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Thesis - Deparment of Biology, PhD..pdf (2.65 MB)

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NEUTROPHIL ELASTASE CONTRIBUTES TO THE EARLY DIABETIC RETINOPATHY

Liu, Haitao
http://rave.ohiolink.edu/etdc/view?acc_num=case1552485945496003

Abstract Details

2019, Doctor of Philosophy, Case Western Reserve University, Biology.
It is well documented that oxidative stress and inflammation are involved in the degeneration of retinal capillaries in diabetes, a hall mark of diabetic retinopathy (DR), and it has been shown that leukocytes, especially neutrophils, play a causal role in retinal abnormalities including diabetic-induced degeneration of retinal capillaries observed in DR. However, the mechanism by which neutrophil cause such degeneration is unknown. Neutrophil serine proteases (NSPs), granules-associated enzymes secreted by neutrophils have been reported to participate in a variety of inflammatory diseases such as chronic obstructive pulmonary disease. Then, in the present work we investigated the potential involvement of NSPs in the development of capillary degeneration associated with DR. Neutrophil elastase (NE), one of the 3 NSPs, was selectively inhibited in diabetic mice using (i) sivelestat or (ii) in mice lacking NE, and (iii) where general protease activity was inhibited by over expression of protease inhibitor alpha-1 antitrypsin. These groups of mice were made diabetic and assessed for diabetes-induced retinal superoxide generation, inflammation, leukostasis, and retinal capillary degeneration and retinal vascular leakage. In 2-month diabetic mice, selective inhibition of NE or deletion of NE inhibited diabetes-induced retinal superoxide production, inflammation and leukocyte-mediated cytotoxicity to retinal endothelial cells. In 8-month diabetic mice, genetic deletion of NE significantly inhibited diabetes-induced leakage and degeneration retinal capillaries. In vitro studies show that NE induced increased permeability of retinal endothelial cells was inhibited by protease-activated receptor (PAR)-2 inhibitor. Taking together, these results suggest that NE may contribute to the development of diabetic retinopathy, and thus blocking NE activity could be a novel therapy to prevent DR.
Timothy Kern (Advisor)
Sarah Diamond (Committee Chair)
Patricia Taylor (Committee Member)
Sarah Bagby (Committee Member)
Jean Welter (Committee Member)
136 p.
Biomedical Research
diabetic retinopathy, neutrophil elastase

Recommended Citations

Citations

  • Liu, H. (2019). NEUTROPHIL ELASTASE CONTRIBUTES TO THE EARLY DIABETIC RETINOPATHY [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1552485945496003

    APA Style (7th edition)

  • Liu, Haitao . NEUTROPHIL ELASTASE CONTRIBUTES TO THE EARLY DIABETIC RETINOPATHY. 2019. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1552485945496003.

    MLA Style (8th edition)

  • Liu, Haitao . "NEUTROPHIL ELASTASE CONTRIBUTES TO THE EARLY DIABETIC RETINOPATHY." Doctoral dissertation, Case Western Reserve University, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=case1552485945496003

    Chicago Manual of Style (17th edition)

case1552485945496003
546
© 2019, some rights reserved.Creative Commons License NEUTROPHIL ELASTASE CONTRIBUTES TO THE EARLY DIABETIC RETINOPATHY by Haitao Liu is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License. Based on a work at etd.ohiolink.edu.
This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.