Acute lung injuries (ALI) is characterised by acute hypoxic respiratory system failure, lung edema and inflammatory infiltration. ALI includes a high mortality rate (~30%) within the clinical setting therefore, concentrating on treating lung edema and inflammatory responses in ALI is of significance. The current study investigated the result from the p38 mitogen?activated protein kinase (p38MAPK) inhibitor, SB203580, on lung edema and inflammatory responses in ALI in vivo. A mouse type of ALI started to evaluate the result of SB203580 on edema, proinflammatory cytokine production, and also the expression of interferon regulatory factor 5 (IRF5) and inducible nitric oxide supplement synthase (iNOS) in lung tissues using immunoblotting, immunohistochemistry, immunofluorescence, hematoxylin and eosin staining, and ELISA. SB203580 inhibited LPS?caused lung injuries and proinflammatory cytokine expression, including tumor necrosis factor?α and interleukin?1β. SB203580 also downregulated LPS?caused IRF5 and iNOS expression, that are broadly utilized as markers of proinflammatory macrophages. With each other, the current study shown that SB203580 shielded from inflammatory responses and lung injuries by inhibiting lung edema and downregulating proinflammatory mediators in LPS?caused lung injuries.