POLYMORPHONUCLEAR LEUKOCYTE FUNCTION IN DIABETES

糖尿病中的多形核白细胞功能

• 批准号: 3240511
• 负责人: CHRISTOPHER P NIELSON
• 金额: $ 6.95万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-08-01 至 1992-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3240511
• 关键词: aldehyde reductase; arachidonate; blood glucose; calcium; cellular respiration; cyclic AMP; diabetes mellitus; fluorescent dye /probe; gas chromatography mass spectrometry; glucose metabolism; high performance liquid chromatography; human subject; hypoglycemia; immunoregulation; insulin; membrane lipids; neutrophil; oxidoreductase inhibitor; phosphatidylinositols; protein kinase C; radioimmunoassay; stimulus /response; superoxides

The objective of this project is to determine how polymorphonuclear leukocyte (PMN) function is impaired in diabetes and whether the impairments in cell function are reversible. Although altered PMN function has been previously reported to occur in diabetes, the causes of cell dysfunction are not well understood. In addition, therapeutic interventions to improve PMN function are not established. Because infection is a major cause of morbidity in diabetic patients, the causes of impaired PMN function and means to improve cell function may of clinical importance. Glucose metabolism through the polyol pathway during periods of hyperglycemia may be associated with depletion of cellular myo- inositol. Myo-inositol is in an equilibrium with phosphatidyinositol, a phospholipid of critical importance in PMN stimulus-response coupling. It is therefore proposed that altered phosphatidylinositol metabolism is a cause of impaired PMN function in diabetes. Impaired PMN function caused by glucose metabolism through the polyol pathway may be of clinical importance because therapeutic interventions to prevent or reverse depletion of myo-inositol are available. Aldose-reductase inhibitors reduce glucose metabolism through the polyol pathway and myo-inositol supplementation restores cellular inositol concentrations. The proposed studies will characterize an in vitro model of impaired PMN function induced by elevated glucose concentrations. Using this model, the effects of insulin, aldose- reductase inhibitors and myo-inositol on PMN function will be evaluated. PMN from diabetic subjects will be then by studied to determine whether cell function may be improved following normalization of extracellular glucose, treatment with insulin, incubation with aldose-reductase inhibitors or exposure to myo- inositol. The results of these studies may be of value in both the care of diabetic subjects and development of new therapeutic interventions. Methods for rapidly evaluating stimulus-response coupling and PMN function in diabetic patients will be developed. The specific defects in PMN function which are induced by hyperglycemia will be characterized. Potential therapeutic interventions to improve PMN function will be evaluated. The proposed experiments are unique, the model of PMN function is novel but straightforward and the results are likely to be relevant to the care of diabetic patients.

The objective of this project is to determine how polymorphonuclear leukocyte (PMN) function is impaired in diabetes and whether the impairments in cell function are reversible. Although altered PMN function has been previously reported to occur in diabetes, the causes of cell dysfunction are not well understood. In addition, therapeutic interventions to improve PMN function are not established. Because infection is a major cause of morbidity in diabetic patients, the causes of impaired PMN function and means to improve cell function may of clinical importance. Glucose metabolism through the polyol pathway during periods of hyperglycemia may be associated with depletion of cellular myo- inositol. Myo-inositol is in an equilibrium with phosphatidyinositol, a phospholipid of critical importance in PMN stimulus-response coupling. It is therefore proposed that altered phosphatidylinositol metabolism is a cause of impaired PMN function in diabetes. Impaired PMN function caused by glucose metabolism through the polyol pathway may be of clinical importance because therapeutic interventions to prevent or reverse depletion of myo-inositol are available. Aldose-reductase inhibitors reduce glucose metabolism through the polyol pathway and myo-inositol supplementation restores cellular inositol concentrations. The proposed studies will characterize an in vitro model of impaired PMN function induced by elevated glucose concentrations. Using this model, the effects of insulin, aldose- reductase inhibitors and myo-inositol on PMN function will be evaluated. PMN from diabetic subjects will be then by studied to determine whether cell function may be improved following normalization of extracellular glucose, treatment with insulin, incubation with aldose-reductase inhibitors or exposure to myo- inositol. The results of these studies may be of value in both the care of diabetic subjects and development of new therapeutic interventions. Methods for rapidly evaluating stimulus-response coupling and PMN function in diabetic patients will be developed. The specific defects in PMN function which are induced by hyperglycemia will be characterized. Potential therapeutic interventions to improve PMN function will be evaluated. The proposed experiments are unique, the model of PMN function is novel but straightforward and the results are likely to be relevant to the care of diabetic patients.

项目成果

Chemotactic peptide stimulation of arachidonic acid release in HL60 cells, an interaction between G protein and phospholipase C mediated signal transduction.

趋化肽刺激 HL60 细胞中花生四烯酸的释放，这是 G 蛋白和磷脂酶 C 介导的信号转导之间的相互作用。

• DOI: 10.1016/0167-4889(91)90048-3
• 发表时间: 1991
• 期刊: Biochimica et biophysica acta
• 作者: Nielson,CP;Stutchfield,J;Cockcroft,S
• 通讯作者: Cockcroft,S

Regulation of the respiratory burst by cyclic 3',5'-AMP, an association with inhibition of arachidonic acid release.

环状 3,5-AMP 对呼吸爆发的调节，与花生四烯酸释放的抑制有关。

• 发表时间: 1992
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Nielson,CP;Bayer,C;Hodson,S;Hadjokas,N
• 通讯作者: Hadjokas,N

Inhibition of polymorphonuclear leukocyte respiratory burst by elevated glucose concentrations in vitro.

体外升高葡萄糖浓度抑制多形核白细胞呼吸爆发。

• DOI: 10.2337/diab.38.8.1031
• 发表时间: 1989
• 期刊: Diabetes
• 影响因子: 7.7
• 作者: Nielson,CP;Hindson,DA
• 通讯作者: Hindson,DA

Impaired stimulus-response coupling in association with increased growth rate of HL60 cells.

刺激-反应耦合受损与 HL60 细胞生长速率增加相关。

• DOI: 10.1002/jlb.52.2.157
• 发表时间: 1992
• 期刊: Journal of leukocyte biology
• 影响因子: 5.5
• 作者: Hadjokas,N;Bayer,C;Nielson,CP
• 通讯作者: Nielson,CP