammatory response, characterized by up‐regulated level of IL‐1b, IL‐6, MPO activity and pulmonary vascular hyper‐permeability in lung tissue of PP2ACCKO mice was significantly elevated as compared to WT littermate control. Mechanistically, we showed that PP2AC deletion in mouse lung‐EC and in human lung‐EC markedly augmented Ser727‐phosphorylation‐mediated STAT3 activation and MMP9 level in response to lipopolysaccharide. Intriguingly, administration of a STAT3 inhibitor suppressed lipopolysaccharide‐induced production of MMP9 and proinflammatory cytokines IL‐1b, IL‐6, MPO activity and pulmonary vascular hyper‐permeability and thus rescued the augmented inflammatory phenotype in PP2ACCKO mice lung. In conclusion, these data showed the protective role of endothelial‐PP2AC in limiting endothelial barrier dysfunction and inflammation, and thereby it attenuates sepsis‐induced lung injury by preventing hyper‐activated STAT3 signaling.