MICA: Evaluation of anti diabetic drugs in the treatment of respiratory disease

MICA：抗糖尿病药物治疗呼吸系统疾病的评价

• 批准号: MR/K012770/1
• 负责人: Deborah Baines
• 金额: $ 46.48万
• 依托单位: St George's, University of London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2013
• 资助国家: 英国
• 起止时间: 2013 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FK012770%2F1
• 关键词: MICA; Evaluation; anti; diabetic; drugs

The airways of the lung are lined with a thin layer of fluid (airway surface liquid, ASL) which is important for lung defence against infection. To optimise its function, the volume and composition of ASL are tightly regulated by the surface cells of the airway (epithelium). We have shown that the concentration of glucose (sugar) in ASL is normally much lower than that of blood. Our evidence indicates that this serves as a protective mechanism as glucose is a growth substrate for many organisms including infectious microbes. However, glucose concentration in ASL increases when the airways are inflamed, when blood glucose concentration is raised (hyperglycaemia, associated with diabetes or severe illness) and, more potently, when inflammation and hyperglycaemia are both present. This makes the airway more susceptible to infection particularly with pathogens such as methicillin resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa. We have developed a cell model of human airway epithelium to understand how glucose concentration in ASL is regulated. We have shown that glucose applied to the basolateral (blood) side can get across the epithelium into the ASL. Normally the movement of glucose between the epithelial cells is restricted. However, when the epithelium becomes inflamed, it becomes leakier allowing glucose to pass across it more easily. If this is coupled with increased glucose concentration on the basolateral side (as in diabetes), even more glucose gets across. In this situation, we showed that the growth of bacteria in ASL was increased. In an exciting new development, we prevented the growth of bacteria by treating the epithelium with metformin (a drug already in clinical use). Metformin predominantly acted to prevent glucose getting into ASL and supporting bacterial growth. This could potentially provide a new therapeutic route for treatment of lung disease particularly in the light of increased resistance of bacteria to antibiotic therapy. It is difficult to investigate how inflammation and diabetes increase glucose in ASL in the lungs of human subjects. Therefore, we will use our cell model and animal models of human lung disease to gain an understanding of how this occurs. We will investigate whether metformin can reduce glucose concentrations in ASL and suppress respiratory infection. We will also investigate whether other drugs that are predicted to reduce glucose movement into ASL will have a similar effect. In addition, we will test whether new drugs that are being developed to reduce blood sugar levels in diabetes have an additive beneficial effect. This project will increase our understanding of how glucose is increased in ASL in lung disease and when blood sugar levels are raised and how these two events promote infection. It will also tell us whether metformin or other drugs that reduce glucose movement across the epithelium or reduce blood glucose could be used to treat patients with these conditions. This could have important economic and social impact particularly in wealthy countries where the ageing population is expanding, chronic illness is more prevalent and the incidence of diabetes is increasing.

肺的呼吸道内有一层薄薄的液体(呼吸道表面液体，ASL)，这对肺部防御感染很重要。为了优化其功能，ASL的体积和组成受到呼吸道(上皮)表面细胞的严格调节。我们已经证明，ASL中的葡萄糖(糖)浓度通常远低于血液中的浓度。我们的证据表明，这是一种保护机制，因为葡萄糖是包括感染性微生物在内的许多生物的生长底物。然而，当呼吸道发炎时，当血糖浓度升高(高血糖，与糖尿病或严重疾病相关)时，ASL中的葡萄糖浓度会增加，更有可能的是，当炎症和高血糖同时存在时。这使得呼吸道更容易受到感染，特别是耐甲氧西林金黄色葡萄球菌(MRSA)和铜绿假单胞菌等病原体。我们开发了一个人类呼吸道上皮细胞模型，以了解ASL中的葡萄糖浓度是如何调节的。我们已经证明，葡萄糖应用于基底外侧(血液)侧可以穿过上皮进入ASL。正常情况下，葡萄糖在上皮细胞之间的移动是受限制的。然而，当上皮细胞发炎时，它会变得更容易渗漏，从而使葡萄糖更容易通过它。如果再加上基底外侧的葡萄糖浓度升高(如糖尿病)，就会有更多的葡萄糖通过。在这种情况下，我们发现ASL中细菌的生长增加了。在一个令人兴奋的新发展中，我们通过用二甲双胍(一种已经在临床使用的药物)治疗上皮细胞来防止细菌的生长。二甲双胍主要作用是阻止葡萄糖进入ASL并支持细菌生长。这可能会为肺部疾病的治疗提供一条新的治疗途径，特别是考虑到细菌对抗生素治疗的耐药性增加。很难研究炎症和糖尿病是如何增加受试者肺中ASL中的葡萄糖的。因此，我们将使用我们的细胞模型和人类肺部疾病的动物模型来了解这种情况是如何发生的。我们将研究二甲双胍是否可以降低ASL中的葡萄糖浓度和抑制呼吸道感染。我们还将调查其他预计将减少葡萄糖进入ASL的药物是否会有类似的效果。此外，我们将测试正在开发的降低糖尿病患者血糖水平的新药是否具有附加的有益作用。这个项目将增加我们对肺部疾病中ASL中葡萄糖是如何增加的，以及血糖水平何时上升以及这两个事件如何促进感染的理解。它还将告诉我们，二甲双胍或其他减少葡萄糖在上皮细胞中移动或降低血糖的药物是否可以用于治疗患有这些疾病的患者。这可能会产生重要的经济和社会影响，特别是在富裕国家，这些国家的老龄化人口正在扩大，慢性病更加普遍，糖尿病的发病率也在增加。

项目成果

Increased airway glucose increases airway bacterial load in hyperglycaemia.

• DOI: 10.1038/srep27636
• 发表时间: 2016-06-08
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Gill SK;Hui K;Farne H;Garnett JP;Baines DL;Moore LS;Holmes AH;Filloux A;Tregoning JS
• 通讯作者: Tregoning JS

Differential Effect of LPS on Glucose, Lactate and Inflammatory Markers in the Lungs of Normal and DiabeticMice. Pulmonary and Respiratory Medicine Open Access 2017.

LPS 对正常小鼠和糖尿病小鼠肺部葡萄糖、乳酸和炎症标志物的不同影响。

• 发表时间: 2017
• 期刊: Journal of Pulmonary and Respiratory Medicine
• 作者: Holmberg CH

Kinases as targets for ENaC regulation.

• DOI: 10.2174/18744672112059990028
• 发表时间: 2013-02
• 期刊: Current molecular pharmacology
• 影响因子: 2.7
• 作者: D. Baines

Metformin in severe exacerbations of chronic obstructive pulmonary disease: a randomised controlled trial.

• DOI: 10.1136/thoraxjnl-2015-208035
• 发表时间: 2016-07
• 期刊: Thorax
• 影响因子: 10
• 作者: Hitchings AW;Lai D;Jones PW;Baker EH;Metformin in COPD Trial Team
• 通讯作者: Metformin in COPD Trial Team

Getting sweeter: new evidence for glucose transporters in specific cell types of the airway?

• DOI: 10.1152/ajpcell.00140.2022
• 发表时间: 2023-01-01
• 期刊: American journal of physiology. Cell physiology