Therapeutic strategies for acute lung injury (ALI), a major cause of morbidity and mortality in critically ill patients, are extremely limited. A defining feature of ALI and a target for intervention is the disruption of the lung vascular endothelial cell (EC) barrier which results in leakage of fluid, protein and cells into the airspaces of the lungs. Our novel studies indicate that the extracellular matrix component, hyaluronan (HA), and its cell surface receptor family, CD44, are important in normal EC function and angiogenesis. We have demonstrated that the ligation of the CD44 isoform, CD44s (standard form) by high molecular weight HA (HMW-HA) results in Rac1-dependent cortical actin formation and EC barrier enhancement. In contrast, low molecular weight HA ((LMW-HA), produced in pathological states by hyaluronidase enzymes) occupies CD44 variant 10 (CD44v10) and mediates RhoA-dependent actin stress fiber formation and EC barrier disruption. Therefore, enhancing the effects of HMW-HA/CD44s signaling pathways and diminishing the effects of LMW-HA/CD44v10 signaling may provide a novel therapeutic strategy for ALI via enhancing pulmonary vascular integrity.
Specific Aim #1 will expand our published and preliminary data by determining HMW-HA/CD44s regulation of EC barrier function by specialized structures called caveolin-enriched microdomains (CEM) containing caveolin-1 and dynamin 2.
In Specific Aim #2, we will determine HMW-HA-mediated protection from pulmonary EC barrier disruption through inhibition of RhoA GTPase and activation of Rac1 GTPase. Finally, Specific Aim #3 will employ therapeutic strategies designed to further validate HA/CD44 regulation of vascular integrity (CD44v10-specific blocking antibodies, hyaluronidase and Rho Kinase inhibitors, siRNA) using ACE antibody-directed nanocarrier technologies to target the pulmonary endothelium. These studies will yield novel mechanistic insights into HMW- HA's protection from ALI-associated pathobiology and inflammatory lung injury as well as provide novel therapeutic strategies to reduce ALI-mediated lung injury.

Public Health Relevance

Therapeutic strategies for acute lung injury (ALI), a major cause of morbidity and mortality in critically ill patients, are extremely limited. We are examining the potential use of high molecular weight hyaluronan (HMW-HA), a substance found naturally in the body, to treat ALI through enhancement of vascular integrity. Our studies will yield novel mechanistic insights into HMW-HA's protection from ALI-associated disease processes as well as provide novel treatment modalities to reduce ALI-mediated lung injury.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL095723-04
Application #
8286920
Study Section
Respiratory Integrative Biology and Translational Research Study Section (RIBT)
Program Officer
Harabin, Andrea L
Project Start
2009-09-01
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
Mirzapoiazova, Tamara; Lennon, Frances E; Mambetsariev, Bolot et al. (2015) Extracellular Vesicles from Caveolin-Enriched Microdomains Regulate Hyaluronan-Mediated Sustained Vascular Integrity. Int J Cell Biol 2015:481493
Lennon, Frances E; Mirzapoiazova, Tamara; Mambetsariev, Nurbek et al. (2014) Transactivation of the receptor-tyrosine kinase ephrin receptor A2 is required for the low molecular weight hyaluronan-mediated angiogenesis that is implicated in tumor progression. J Biol Chem 289:24043-58
Singleton, Patrick A (2014) Hyaluronan regulation of endothelial barrier function in cancer. Adv Cancer Res 123:191-209
Birukova, Anna A; Singleton, Patrick A; Gawlak, Grzegorz et al. (2014) GRP78 is a novel receptor initiating a vascular barrier protective response to oxidized phospholipids. Mol Biol Cell 25:2006-16
Ephstein, Yulia; Singleton, Patrick A; Chen, Weiguo et al. (2013) Critical role of S1PR1 and integrin β4 in HGF/c-Met-mediated increases in vascular integrity. J Biol Chem 288:2191-200
Sun, Xiaoguang; Singleton, Patrick A; Letsiou, Eleftheria et al. (2012) Sphingosine-1-phosphate receptor-3 is a novel biomarker in acute lung injury. Am J Respir Cell Mol Biol 47:628-36
Usatyuk, Peter V; Singleton, Patrick A; Pendyala, Srikanth et al. (2012) Novel role for non-muscle myosin light chain kinase (MLCK) in hyperoxia-induced recruitment of cytoskeletal proteins, NADPH oxidase activation, and reactive oxygen species generation in lung endothelium. J Biol Chem 287:9360-75
Mirzapoiazova, Tamara; Moitra, Jaideep; Moreno-Vinasco, Liliana et al. (2011) Non-muscle myosin light chain kinase isoform is a viable molecular target in acute inflammatory lung injury. Am J Respir Cell Mol Biol 44:40-52
Lennon, Frances E; Singleton, Patrick A (2011) Role of hyaluronan and hyaluronan-binding proteins in lung pathobiology. Am J Physiol Lung Cell Mol Physiol 301:L137-47
Singleton, Patrick A; Lennon, Frances E (2011) Acute Lung Injury Regulation by Hyaluronan. J Allergy Ther Suppl 4:

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