Absence of Lipopolysaccharide-Induced Inhibition of Neutrophil Apoptosis in Patients With Diabetes

Abstract

Background: Patients with diabetes mellitus are considered to be at increased risk for infections and often experience more serious and prolonged infections. Defects in neutrophil microbicidal function have been identified in diabetic patients and are believed to contribute to this problem. Neutrophil apoptosis or programmed cell death regulates functional longevity, and is an integral component of inflammation and its resolution. It remains unknown whether neutrophils from diabetic patients demonstrate defects in apoptosis. Hypothesis: Neutrophils from diabetic patients have defects in spontaneous and/or endotoxin (lipopolysaccharide [LPS])-induced apoptosis.Design: Peripheral venous blood samples were collected from healthy volunteers and insulin-dependent diabetic patients to harvest neutrophils for in vitro study. Interventions and Main Outcome Measures:Neutrophils were cultured for 0 and 24 hours in the absence and presence of LPS. Normal neutrophils were also cultured under conditions of normal or high glucose con-centration. Percentage of apoptotic cells was determined by flow cytometry.Results: Normal neutrophils undergo significant apoptosis after 24 hours, and the percentage of apoptotic cells is reduced in the presence of LPS. Diabetic neutrophils undergo normal spontaneous apoptosis, but do not demonstrate LPS-induced inhibition of apoptosis. The LPSinduced inhibition of apoptosis in normal neutrophils is prevented under high-glucose conditions. Conclusions: Neutrophils from diabetic patients demonstrated defects in LPS-induced apoptosis. Highglucose environment may mediate these findings. The inability of diabetic neutrophils to reduce apoptosis following LPS exposure resulted in relatively increased apoptosis. This would cause decreased functional longevity of neutrophils and increased neutrophil clearance from infectious sites, possibly contributing to the increased susceptibility and severity of infections in diabetic patients.

Neutrophils and monocytes as potentially important sources of proinflammatory cytokines in diabetes

“…Our findings suggest that part of the clinical picture found in type 2 diabetic patients is associated with excessive release of proinflammatory cytokines by neutrophils and monocytes, because the cytokines determined in this study exert profound effects on the biological signals involved in the regulation of important physiological events impaired in diabetes, such as the wound healing process [33][34][35] and apoptosis [8].…”

Efeito Do Plasma Rico Em Glicose Na Apoptose De Neutrófilos De Cães

“…Estes resultados comprovam que a hiperglicemia acelera a apoptose dos neutrófilos de cães e que este efeito é dependente do tempo. Anteriormente, Tennenberg et al (1999) verificaram que em humanos a alta concentração de glicose provoca diminuição da longevidade funcional dos neutrófilos, aumenta a retirada destes do foco inflamatório, possibilitando uma maior susceptibilidade à infecções ou infecções mais severas. A aceleração da apoptose de neutrófilos e o aumento da susceptibilidade a infecções também foi observada em ratos diabéticos (AlbaLoureiro et al, 2007).…”

“…Segundo Tennenberg et al (1999) Considerando que são diversos os mecanismos que afetam a função neutrofílica de pacientes portadores de doenças hiperglicêmicas in vivo, decidiu-se desenvolver um protocolo que permita avaliar o efeito isolado de plasma enriquecido com glicose sobre a taxa de apoptose dos neutrófilos de cães sadios a fim de testar in vitro a hipótese de que o plasma enriquecido Nogueira et al (2013) Archives of Veterinary Science, v.18, n.2, p.27-32, 2013. com alta concentração de glicose acelera a apoptose de neutrófilos de cães sadios.…”

Diabetes mellitus and apoptosis: inflammatory cells

“…LPS inhibits apoptosis in normal neutrophils but fails to do so in diabetic neutrophils potentially compromising effective host defence [75].…”