ALI/ARDS is a serious condition with high mortality rates, and more complete understanding of pathologic mechanisms mediating lung vascular inflammation and barrier dysfunction in ARDS is critical for development of efficient therapeutic approaches to confront this devastating disease. Previous studies by our and other groups revealed pronounced anti-inflammatory and barrier enhancing effects of cyclic AMP elevating agonists on pulmonary vascular endothelium, which accelerated ALI recovery. Endogenous cAMP levels also appear to be critical for the maintenance of endothelial cell anti-inflammatory status and barrier function. However, septic and ALI conditions lead to impairment of cAMP homeostasis, which may contribute to severity of endothelial dysfunction and lung injury in ARDS. The importance of this mechanism is supported by beneficial effects of pharmacological inhibition of cAMP hydrolyzing enzyme, phosphodiesterase (PDE) in preclinical models of septic ALI. Despite these encouraging results, precise molecular mechanisms of PDE activation in inflammatory conditions still remain to be elucidated. Coagulation and inflammation are activated by the same types of challenges and correlate both temporally and spatially in different pathologies, but mechanistic interactions between these two processes are incompletely understood. Fibrinogen is a key component of the coagulation system. Increased levels of fibrinogen and fibrin deposition are distinctive features of advanced ALI and septic syndromes. Fibrinogen directly interacts with ?5?1 integrin adhesion receptor expressed by pulmonary endothelial cells. Our exciting pilot studies show that this interaction may augment EC inflammation and barrier dysfunction caused by bacterial pathogens via recruitment of PDE4 to the ?5-integrin associated signaling protein complex. This proposal will investigate for the first time the molecular mechanism of synergy between ARDS-relevant coagulation component fibrinogen and lung EC inflammation caused by bacterial particles.
Aim -1 will employ in vitro and in vivo models of ALI caused by Gram-positive bacterial particles to evaluate fibrinogen role in lung vascular endothelial dysfunction and severity of lung injury.
Aim -2 will investigate assembly and activation of ?5-integrin-ILK-paxillin signalosome and evaluate its role in the mediation of fibrinogen-induced exacerbation of endothelial dysfunction and lung inflammation.
Aim -3 will study targeting of PDE4 to fibrinogen-activated ?5-integrin-ILK-paxillin signalosome and its significance for PDE4- dependent suppression of intracellular cAMP and augmentation of HKSA-induced ALI.

Public Health Relevance

Acute respiratory distress syndrome (ARDS) remains a life-threatening condition with an overall mortality of 30- 40%; 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 new signaling mechanisms activated by the component of the coagulation system, fibrinogen, which lead to exacerbation of pulmonary vascular endothelial dysfunction and delayed recovery during acute lung injury (ALI) caused by Gram-positive pathogens. The results of this project will expand our knowledge about molecular mechanisms contributing to development and recovery of ALI/ ARDS.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL087823-10
Application #
9465470
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Tigno, Xenia
Project Start
2008-07-01
Project End
2021-03-31
Budget Start
2018-04-01
Budget End
2019-03-31
Support Year
10
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Maryland Baltimore
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
188435911
City
Baltimore
State
MD
Country
United States
Zip Code
21201
Oskolkova, Olga; Sarich, Nicolene; Tian, Yufeng et al. (2018) Incorporation of iloprost in phospholipase-resistant phospholipid scaffold enhances its barrier protective effects on pulmonary endothelium. Sci Rep 8:879
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
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) Dual role of vinculin in barrier-disruptive and barrier-enhancing endothelial cell responses. Cell Signal 28:541-51
Tian, Yufeng; Gawlak, Grzegorz; O'Donnell 3rd, James J et al. (2016) Activation of Vascular Endothelial Growth Factor (VEGF) Receptor 2 Mediates Endothelial Permeability Caused by Cyclic Stretch. J Biol Chem 291:10032-45
Meliton, Angelo; Meng, Fanyong; Tian, Yufeng et al. (2015) Role of Krev Interaction Trapped-1 in Prostacyclin-Induced Protection against Lung Vascular Permeability Induced by Excessive Mechanical Forces and Thrombin Receptor Activating Peptide 6. Am J Respir Cell Mol Biol 53:834-43
Meliton, Angelo Y; Meng, Fanyong; Tian, Yufeng et al. (2015) Oxidized phospholipids protect against lung injury and endothelial barrier dysfunction caused by heat-inactivated Staphylococcus aureus. Am J Physiol Lung Cell Mol Physiol 308:L550-62

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