title: Activation of the STAT pathway in acute lung injury.
abstract: Acute lung injury (ALI) is a devastating clinical problem with a mortality as high as 60%. It is now appreciated that ALI represents a cytokine excess state that involves the microvasculature of multiple organs. The signal transducers and activators of transcription (STAT) family of transcription factors activate critical mediators of cytokine responses, but there is limited knowledge about their role in mediating ALI. In the present study, we demonstrate that the STAT transcription factors are activated rapidly in the lungs after intraperitoneal and intranasal LPS administration in mice. We also demonstrated that LPS activates both the STAT kinases, Src and JAK, in the lung with kinetics that are consistent with STAT activation. LPS treatment resulted in STAT3 activation throughout the resident lung cells, as well as in the recruited inflammatory cells. Whereas direct LPS treatment did not lead to STAT activation in cultured epithelial or endothelial cells, IL-6 activated STAT3 in both of these cell types. Furthermore, IL-6 was induced by LPS in serum and in the lung with kinetics consistent with STAT3 activation, suggesting that IL-6 may be one mechanism of STAT activation by LPS. In addition, STAT activation required reactive oxygen species, as the overexpression of catalase in mice prevented LPS-mediated STAT activation in the lung. STATs may be a common pathway for mediating ALI, regardless of the inciting factor, as STAT activation also occurred in both a gastric acid aspiration and acute pancreatitis model of ALI. Finally, STATs are activated in the lung long before signs of ALI are present, suggesting that the STAT transcription factors may play a role in initiating the inflammatory response seen in the lung.
authors.affiliation: Pulmonary and Critical Care Division, Tufts-New England Medical Center, Boston, MA 02111, USA.
authors.forename: Mariano
authors.initials: M
authors.lastname: Severgnini
authors.forename: Satoe
authors.initials: S
authors.lastname: Takahashi
authors.forename: Liliana M
authors.initials: LM
authors.lastname: Rozo
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Homer
authors.forename: Charles
authors.initials: C
authors.lastname: Kuhn
authors.forename: Jhung W
authors.initials: JW
authors.lastname: Jhung
authors.forename: George
authors.initials: G
authors.lastname: Perides
authors.forename: Michael
authors.initials: M
authors.lastname: Steer
authors.forename: Paul M
authors.initials: PM
authors.lastname: Hassoun
authors.forename: Barry L
authors.initials: BL
authors.lastname: Fanburg
authors.forename: Brent H
authors.initials: BH
authors.lastname: Cochran
authors.forename: Amy R
authors.initials: AR
authors.lastname: Simon
mesh_terms: D000208:Acute Disease; D000818:Animals; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004195:Disease Models, Animal; D006851:Hydrochloric Acid; D015850:Interleukin-6 / Q000097:blood; D053614:Janus Kinase 2; D007700:Kinetics; D008070:Lipopolysaccharides; D008099:Liver / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010084:Oxidation-Reduction; D010195:Pancreatitis / Q000150:complications / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D012128:Respiratory Distress Syndrome / Q000139:chemically induced / Q000378:metabolism*; D020545:Respiratory Mucosa / Q000166:cytology / Q000378:metabolism; D050796:STAT3 Transcription Factor; D015534:Trans-Activators / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D015850:Interleukin-6; D008070:Lipopolysaccharides; D011518:Proto-Oncogene Proteins; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D015534:Trans-Activators; D014409:Tumor Necrosis Factor-alpha; D011505:Protein-Tyrosine Kinases; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2; D019061:src-Family Kinases; D020928:Mitogen-Activated Protein Kinases; D006851:Hydrochloric Acid