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

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.

The respiratory tract is lined with a thin layer of fluid (airway surface liquid, ASL), which is important for lung defence against infection. Glucose concentrations in ASL are normally 12x lower than that of blood. However, they are raised in people during airway inflammation, hyperglycaemia and, more potently, when both are present, making the airway more susceptible to infection from pathogens such as methicillin-resistant S.aureus and P.aeruginosa.

We have shown in airway epithelial cells in vitro that, under normal conditions, glucose diffuses from blood into ASL but accumulation is limited by the permeability of the epithelium, blood glucose concentration, glucose uptake into the epithelial cell via GLUT transporters and its metabolism. Inflammation increased transepithelial permeability to glucose and elevated glucose in ASL. In addition, increasing basolateral glucose concentration increased glucose in ASL and promoted the growth of S.aureus on the apical surface of lung epithelial cells. In vitro, pre-treatment of airway epithelia with metformin (a drug used in the treatment of type II diabetes) reduced epithelial permeability to glucose and prevented the apical growth of S. aureus. Metformin had no direct effect on bacterial growth or on basolateral glucose concentration.

This project will investigate how lung glucose homeostasis is modified by inflammation and hyperglycaemia in vitro and in vivo. It will identify whether metformin inhibits glucose accumulation in ASL and limits the growth of respiratory pathogens in vivo. It will also investigate the therapeutic effect of other drugs which are reported to reduce epithelial permeability or reduce blood glucose concentrations. e.g. azithromycin, glucokinase activators and SGLT2 inhibitors. The outcomes of this project will determine whether these drugs have potential therapeutic benefit in the prevention and treatment of respiratory infection and chronic pulmonary disease.

This project has potential to impact the public sector, commercial private sector and the wider public. We have identified a drug that has the potential to treat epithelial disease and reduce infection that is distinct from current antibiotic and steroid therapies therefore opening up new possibilities for academic and pharmaceutical research in the short term. Investigation of how this drug works in both in vitro and in vivo systems will add to understanding of the function of epithelial tissues and aid identification of potential new targets for drug development for respiratory disease. This project will therefore directly impact scientists working in epithelia, inflammatory disease, infection and immunity and diabetes.
The main output of this study will be new insights into glucose homeostasis in airway epithelium and its role in preventing infection. As part of this study we will characterise the effects of hyperglycaemia on glucose homeostasis in in vitro and in vivo models of airway epithelial disease. We will use bacterial co-culture/infection techniques to investigate the effect of hyperglycaemia on the growth of respiratory pathogens. The in vitro model we have developed will provide a useful tool for initial drug screening in development of non-antibiotic drugs to prevent lung infection and meets the principles of the 3Rs (Replacement, Refinement and Reduction). We are working with Astra Zeneca to utilize their models of inflammatory lung disease to translate our in vitro findings. They will also provide drugs have been developed but not yet fully available to test in these systems. Their involvement will promote development and translation and therefore enhance impact in this area.
In the long term, we anticipate that understanding of the normal mechanisms that regulate glucose concentrations in the healthy airway, how factors associated with chronic disease and diabetes (prevalent in an ageing population) alter epithelial function and glucose homeostasis, together with the identification of drugs that prevent these effects, will ultimately benefit human and animal health with social and economic impact. Metformin is a drug already in clinical use with very few side effects. Understanding its action on epithelia and how this inhibits glucose flux and the growth of common pathogens such as S. aureus and Ps. aeruginosa provides a new and novel therapeutic mechanism and adds to the known activities of this drug. Data from this study will also add to the known activities of the other drugs studied. We anticipate that this knowledge will facilitate future assessment of the action of these drugs in vivo and translation into treatment could be rapid, with long term benefits to the wider public by enhancing quality of life and health. To enhance impact in this area we already have studies underway to investigate the effect of metformin on exacerbations in patients with chronic obstructive pulmonary disease. Prof. Baker also runs a patient advisory group, comprising patients and their carers who work collaboratively with researchers and clinicians to develop such projects. This group also provides advice for and a route of dissemination of results to patients.
We are currently the only research group in the UK investigating the role of glucose homeostasis in the lung. We are leading the world in this field, which, through publication and presentation of the data at international scientific meetings, is now receiving significant attention overseas. This industrial collaboration will increase impact in this area by aiding translation and development of this novel research into therapies. The success of this project and its future development could therefore contribute to the economic competitiveness of the UK.