Lung inflammation and alterations in endothelial permeability play a major role in the pathophysiology of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), the conditions associated with high mortality rates. Low efficiency of current therapies may be explained in part by focus on drug treatments aimed at prevention of the onset of ALI, while endogenous feedback mechanisms which subside inflammatory activation and endothelial barrier dysfunction, although much more clinically relevant, remain poorly understood. Our studies in the previous cycle identified a novel role of microtubule peripheral network in the control of lung endothelial barrier function. We discovered that stimulation of microtubule peripheral growth by barrier enhancing agonists, such as hepatocyte growth factor, promoted Rac GTPase-dependent and attenuated Rho GTPase-dependent signaling, thus leading to downregulation of vascular leak. We defined a novel paradigm of dual regulation of Rac and Rho pathways by microtubule-associated guanine nucleotide exchange factors Asef and GEF-H1 and demonstrated essential role of the microtubules in the mechanisms of Rac-Rho crosstalk and control of endothelial permeability. However, the entire mechanism of microtubule-dependent regulation of onset and resolution of ALI, and specifically, microtubule-dependent modulation of inflammatory cascades, remains poorly understood. During the screening of potential signaling proteins associated with the microtubules in control and inflamed pulmonary endothelium, we discovered an association of a negative regulator of inflammatory signaling, SOCS1, with the microtubule fraction. This serendipity finding suggested a novel link between the microtubule cytoskeleton and control of endothelial inflammation and inflammation-induced permeability. Currently, a role of microtubules in the modulation of endothelial barrier response to bacterial wall compounds, cytokines, etc., remains virtually unknown. We hypothesize that cellular feedback mechanisms modulating cell inflammatory response critically require microtubule-assisted SOCS1 targeting to the submembrane compartment, where it interacts with its cytokine receptor- and TLR-associated protein targets. Using cell, ex vivo, and in vivo models of LPS-induced ALI this application will characterize regulation of LPS-induced inflammation by SOCS1, investigate involvement of microtubules in control of SOCS1 anti-inflammatory function, and will identify molecular mechanisms of active microtubule-assisted SOCS1 transport and submembrane targeting. The results of this project will delineate novel microtubule-dependent mechanisms regulating lung barrier dysfunction and inflammation, which may lead to discovery of a new group of pharmacological molecules for the treatment of ALI/ARDS.

Public Health Relevance

Acute respiratory distress syndrome (ARDS) remains a life-threatening conditions with an overall mortality of 30-40%, and the acute phase of lung injury is characterized by increased endothelial permeability and compromise of the blood-gas barrier causing pulmonary edema. This study will investigate a new mechanism of microtubule-dependent control of lung vascular dysfunction and acute lung injury caused by bacterial endotoxin LPS. The results of this project will expand our knowledge about molecular mechanisms leading to resolution of acute lung injury and may lead to the discovery of a new group of pharmacological molecules for the treatment of ARDS.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
7R01HL107920-06
Application #
9230425
Study Section
Special Emphasis Panel (ZRG1-CVRS-G (02))
Program Officer
Reineck, Lora A
Project Start
2011-08-01
Project End
2020-04-30
Budget Start
2017-05-09
Budget End
2018-04-30
Support Year
6
Fiscal Year
2017
Total Cost
$385,938
Indirect Cost
$135,938
Name
University of Maryland Baltimore
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
188435911
City
Baltimore
State
MD
Country
United States
Zip Code
21201
Oskolkova, Olga; Gawlak, Grzegorz; Tian, Yufeng et al. (2017) Prostaglandin E receptor-4 receptor mediates endothelial barrier-enhancing and anti-inflammatory effects of oxidized phospholipids. FASEB J 31:4187-4202
Ke, Yunbo; Zebda, Noureddine; Oskolkova, Olga et al. (2017) Anti-Inflammatory Effects of OxPAPC Involve Endothelial Cell-Mediated Generation of LXA4. Circ Res 121:244-257
Ohmura, Tomomi; Tian, Yufeng; Sarich, Nicolene et al. (2017) Regulation of lung endothelial permeability and inflammatory responses by prostaglandin A2: role of EP4 receptor. Mol Biol Cell 28:1622-1635
Tian, Xinyong; Ohmura, Tomomi; Shah, Alok S et al. (2017) Role of End Binding Protein-1 in endothelial permeability response to barrier-disruptive and barrier-enhancing agonists. Cell Signal 29:1-11
Ke, Yunbo; Oskolkova, Olga V; Sarich, Nicolene et al. (2017) Effects of prostaglandin lipid mediators on agonist-induced lung endothelial permeability and inflammation. Am J Physiol Lung Cell Mol Physiol 313:L710-L721
Huang, Ru-Ting; Wu, David; Meliton, Angelo et al. (2017) Experimental Lung Injury Reduces Kr├╝ppel-like Factor 2 to Increase Endothelial Permeability via Regulation of RAPGEF3-Rac1 Signaling. Am J Respir Crit Care Med 195:639-651
Birukova, Anna A; Shah, Alok S; Tian, Yufeng et al. (2016) Selective Role of Vinculin in Contractile Mechanisms of Endothelial Permeability. Am J Respir Cell Mol Biol 55:476-486
Tian, Yufeng; Gawlak, Grzegorz; O'Donnell 3rd, James J et al. (2016) Modulation of Endothelial Inflammation by Low and High Magnitude Cyclic Stretch. PLoS One 11:e0153387
Tian, Yufeng; Gawlak, Grzegorz; Tian, Xinyong et al. (2016) Role of Cingulin in Agonist-induced Vascular Endothelial Permeability. J Biol Chem 291:23681-23692
Birukova, Anna A; Shah, Alok S; Tian, Yufeng et al. (2016) Dual role of vinculin in barrier-disruptive and barrier-enhancing endothelial cell responses. Cell Signal 28:541-51

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