In vitro models of lung injury
Dr Mark Griffiths & Prof Timothy Evans
Royal Brompton Hospital, London
2006 – 2008 Research Technician
The development of complex in vitro models of ventilator-associated lung injury.
Dr Mark Griffiths is a Consultant Physician in Intensive Care Medicine at the Royal Brompton Hospital, and Honorary Senior Lecturer at Imperial College London.
Prof Timothy Evans is leader of the Critical Care Group at the National Heart and Lung Institute, Imperial College London.
Patients with acute respiratory distress syndrome (ARDS) require artificial ventilation, although sometimes this itself can cause further lung damage, known as ventilator-associated lung injury (VALI). Despite advances in the treatment of these patients, VALI remains a major problem and can even be fatal.
A substantial number of animal experiments are conducted worldwide to study this type of lung injury and search for new treatments. Most involve mechanically over-inflating the lungs of rodents to cause measurable injury in a short time. There is a move to use larger animals, commonly pigs and sheep, in the hopes that these will more closely model the clinical scenario. Animals are sometimes also subjected to initial lung damage, for example with a toxic chemical, before being artificially ventilated.
Understanding the cellular components of VALI is essential if drug therapies to improve the outcome ARDS are to be developed. This Dr Hadwen Trust-funded project will make use of ethically-sourced human tissue models that can be maintained and investigated for at least a week in vitro, far longer than most animal ‘models’ of VALI. Using human tissue is more relevant because it may uncover novel human targets for drug treatment of VALI. Further, biomarkers may be found that would facilitate the fine tuning of a ventilation strategy for individual patients, so as to minimise further injury.
A Flexercell apparatus is used to apply cyclic mechanical strain to monolayers of cells grown on a distensible membrane. Signalling pathways that mediate stretch-induced production of chemokines will be studied. The contributions of different cell types using co-cultures of epithelial cells and macrophages, and endothelial cells and neutrophils, will be investigated. Similarly the role of intercellular and cell-matrix interactions will be interrogated by stretching precision-cut slices of human lung. The effects of hypoxia and hyperoxia on signal transduction pathways in these models will be assessed.
The development and investigation of these models will enhance understanding of VALI and prospects of modifying it.