Leukocytes and inflammation in the pathogenesis of the early stages of diabetic retinopathy
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Case Western Reserve University School of Graduate Studies / OhioLINK
2013
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| Online Access: | http://rave.ohiolink.edu/etdc/view?acc_num=case1386594868 |
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ndltd-OhioLink-oai-etd.ohiolink.edu-case13865948682021-08-03T06:21:06Z Leukocytes and inflammation in the pathogenesis of the early stages of diabetic retinopathy Veenstra, Alexander A. Pharmacology Molecular Biology leukocytes diabetic retinopathy retina inflammation neutrophil inhibitory factor NFkB1 integrin amb2 Retinal vascular loss, a critical precursor to visual imparment in diabetic retinopathy, is generally attributed to diabetes-induced aberrant biochemical processes intrinsic to the cells of the retinal vasculature. The role of leukocytes and inflammation in the pathogenesis of diabetic retinopathy was investigated. Abnormalities characteristic of early stages of the retinopathy were measured in chimeric mice lacking iNOS (inducible nitric oxide synthase) or PARP1 (Poly(ADP-ribose) polymerase 1), proteins which play a role in inflammation and diabetes-induced retinal capillary loss. Diabetes-induced capillary degeneration, leukostasis and, and superoxide production in the retina, were inhibited in animals lacking iNOS or PARP1 in only their marrow-derrived cells. Neutrophils (and monocytes) play a major role in the retinopathy development, because retinal capillary degeneration likewise was significantly inhibited in diabetic chimeric mice lacking Granulocyte Colony Stimulating Factor receptor in only their marrow-derived cells. Immunodepletion of neutrophils or monocytes inhibited endothelial death otherwise observed when co-culturing leukocytes from wild type diabetic animals with retinal endothelium. Leukocyte integrin amß2 has been shown to mediate adhesion dependent leukocyte mediated damage.The ability of the selective antagonist of amß2, Neutrophil Inhibitory Factor (NIF) to prevent diabetes-induced retinal vascular abnormalities and leukocyte activation was investigated in transgenic mice expressing NIF. Diabetes-induced superoxide production, leukostasis and capillary loss in the retina were significantly increased in wild type mice. In contrast, mice expressing NIF did not develop any of these abnormalities. Importantly, NIF did not significantly impair the ability of mice to clear an opportunistic bacterial challenge. The inflammation associated transcription factor (NF¿B) p50 (a product of p105) is increased in retinal vascular endothelial cells of diabetic animals. Diabetes-induced increases in retinal capillary loss and superoxide generation were significantly increased in p105-/- mice. Likewise, leukocytes from diabetic animals lacking p105 killed more endothelial cells in co-culture than diabetic controls.We conclude that neutrophils (and monocytes) mediate diabetes-induced loss of capillaries in the retina and that inhibition of leukocyte binding integrin amß2 may have clinical benefits in the prevention of the early stages of diabetic retinopathy. However, loss of p105/p50 exacerbated diabetes-induced inflammation and vascular pathology of the retina. 2013 English text Case Western Reserve University School of Graduate Studies / OhioLINK http://rave.ohiolink.edu/etdc/view?acc_num=case1386594868 http://rave.ohiolink.edu/etdc/view?acc_num=case1386594868 unrestricted This thesis or dissertation is protected by copyright: some rights reserved. It is licensed for use under a Creative Commons license. Specific terms and permissions are available from this document's record in the OhioLINK ETD Center. |
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NDLTD |
| language |
English |
| sources |
NDLTD |
| topic |
Pharmacology Molecular Biology leukocytes diabetic retinopathy retina inflammation neutrophil inhibitory factor NFkB1 integrin amb2 |
| spellingShingle |
Pharmacology Molecular Biology leukocytes diabetic retinopathy retina inflammation neutrophil inhibitory factor NFkB1 integrin amb2 Veenstra, Alexander A. Leukocytes and inflammation in the pathogenesis of the early stages of diabetic retinopathy |
| author |
Veenstra, Alexander A. |
| author_facet |
Veenstra, Alexander A. |
| author_sort |
Veenstra, Alexander A. |
| title |
Leukocytes and inflammation in the pathogenesis of the early stages of diabetic retinopathy |
| title_short |
Leukocytes and inflammation in the pathogenesis of the early stages of diabetic retinopathy |
| title_full |
Leukocytes and inflammation in the pathogenesis of the early stages of diabetic retinopathy |
| title_fullStr |
Leukocytes and inflammation in the pathogenesis of the early stages of diabetic retinopathy |
| title_full_unstemmed |
Leukocytes and inflammation in the pathogenesis of the early stages of diabetic retinopathy |
| title_sort |
leukocytes and inflammation in the pathogenesis of the early stages of diabetic retinopathy |
| publisher |
Case Western Reserve University School of Graduate Studies / OhioLINK |
| publishDate |
2013 |
| url |
http://rave.ohiolink.edu/etdc/view?acc_num=case1386594868 |
| work_keys_str_mv |
AT veenstraalexandera leukocytesandinflammationinthepathogenesisoftheearlystagesofdiabeticretinopathy |
| _version_ |
1719434911241207808 |