Loss of endothelial cell (EC) barrier function is important in the development of indirect acute lung injury (ALI). We have shown, in a novel murine model of hemorrhage (shock) with a subsequent septic challenge caused by cecal ligation and performation (CLP), that neutrophil (PMN) interactions with resident pulmonary cells are central to this pathology. In ALI, unresolved inflammation elicits a pathological process with loss of EC barrier integrity and impaired lung function. EC growth factors, Angiopoietin (Ang)-i and 2, under physiological conditions, maintain vascular homeostasis through competitive interactions wdth the t3T:osine kinase receptor, Tie2, expressed on ECs. Ang-1/Tie2 binding has been shown to stabilize vessels and stimulate down stream pro-survival/anti-inflammatory signaling, in contrast, Ang-2, released from storage granules of activated ECs, destabilizes vessels. Recent findings report that plasma Ang-2 levels are significantly elevated in patients that develop ALI. We find similar elevation in the lungs and plasma in our shock/CLP model, and we have found that depletion of PMNs prior to shock abrogates Ang-2 elevation. We propose the following central hypothesis: Ang-2 causes loss of pulmonary EC barrier function in ALI due to shock/CLP, initiated by EC interaction with shock-primed PMNs. We propose the following specific aims:
Aim 1 will determine the kinetics of change in Ang-1:Ang-2 and Ang-2 expression and re-synthesis as well as its relationship to changes in indices of inflammation. We will use Ang-2 (si)RNA to suppress lung tissue expression, Ang-2 protein specific inhibition, and Ang-1 competitive inhibition of Ang-2/Tie2 binding to assess the contribution of Ang-2 release in shock priming for the development of ALI.
Aim 2 will determine mechanisms by which Ang-2 changes pulmonary EC phenotype/activation in response to plasma from mice with ALI/ARDS.
Aim 3 will determine mechanisms by which Ang-2 mediates changes in EC phenotype /activation in cultured mouse ECs following co-culture with shock-primed PMNs. The studies in this proposal will provide novel insights into the mechanisms of PMN associated, Ang-2 mediated ALI and will elucidate pathways that hold potential for therapeutic intervention.

Public Health Relevance

Acute lung injury (ALI) is a progressive syndrome with significant mortality in trauma patients. Identifying the cellular interactions and protein mediators involved in the development of indirect ALI is a critical step in the discovery of effective therapies. This project will identity mechanisms by which endothelial growth factor, Angiopoietin-2, and shock primed neutrophils contribute to lung edema in the development of ALI.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Exploratory Grants (P20)
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Ocean State Research Institute, Inc.
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Liang, Olin D; So, Eui-Young; Egan, Pamela C et al. (2017) Endothelial to haematopoietic transition contributes to pulmonary arterial hypertension. Cardiovasc Res 113:1560-1573
Bailey, Grant; Healy, Abigail; Young, Bryan D et al. (2017) Relative predictive value of lung cancer screening CT versus myocardial perfusion attenuation correction CT in the evaluation of coronary calcium. PLoS One 12:e0175678
Hwangbo, Cheol; Wu, Jingxia; Papangeli, Irinna et al. (2017) Endothelial APLNR regulates tissue fatty acid uptake and is essential for apelin's glucose-lowering effects. Sci Transl Med 9:
Ahmad, Tanveer; Sundar, Isaac K; Tormos, Ana M et al. (2017) Shelterin Telomere Protection Protein 1 Reduction Causes Telomere Attrition and Cellular Senescence via Sirtuin 1 Deacetylase in Chronic Obstructive Pulmonary Disease. Am J Respir Cell Mol Biol 56:38-49
Ceneri, Nicolle; Zhao, Lina; Young, Bryan D et al. (2017) Rac2 Modulates Atherosclerotic Calcification by Regulating Macrophage Interleukin-1? Production. Arterioscler Thromb Vasc Biol 37:328-340
Potz, Brittany A; Scrimgeour, Laura A; Feng, Jun et al. (2017) Diabetes and Cardioplegia. J Nat Sci 3:
Lu, Qing; Mundy, Miles; Chambers, Eboni et al. (2017) Alda-1 Protects Against Acrolein-Induced Acute Lung Injury and Endothelial Barrier Dysfunction. Am J Respir Cell Mol Biol 57:662-673
Sakhatskyy, Pavlo; Wang, Zhengke; Borgas, Diana et al. (2017) Double-hit mouse model of cigarette smoke priming for acute lung injury. Am J Physiol Lung Cell Mol Physiol 312:L56-L67
Aliotta, Jason M; Pereira, Mandy; Wen, Sicheng et al. (2017) Bone Marrow Endothelial Progenitor Cells Are the Cellular Mediators of Pulmonary Hypertension in the Murine Monocrotaline Injury Model. Stem Cells Transl Med 6:1595-1606
Scrimgeour, Laura A; Potz, Brittany A; Elmadhun, Nassrene Y et al. (2017) Alcohol attenuates myocardial ischemic injury. Surgery 162:680-687

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