WANG Ping

(The Feinstein Institute for Medical Research，New York 11030，USA)

Excessive neutrophil infiltration in the lungs is a hallmark of acute lung injury(ALI).Although milk fat globule－epidermal growth factor 8(MFG－E8)was originally identified for phagocytosis of apoptotic cells，subsequent studies revealed its diverse cellular functions.However，whether MFG － E8 can regulate neutrophil function to alleviate inflammation is unknown.We therefore aimed to reveal the roles of MFG－E8 in regulating lung neutrophil infiltration during ALI.To induce ALI，C57BL/6J wild －type(WT)and Mfge8－/－mice were intratracheally injected with LPS(5 mg/kg).Lung tissue damage was assessed by histology and the infiltrated neutrophils were counted by a hemacytometer.Apoptotic cells in lungs were determined by TUNEL，while caspase－3 and myeloperoxidase(MPO)activity was assessed spectrophotometrically.CXCR2 and G protein－coupled receptor kinase 2(GRK2)expression in neutrophils was measured by flow cytometry.Following LPS challenge，Mfge8－/－mice exhibited extensive lung tissue damage due to exaggerated infiltration of neutrophils and elevated production of TNF－α，MIP－2 and MPO.Increased number of apoptotic cells was trapped into the lungs of Mfge8－/－mice than corresponding WT mice，which may be due to insufficient phagocytosis of apoptotic cells or increased occurrence of apoptosis through the activation of caspase－3.In vitro studies using MIP－2－mediated chemotaxis revealed higher migration of bone marrow－derived neutrophils(BMDN)of Mfge8－/－mice than WT mice via increased surface exposure to CXCR2.Administration of recombinant mouse MFG－E8 reduced neutrophil migration through up－regulation of GRK2，and down－regulation of surface CXCR2 expression.Conversely，these effects could be blocked by anti－αV－integrin antibodies.These studies clearly indicate the importance of MFG－E8 in ameliorating neutrophil infiltration and suggest MFG－E8 as a novel therapeutic potential for ALI.