The phosphodiesterase (PDE) inhibitors Pentoxifylline (PTX), a general inhibitor, and Rolipram (ROL), a type 4 inhibitor, have been shown to have anti-inflammatory effects. They elevate intracellular CAMP levels and suppress the production of inflammatory cytokines such as tumor necrosis factor (TNF)alpha, interferon (IFN)gamma, and interleukin-12 (IL-12). These drugs have also been reported to modulate the immune response in favor of Th2 responses and to be therapeutically effective in various models of autoimmune and/or inflammatory disorders. Their effects on nitric oxide (NO) production are not well studied. Inflammatory cytokines and NO are important mediators implicated in islet beta-cell destruction. / In the first part of the study, we examined the effect of PTX and ROL in preventing insulitis and diabetes in non-obese diabetes-prone (NOD) mice as a spontaneous model of insulin-dependent diabetes (IDDM). We found that a 4 week treatment with either PTX or ROL had a strong protective effect, that was still apparent 11 weeks after withdrawing the drugs. Both drugs were equally effective at optimal doses in preventing mstiulitis and diabetes in NOD mice. / In the second part of the study, we examined the effects of PDE inhibitors on NO production by peritoneal macrophages and RAW 246.7 cells. We also correlated these effects with elevated cAMP levels. We found that both PTX and ROL suppress NO production by IFNgamma and lipopolysaccharide (LPS)-activated macrophages. The inhibitory effects correlated with elevated CAMP levels and were mimicked by other agents which elevate CAMP levels such as dibutyryl cAMP, 8-bromo cAMP, and Forskolin. This suppression was found to be at the transcriptional level. In vivo, ROL treatment prevented macrophage activation by staphylococcal enterotoxin B (SEB) and suppressed NO production by these macrophages in ex vivo culture. / In the third part of the study, we examined the effects of PDE inhibitors on NO production by insulin-producing NIT-1 insulinoma cells and normal islet cells. It has been reported that islet beta-cells express PDE3 and PDE4. We found that inhibitors of PDE4 (ROL), PDE3 (Cilostamide; CIL), or a general inhibitor (PTX), suppressed NO production by islet cells. A combination of ROL and CIL appeared to have more than an additive effect, suggesting synergism. Like in macrophages, the suppression was at the transcriptional level and mimicked by other agents which elevate cAMP levels. In vivo, ROL treatment suppress iNOS expression in the islets of NOD mice with cyclophosphamide-accelerated disease, as determined by immunohistochemistry. / These studies establish for the first time that PDE inhibitors have a therapeutic potential in IDDM and other NO-and/or cytokine-mediated inflammatory disorders.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:QMM.38152 |
| Date | January 2001 |
| Creators | Beshay, Evette A. |
| Contributors | Prud'homme, Gerald J. (advisor) |
| Publisher | McGill University |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Format | application/pdf |
| Coverage | Doctor of Philosophy (Department of Pathology.) |
| Rights | All items in eScholarship@McGill are protected by copyright with all rights reserved unless otherwise indicated. |
| Relation | alephsysno: 001862296, proquestno: NQ78648, Theses scanned by UMI/ProQuest. |
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