Acute lung injury (ALI) and its progression to adult respiratory distress syndrome (ARDS) remain leading factors of morbidity and mortality in critically ill patients. Although the expanding knowledge involving the cytokine-transcription factor network has provided new insights into the acute lung inflammatory responses, elucidation of the function of these inflammation-related transcription factors in the lung is still a daunting challenge. Functioning as a transcription factor, STAT3 participates in the signaling pathways for many cytokines that are regulated by the suppressor of cytokine signaling (SOCS) family, including SOCS3. While STAT3 is expressed in various cell types in lung, little is known about the function role of STAT3 and the molecular mechanism exerted by STAT3 to regulate acute lung inflammatory responses. Furthermore, there is no clear understanding of exactly how STAT3 activation is regulated in the lung. Our preliminary data indicate that STAT3 can participate in lung inflammatory outcomes and seems to play a dual role in both IgG immune complex and LPS lung injury models and alveolar macrophages. The hypothesis of this study is that STAT3 may exert its regulatory function in vivo during ALI by activating multiple target genes, which then differentially regulate Fc3R-mediated and TLR4-mediated inflammatory responses in the lung. Therefore, this study is designed to elucidate the roles of STAT3 and SOCS3 signaling in ALI occurring after intrapulmonary deposition of IgG immune complex or LPS, and the underlying molecular mechanisms. In the first aim, we will pursue preliminary information that siRNA-mediated suppression of STAT3 in vivo intensifies injury in IgG immune complex model of ALI and attenuates injury in the LPS model of ALI and determine if measurements of the pro- and anti-inflammatory mediators correlate with ALI outcomes. In the second aim, we will define STAT3 acetylation and molecular mechanisms by which acetylation regulates STAT3 activity in alveolar macrophages and lung injury. In the third aim, we will determine the mechanisms by which SOCS3 regulates IgG immune complex-induced and LPS-induced STAT3 activation and inflammatory response in alveolar macrophage. Proteomic analysis will be performed to identify SOCS3 interacting proteins. The results of our studies are expected to provide important information on inflammatory cascades in the lung and the regulatory roles of STAT3 and SOCS3 in the lung inflammatory response. This knowledge will represent a new paradigm for approaching the development of new therapeutic targets for treatment of ALI. PROJECT NARRATIVE: This proposed project will investigate whether STAT3 contributes to immune complex and sepsis-related acute lung injury. This project will also define if post-translational mechanisms such as protein acetylation and protein-protein interaction contribute to STAT3 activity in acute lung injury. These studies will be essential to identify novel therapeutic targets for treatment of acute lung injury. ? ? ?
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