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Although the mechanisms and pathways mediating ARDS have been studied extensively, less attention has been given to the mechanisms and pathways that counteract injury responses. This study found that the apelin-APJ pathway is an endogenous counterinjury mechanism that protects against ARDS. ⋯ The apelin-APJ signaling pathway is an endogenous anti-injury and organ-protective mechanism that is activated during ARDS to counteract the injury response and to prevent uncontrolled lung injury.