title: Role for macrophage migration inhibitory factor in acute respiratory distress syndrome.
abstract: The critical role of macrophage migration inhibitory factor (MIF) in mediating inflammatory lung injury in acute respiratory distress syndrome (ARDS) has been raised recently. The present study has identified enhanced MIF protein expression in alveolar capillary endothelium and infiltrating macrophages in lung tissues from ARDS patients. The possibility that MIF up-regulates its synthesis in an autocrine fashion in ARDS was tested using cultured endothelial cells stimulated with MIF and a murine model of lipopolysaccharide (LPS)-induced acute lung injury. MIF induced significant MIF and tumour necrosis factor (TNF)-alpha synthesis in cultured endothelial cells and the effect was blocked by neutralizing anti-MIF antibody. A similar blocking effect was observed when MIF-stimulated endothelial cells were pretreated with neutralizing anti-TNF-alpha antibody or glucocorticoid, supporting the notion that MIF induced TNF-alpha production via an amplifying pro-inflammatory loop. Treatment with anti-MIF or glucocorticoid effectively attenuated pulmonary pathology and the synthesis of MIF or TNF-alpha in mice with LPS-induced acute lung injury. Mildly augmented expression of aquaporin 1 (AQP1) was also detected in alveolar capillary endothelium in ARDS. In vitro studies revealed that both MIF and TNF-alpha induced a small increase of AQP1 synthesis in cultured endothelial cells. These findings suggest that MIF plays a crucial pathological role leading to alveolar inflammation in ARDS. Anti-MIF and early glucocorticoid therapy may represent a novel therapeutic approach for reducing alveolar inflammation in ARDS.
authors.affiliation: Department of Medicine, University of Hong Kong, Queen Mary Hospital, Pokfulam Road, Hong Kong. knlai@hkucc.hku.hk
authors.forename: Kar Neng
authors.initials: KN
authors.lastname: Lai
authors.forename: Joseph C K
authors.initials: JC
authors.lastname: Leung
authors.forename: Christine N
authors.initials: CN
authors.lastname: Metz
authors.forename: Fernand M
authors.initials: FM
authors.lastname: Lai
authors.forename: Richard
authors.initials: R
authors.lastname: Bucala
authors.forename: Hui Yao
authors.initials: HY
authors.lastname: Lan
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D051398:Aquaporin 1; D020346:Aquaporins / Q000096:biosynthesis; D001789:Blood Group Antigens; D002478:Cells, Cultured; D003907:Dexamethasone / Q000627:therapeutic use; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression; D005938:Glucocorticoids / Q000627:therapeutic use; D006801:Humans; D008070:Lipopolysaccharides; D008263:Macrophage Migration-Inhibitory Factors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D011650:Pulmonary Alveoli / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D012128:Respiratory Distress Syndrome / Q000503:physiopathology* / Q000517:prevention & control; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000276:immunology
chemical_list: C496020:AQP1 protein, human; D000911:Antibodies, Monoclonal; C496021:Aqp1 protein, mouse; D020346:Aquaporins; D001789:Blood Group Antigens; D005938:Glucocorticoids; D008070:Lipopolysaccharides; D008263:Macrophage Migration-Inhibitory Factors; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D051398:Aquaporin 1; D003907:Dexamethasone