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Activation of the STAT pathway in acute lung injury

Mariano Severgnini,^1,2 Satoe Takahashi,^1,2 Liliana M. Rozo,^1,2 Robert J. Homer,³ Charles Kuhn,^,4 Jhung W. Jhung,⁴ George Perides,⁵ Michael Steer,⁵ Paul M. Hassoun,¹ Barry L. Fanburg,¹ Brent H. Cochran,² and Amy R. Simon^1,2

¹Pulmonary and Critical Care Division and ⁵General Surgery Division, Tufts-New England Medical Center, and ²Department of Physiology, Tufts University School of Medicine, Boston, Massachusetts 02111; and ³Department of Pathology, Yale University School of Medicine, New Haven, Connecticut 06510; and ⁴Department of Pathology, Brown University School of Medicine, Providence, Rhode Island 02912

Submitted 15 December 2003 ; accepted in final form 5 January 2004

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.

signal transducers and activators of transcription; lipopolysaccharide; reactive oxygen species

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