Project Title Mucosal Hypoxia Inducible Factor in Acute Lung Injury Project Summary Over the last decades, convincing evidence has demonstrated a central role of hypoxia inducible factor (HIF) in mammalian oxygen homeostasis. As such, HIF-driven responses are tailored towards adaptation to limited oxygen availability and restoring adequate tissue oxygen levels. More recently, several studies also implicated HIF in transcriptional coordination of inflammatory responses. However, the role of HIF during acute lung injury (ALI) is unknown. Preliminary data from stretch exposure of pulmonary epithelia demonstrates HIF stabilization in vitro. Moreover, in vivo studies of ALI show a protective role of epithelial HIF signaling. Therefore, we hypothesize that HIF-1 is stabilized during ALI, and dampens lung inflammation and tissue injury.
Three specific aims were designed to address novel roles for HIF in ALI. In the first aim, we propose to study mechanisms of mucosal HIF stabilization during cyclic mechanical stretch exposure in vitro, or during ALI in vivo. In the second aim, we will study the role of mucosal HIF in regulating lung inflammation and leukocyte trafficking during ALI. In the third aim, we will study the role of mucosal HIF during the resolution phase of ALI. These studies will shed new light on endogenous pathways that regulate lung inflammation and pulmonary injury. Targeting such pathways will lay the groundwork for novel and specific therapeutic approaches in the treatment of ALI, which are urgently needed to improve morbidity and mortality of critical illness. PHS 398/2590 (Rev. 09/04, Reissued 4/2006) Page Continuation Format Page

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Study Section
Lung Injury, Repair, and Remodeling Study Section (LIRR)
Program Officer
Harabin, Andrea L
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University of Colorado Denver
Internal Medicine/Medicine
Schools of Medicine
United States
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Idzko, Marco; Ferrari, Davide; Riegel, Ann-Kathrin et al. (2014) Extracellular nucleotide and nucleoside signaling in vascular and blood disease. Blood 124:1029-37
Keely, S; Campbell, E L; Baird, A W et al. (2014) Contribution of epithelial innate immunity to systemic protection afforded by prolyl hydroxylase inhibition in murine colitis. Mucosal Immunol 7:114-23
Bartels, Karsten; Grenz, Almut; Eltzschig, Holger K (2014) Sphingosine-1-phosphate receptor signaling during acute kidney injury: the tissue is the issue. Kidney Int 85:733-5
Tak, Eunyoung; Ridyard, Douglas; Kim, Jae-Hwan et al. (2014) CD73-dependent generation of adenosine and endothelial Adora2b signaling attenuate diabetic nephropathy. J Am Soc Nephrol 25:547-63
Bartels, Karsten; Grenz, Almut; Eltzschig, Holger K (2014) Transforming high risk to high yield. Anesthesiology 120:1072-4
Eckle, Tobias; Kewley, Emily M; Brodsky, Kelley S et al. (2014) Identification of hypoxia-inducible factor HIF-1A as transcriptional regulator of the A2B adenosine receptor during acute lung injury. J Immunol 192:1249-56
Idzko, Marco; Ferrari, Davide; Eltzschig, Holger K (2014) Nucleotide signalling during inflammation. Nature 509:310-7
Eltzschig, Holger K; Bratton, Donna L; Colgan, Sean P (2014) Targeting hypoxia signalling for the treatment of ischaemic and inflammatory diseases. Nat Rev Drug Discov 13:852-69
Bartels, Karsten; Sullivan, Breandan L; Eltzschig, Holger K (2014) TnT: blowing the cover from perioperative myocardial injury. Anesthesiology 120:533-5
Masterson, Joanne C; McNamee, Eoin N; Hosford, Lindsay et al. (2014) Local hypersensitivity reaction in transgenic mice with squamous epithelial IL-5 overexpression provides a novel model of eosinophilic oesophagitis. Gut 63:43-53

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