Development of effective therapies for treatment of acute lung injury (ALI) and adult respiratory distress syndrome (ARDS) remains a challenging task. Many experimental models for testing of novel protective agents utilize preventive or concurrent treatment during ALI induction, while post-treatment represents more clinically relevant intervention. Such differences in the timing of drug administration may have dramatic impact on the efficiency of treatment and activation of specific molecular mechanisms directing resolution of ongoing injury in contrast to blocking onset of ALI by drug pretreatment. This proposal will fill this void and explore effects of post-treatment with FDA-approved prostacyclin (PC) analog iloprost in the in vitro and in vivo septic ALI models. Inflammation and increased endothelial cell (EC) permeability play a major role in the pathophysiology of ALI. During the previous cycle of this proposal, we characterized for the first time the molecular mechanisms of PC-mediated protection in aseptic model of ventilator induced lung injury. Our preliminary studies suggest potent protective effects of PC pretreatment against LPS-induced lung inflammation and vascular leak. This proposal will investigate effects of PC post-treatment in cell culture and animal models of septic ALI caused by Gram-positive heat-inactivated Staphylococcus Aureus bacteria (HKSA). We hypothesize that signaling by Rap1 GTPase plays a dual role in PC-induced acceleration of ALI resolution via promotion of EC barrier repair and suppression of inflammatory endothelial activation.
Aim -1 will evaluate effects of PC post-treatment and define a role of Rap1 in acceleration of barrier recovery in HKSA challenged EC.
Aim -2 will define molecular mechanisms downstream of Rap1 involved in EC barrier recovery. We will study a role of Rap1 effectors KRIT1 and RIAM in enhancement of EC adhesive structures and peripheral cytoskeleton essential for re-establishment of EC barrier.
Aim -3 will study a role of Rap1, KRIT1 and RIAM stimulation by PC post-treatment in downregulation of HKSA-induced pulmonary EC activation.
Aim -4 will elucidate specific role of Rap1, KRIT1 and Riam in PC-facilitated ALI recovery in vivo using """"""""loss of function"""""""" and """"""""gain of function"""""""" molecular approaches and mouse genetic models. These studies will characterize novel protective mechanisms and identify new protein targets for future therapies aimed at prevention of the pulmonary vascular barrier dysfunction associated with acute lung injury.

Public Health Relevance

Adult 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 endothelial permeability and compromise of the blood-gas barrier, which allows an influx of protein-rich fluid into the air spaces, causing pulmonary edema. Development of effective therapies for ALI/ARDS treatment currently represents major a challenge. This study will investigate molecular mechanisms underlying protective effects of prostacyclin against pulmonary vascular endothelial dysfunction and characterize for the first time novel mechanisms of recovery in the model of Gram-positive septic ALI. These studies will expand our knowledge about molecular mechanisms leading to ALI resolution and may identify new targets for drug therapies.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Respiratory Integrative Biology and Translational Research Study Section (RIBT)
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Harabin, Andrea L
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University of Chicago
Internal Medicine/Medicine
Schools of Medicine
United States
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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
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
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
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
Birukova, Anna A; Meng, Fanyong; Tian, Yufeng et al. (2015) Prostacyclin post-treatment improves LPS-induced acute lung injury and endothelial barrier recovery via Rap1. Biochim Biophys Acta 1852:778-91
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

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