Background: Acute lung injury (ALI) is an acute multifactorial infectious disease induced by trauma, pneumonia, shock, and sepsis. This study aimed to investigate the protective effects of pseudoephedrine and emodin combined treatment in experimental ALI , as well as the mechanisms underlying the regulation of inflammation and pulmonary edema via the VIP /cAMP/PKA pathway.Methods: Wistar rats were divided into a control group, lipopolysaccharide(LPS) group, and a pseudoephedrine + emodin treatment group. Rats in the control group were given intraperitoneal saline injections, while rats in the LPS and treatment groups were given intraperitoneal LPS injections to induce ALI. After being treated with pseudoephedrine and emodin for 24 hours, all animals were sacrifce. Anal temperatures were taken on an hourly basis for eight hours after LPS injection. Pathological examination of lung specimen was performed by H&E staining. Cytokines (IL-1β, TNF-α, IL-6, IL-10, Arg-1, CD86, CD80, CD206, F4/80, VIP) in colon were assayed by ELISA and immunofuorescence.The expression of VIP, CAMP, AQP-1, AQP-5, p-PKA/PKA, p-IκBα/IκBα, and p-p65/p65 protein in lung was determined by western blotting.Results: After rats being treated with pseudoephedrine + emodin, the symptoms (febrility) of ALI were alleviated. The contents of infammatory cytokines (IL-1β, TNF-α, IL-6) were decreased and anti-inflammatory cytokines(IL-10, Arg-1) were signifcantly increased in serum. Pseudoephedrine + emodin treatment effectively promoted VIP cAMP and p-PKA protein expression in lung tissues, and significantly inhibited NF-κB phosphorylation,Pseudoephedrine + emodin treatment can inhibit M1 polarization and promoted M2 polarization via the VIP/cAMP/PKA signaling pathway.Conclusions: The combination of pseudoephedrine hydrochloride and emodin was effective in ameliorating LPS-induced ALI in rats by inducing VIP/cAMP/PKA signaling, inhibiting the NF-κB inflammatory pathway, suppressing macrophage M1 polarization, and promoting macrophage M2 polarization.