Role of NADPH oxidase in the pathogenesis of diabetic complications
Date
2011
DOI
Authors
Zamakhchari, Mai
Version
OA Version
Citation
Abstract
Diabetes mellitus is a metabolic disorder characterized by high blood glucose resulting from defective insulin secretion or action. Increased oxidative stress is thought to contribute to the development of diabetic complications, including periodontal disease. Polymorphonuclear leukocytes are a primary source of superoxide and in diabetes neutrophils are primed for increased superoxide production by the NADPH oxidase. We hypothesized that genetic elimination of superoxide production by neutrophils will rescue diabetic tissues from oxidative tissue damage. We have generated a double mutant mouse model that is diabetic and defective in neutrophil superoxide production, the Akita/Ncf1 mice.
We have observed increased mortality in Akita/Ncf1 mice that was improved with antibiotic prophylaxis. Periodontal bone loss and osteoclast activation was increased Akita/Ncf1 compared to Akita mice, and Akita/Ncf1 mice had increased prevalence of maxillofacial chronic inflammatory lesions. We have observed progressive lung damage that was associated with increased neutrophil infiltration and corresponded with cachexia and death in Akita/Ncf1 mice. These lung changes occurred even under antibiotic therapy when bacterial infection was undetectable in the lungs using 16s bacterial DNA PCR. Evidence of fungal infection was found in Akita/Ncf1 lungs in moribund animals. Akita/Ncf1 lung lesions were more severe and progressed more rapidly in males, where blood glucose is significantly higher. Isolated neutrophils from Akita/Ncf1 mice showed no impairment in zymosan phagocytosis, and no evidence of excessive degranulation in isolated Akita/Ncf1 neutrophils were found.
In summary, lack of neutrophil superoxide production does not rescue diabetic mice from periodontal bone loss and soft tissue damage. While excessive and unregulated superoxide production may contribute to neutrophil-mediated tissue damage, properly regulated neutrophil superoxide is essential for maintaining periodontal and respiratory health in diabetes.
Description
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Dissertation (DSc) --Boston University, Henry M. Goldman School of Dental Medicine, 2011 (Department of Periodontology and Oral Biology)
Includes bibliography: leaves 136-149.
Dissertation (DSc) --Boston University, Henry M. Goldman School of Dental Medicine, 2011 (Department of Periodontology and Oral Biology)
Includes bibliography: leaves 136-149.
License
This work is protected by copyright. Downloading is restricted to the BU community. If you are the author of this work and would like to make it publicly available, please contact open-help@bu.edu.