Acute lung injury and acute respiratory distress symptom (ALI/ARDS) are life-threatening condition in critically ill patients. Macrophages are heterogenous cell components in lung tissues and play important role in the pathogenesis of ALI/ARDS. There are alveolar macrophages (AMs), interstitial macrophages (IMs) and circulating undifferentiated monocytes/macrophages. Our results in vivo revealed that depletion of AMs exacerbated ALI, accompanied with more infiltration of neutrophils, whereas depletion of circulating monocyte/macrophages attenuated ALI, indicating the protective role of AMs and pro-inflammatory function of monocyte/macrophages. Resveratrol (Res) is a natural polyphenol that has anti-oxidative stress and immune suppressive effects. Our study in wild-type (WT) and SOCS3 conditional knock-out (KO) mice revealed that Res treatment significantly reduced ALI severity in WT mice, accompanied with much lower population of Siglec F-CD45+ phenotype macrophages. In addition, the CD206+ M2 subtype macrophages were increased in the WT mice after Res treatment. However, the beneficial effects and alteration of macrophages phenotypes were not observed in the SOCS3 KO mice. The results confirmed the positive relationships of Siglec F-CD45+ and negative relationships of CD206+ M2 subtype macrophages with ALI. Res may exert the therapeutic effects through SOCS3 signaling and subsequently modulation of these macrophage phenotypes. Our further study in recombinant surfactant protein D (rSP-D)-treated mice also indicated the positive relationships between Siglec F-CD45+ phenotype macrophages and ALI, in which rSP-D treatment significantly reduced ALI severity, accompanied with less influx of neutrophils and population of Siglec F-CD45+ phenotype monocytes/macrophages. Thus, we conclude that biological activity of lung macrophages can be modulated by some adjuvants such as anti-oxidants and anti-inflammatory proteins to exert immune protective role in inflammatory diseases such as ALI/ARDS.