Pharmacological application of carbon monoxide ameliorates islet-directed autoimmunity in mice via anti-inflammatory and anti-apoptotic effects.
Diabetologia
; 57(5): 980-90, 2014 May.
Article
em En
| MEDLINE
| ID: mdl-24488023
ABSTRACT
AIMS/HYPOTHESIS:
Recent studies have identified carbon monoxide (CO) as a potential therapeutic molecule for the treatment of autoimmune diseases owing to its anti-inflammatory and anti-apoptotic properties. We explored the efficacy and the mechanisms of action of the CO-releasing molecule (CORM)-A1 in preclinical models of type 1 diabetes.METHODS:
The impact of CORM-A1 on diabetes development was evaluated in models of spontaneous diabetes in NOD mice and in diabetes induced in C57BL/6 mice by multiple low-dose streptozotocin (MLDS). Ex vivo analysis was performed to determine the impact of CORM-A1 both on T helper (Th) cell and macrophage differentiation and on their production of soluble mediators in peripheral tissues and in infiltrates of pancreatic islets. The potential effect of CORM-A1 on cytokine-induced apoptosis in pancreatic islets or beta cells was evaluated in vitro.RESULTS:
CORM-A1 conferred protection from diabetes in MLDS-induced mice and reduced diabetes incidence in NOD mice as confirmed by preserved insulin secretion and improved histological signs of the disease. In MLDS-challenged mice, CORM-A1 attenuated Th1, Th17, and M1 macrophage response and facilitated Th2 cell differentiation. In addition, CORM-A1 treatment in NOD mice upregulated the regulatory arm of the immune response (M2 macrophages and FoxP3(+) regulatory T cells). Importantly, CORM-A1 interfered with in vitro cytokine-induced beta cell apoptosis through the reduction of cytochrome c and caspase 3 levels. CONCLUSIONS/INTERPRETATION:
The ability of CORM-A1 to protect mice from developing type 1 diabetes provides a valuable proof of concept for the potential exploitation of controlled CO delivery in clinical settings for the treatment of autoimmune diabetes.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Monóxido de Carbono
/
Autoimunidade
/
Ilhotas Pancreáticas
/
Apoptose
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Diabetes Mellitus Tipo 1
/
Anti-Inflamatórios
Limite:
Animals
Idioma:
En
Revista:
Diabetologia
Ano de publicação:
2014
Tipo de documento:
Article