Acute lung injury, sepsis, lung inflammation, and ventilator-induced lung injury are life-threatening conditions associated with lung vascular barrier dysfunction, which may lead to pulmonary edema. Increased levels of atrial natriuretic peptide (ANP) in lung circulation reported in these pathologies suggest its potential role in modulation of lung injury process. Although physiological effects of ANP on the vascular tone, plasma volume, and renal function are well known, recent studies discovered novel ANP biological activities including effects on endothelial barrier function, and molecular mechanisms of ANP protective effects on pulmonary EC remain to be elucidated. Our previous studies demonstrated reciprocal relations between small GTPases Rac and Rho in the regulation of endothelial permeability and specific remodeling of actin cytoskeleton and cell contacts. Our preliminary studies strongly suggest the barrier protective effects of ANP against lung EC barrier dysfunction induced by inflammatory agonists in endothelial cell models and animal models of acute lung injury and link them to the ANP-induced downregulation of Rho signaling and cytoskeletal remodeling mediated via cAMP-dependent protein kinase (PKA) and novel Epac-Rap1-Tiam1/Vav2- Rac mechanism. We hypothesize that ANP may attenuate acute pulmonary endothelial dysfunction associated with acute lung injury via inhibition of Rho-dependent pathways of endothelial hyper-permeability. We also hypothesize that ANP may enhance the vascular barrier function in the injured lung by triggering PKA and novel Epac/Rap-mediated signaling leading to activation of Rac-dependent pathways of EC barrier protection.
Specific Aim 1 will investigate a role of Epac/Rap and PKA-mediated mechanisms in the activation of Rac-dependent signaling associated with ANP barrier protective effects.
Specific Aim 2 will focus on molecular mechanisms of ANP-induced Rho downregulation via Rac/PAK-dependent microtubule stabilization and regulation of microtubule-associated Rho-specific guanine nucleotide exchange factor GEF-H1.
Specific Aim 3 will use siRNA transfections, ANP knockout mice and rescue approaches in the animal models of septic and aseptic lung injury to delineate potential role of ANP in the alleviation of acute lung injury in vivo. We believe that these studies may identify novel protein targets and propose new therapies for prevention of pulmonary vascular barrier dysfunction associated with acute lung inflammation and injury.

Public Health Relevance

Acute respiratory distress syndrome (ARDS) remains a major cause of morbidity and mortality with an overall mortality rate of 30-40%. The acute phase of lung injury is characterized by increased permeability of the alveolar-capillary barrier, which allows an influx of protein-rich fluid into the air spaces, causing pulmonary edema. Using multidisciplinary biochemical, cell biology and molecular approaches, this application will examine novel signaling pathways involved in atrial natriudetic peptide-induced lung endothelial barrier enhancement. As molecular basis of acute lung injury is poorly understood, and no specific pharmacologic therapies are currently available, these studies will enhance our understanding of the regulation of lung endothelial barrier function, and will support potential therapeutic significance of atrial natriuretic peptide in the management of acute lung injury.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL089257-04
Application #
8322703
Study Section
Lung Injury, Repair, and Remodeling Study Section (LIRR)
Program Officer
Harabin, Andrea L
Project Start
2009-07-01
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
4
Fiscal Year
2012
Total Cost
$386,100
Indirect Cost
$138,600
Name
University of Chicago
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
005421136
City
Chicago
State
IL
Country
United States
Zip Code
60637
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Higginbotham, Katherine; Tian, Yufeng; Gawlak, Grzegorz et al. (2014) Hepatocyte growth factor triggers distinct mechanisms of Asef and Tiam1 activation to induce endothelial barrier enhancement. Cell Signal 26:2306-16
O'Donnell 3rd, James J; Birukova, Anna A; Beyer, Eric C et al. (2014) Gap junction protein connexin43 exacerbates lung vascular permeability. PLoS One 9:e100931
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Mambetsariev, Isa; Tian, Yufeng; Wu, Tinghuai et al. (2014) Stiffness-activated GEF-H1 expression exacerbates LPS-induced lung inflammation. PLoS One 9:e92670
Tian, Xinyong; Tian, Yufeng; Gawlak, Grzegorz et al. (2014) Control of vascular permeability by atrial natriuretic peptide via a GEF-H1-dependent mechanism. J Biol Chem 289:5168-83
Tian, Xinyong; Tian, Yufeng; Moldobaeva, Nurgul et al. (2014) Microtubule dynamics control HGF-induced lung endothelial barrier enhancement. PLoS One 9:e105912
Wu, Tinghuai; Xing, Junjie; Birukova, Anna A (2013) Cell-type-specific crosstalk between p38 MAPK and Rho signaling in lung micro- and macrovascular barrier dysfunction induced by Staphylococcus aureus-derived pathogens. Transl Res 162:45-55
Meliton, Angelo Y; Munoz, Nilda M; Meliton, Lucille N et al. (2013) Mechanical induction of group V phospholipase A(2) causes lung inflammation and acute lung injury. Am J Physiol Lung Cell Mol Physiol 304:L689-700
Birukova, Anna A; Tian, Xinyong; Tian, Yufeng et al. (2013) Rap-afadin axis in control of Rho signaling and endothelial barrier recovery. Mol Biol Cell 24:2678-88

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