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

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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.