Acute Lung Injury (ALI) is a devastating syndrome with a mortality rate of 30-40 percent. Alveolar epithelial damage is a characteristic morphologic feature in patients with ALl. The loss of epithelial integrity contributes to the alveolar flooding and disrupts normal lung epithelial fluid transport that is important for the removal of pulmonary edema fluid from the airspaces. The molecular steps regulating the development and resolution of alveolar flooding in ALI are poorly understood. The cytokine transforming growth factor beta1 (TGF-beta1) plays a critical role in the resolution of ALI and in the development of lung fibrosis often associated with this syndrome. We previously reported that the expression levels of several TGF-beta1-inducible genes are dramatically increased early after the induction of experimental ALI induced with bleomycin. We also found the alpha-v-beta-6 integrin-mediated local activation of TGF-beta1 is critical to the development of pulmonary edema in ALI and that the activation of TGF-beta1 depends on a change in the conformation of the alpha-v-beta-6 integrin. However, the mechanism of activation of this integrin is still unknown. IL-1beta was found to be biologically active and primarily responsible for the inflammatory activity within the airspaces of patients with ALI. Moreover, transient overexpression of IL-1beta, but not of TNF-alpha, in the lung by adenoviral gene transfer was associated with progressive fibrotic changes and an increased expression of TGF-beta1. Finally, preliminary experiments from our laboratory indicate that IL-1beta, but not TNF-alpha, causes activation of the alpha-v-beta-6-mediated TGF-beta1-dependent cell signaling pathway in alveolar epithelial cells. Thus, this application will test the hypotheses that (a) the release of IL-1beta within the airspaces is responsible for the alpha-v-beta-6 integrin-mediated activation of TGF-beta1 (aim 1); (b) the activation of the focal adhesion kinase (FAK) and/or its downstream cell effectors, phosphoinositol-3-kinase and small GTPases, Rac-1 and RhoA, is required for IL-1beta-induced alpha-v-beta-6 integrin-mediated local activation of TGF-beta1 (aim 2); (c) locally activated TGF-beta1 decreases basal and c-AMP regulated lung epithelial fluid transport by altering the expression of amiloride-sensitive sodium channel, ENaC, on the cell membrane of lung epithelial cells (aim 3).

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
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Special Emphasis Panel (ZHL1-CSR-R (M1))
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University of California San Francisco
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Beitler, Jeremy R; Thompson, B Taylor; Matthay, Michael A et al. (2015) Estimating dead-space fraction for secondary analyses of acute respiratory distress syndrome clinical trials. Crit Care Med 43:1026-35
Pittet, Jean-François; Koh, Hidefumi; Fang, Xiaohui et al. (2013) HMGB1 accelerates alveolar epithelial repair via an IL-1?- and ?v?6 integrin-dependent activation of TGF-?1. PLoS One 8:e63907
Agrawal, Ashish; Zhuo, Hanjing; Brady, Sandra et al. (2012) Pathogenetic and predictive value of biomarkers in patients with ALI and lower severity of illness: results from two clinical trials. Am J Physiol Lung Cell Mol Physiol 303:L634-9
Fricks-Lima, J; Hendrickson, C M; Allgaier, M et al. (2011) Differences in biofilm formation and antimicrobial resistance of Pseudomonas aeruginosa isolated from airways of mechanically ventilated patients and cystic fibrosis patients. Int J Antimicrob Agents 37:309-15
Srinivasan, Ramya; Song, Yuanlin; Wiener-Kronish, Jeanine et al. (2011) Plasminogen activation inhibitor concentrations in bronchoalveolar lavage fluid distinguishes ventilator-associated pneumonia from colonization in mechanically ventilated pediatric patients. Pediatr Crit Care Med 12:21-7
Singh, G; Wu, B; Baek, M S et al. (2010) Secretion of Pseudomonas aeruginosa type III cytotoxins is dependent on pseudomonas quinolone signal concentration. Microb Pathog 49:196-203
Lynch, Susan V; Flanagan, Judith L; Sawa, Teiji et al. (2010) Polymorphisms in the Pseudomonas aeruginosa type III secretion protein, PcrV - implications for anti-PcrV immunotherapy. Microb Pathog 48:197-204
Ware, Lorraine B; Koyama, Tatsuki; Billheimer, D Dean et al. (2010) Prognostic and pathogenetic value of combining clinical and biochemical indices in patients with acute lung injury. Chest 137:288-96
Roux, Jérémie; Carles, Michel; Koh, Hidefumi et al. (2010) Transforming growth factor beta1 inhibits cystic fibrosis transmembrane conductance regulator-dependent cAMP-stimulated alveolar epithelial fluid transport via a phosphatidylinositol 3-kinase-dependent mechanism. J Biol Chem 285:4278-90
Goolaerts, Arnaud; Roux, Jérémie; Ganter, Michael T et al. (2010) Serotonin decreases alveolar epithelial fluid transport via a direct inhibition of the epithelial sodium channel. Am J Respir Cell Mol Biol 43:99-108

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