Respiratory Physiology and Airways Remodelling

The group is focussed on the physiology and pharmacology of chronic respiratory disease, including asthma, COPD and sleep apnoea, and the effects of hypoxia and oxidant stress.

Ward and colleagues are studying calcium homeostasis in human airway smooth muscle cells from asthmatics to define the molecular basis of the abnormal airway smooth muscle phenotype in asthma. They have discovered that the expression of a key protein (SERCA2) is reduced in asthmatic airway smooth muscle, and that expression of other proteins associated with calcium is affected by inflammatory mediators and oxidative stress. Together, these changes may underlie the modified phenotype and smooth muscle hyperresponsiveness in asthma. They will be analysing both the causes and consequences of such changes and the influence of key therapies, particularly in terms of airway remodelling in severe asthma.

Woszczek and colleagues have been investigating leukotriene receptors, and have recently shown that Leukotriene B4 and LTD4 display both redundant and cooperative effects on intracellular signaling, gene expression, and chemotaxis in human monocytes. They will be examining these interactions in terms of differential receptor signalling and also in airway smooth muscle from severe and steroid resistant asthma.rn

Aaronson, Knock and Ward have shown that oxidant signalling is critical for both the hypoxia-induced calcium elevation and Rho kinase activation in pulmonary artery smooth muscle, and may involve members of the src-kinases family. Membrane associated oxidant signalling induced by agonists such as sphingolipids may also facilitate or potentiate calcium entry mechanisms in pulmonary and system arteries, which may underlie vascular hyperresponsiveness in some forms of chronic or inflammatory disease.

Sleep apnoea is a very common condition, which is associated with increased risk of cardiovascular disease and type 2 diabetes. It has been strongly associated with increased oxidant stress as a result of intermittent hypoxia. The large cohort of patients with sleep disordered breathing, coupled with the cellular expertise available within the group, will facilitate studies on the causes and consequences of this condition and possible remedial therapies and novel management regimens, led by Hart and Ward.

Other studies include investigations on muscle weakness in COPD and aging patients and mechanisms to reverse this process (Rafferty, Hart, Moxham and Harridge).