The role of bronchoconstriction in the development of airway remodelling and its effects upon lung function

Asthma is a common condition leading to significant morbity in the UK population. It is estimated that 5.4 million people in the UK suffer from asthma, with 4.1 million GP consultations and 69,000 hospital admissions every year. The total cost to the UK economy is £2.3billion and this is expected to rise with the increasing incidence of the disease. There are still over 1400 deaths from asthma every year and the decline in mortality is slowing. Approximately 10% of patients have symptoms of severe asthma but these people require a disproportionate proportion of resources (www.asthma.org.uk). Many patients with severe asthma have airway remodelling, characterised by structural changes, including increased matrix deposition and increased airway smooth muscle mass, in the airways and this is associated with deteriorating lung function (Lange et al. 1998). Currently there is no effective treatment for airway remodelling.

Recent work has suggested that bronchoconstriction, a defining feature of asthma, promotes airway remodelling (Grainge et al 2011.). I have identified a role for the αVβ5 integrin in asthmatic airway remodelling (Tatler et al 2011.). I have shown that airway smooth muscle cells expressing αVβ5 integrins can activate TGF-β, a potent pro-fibrotic mediator implicated in airway remodelling, in response to bronchoconstrictors in vitro. Furthermore, inhibition of, or genetic loss of, the αVβ5 integrin in vivo reduces allergen-induced increases in airway smooth muscle layer thickness, which is a key feature of asthmatic airway remodelling. I also observed that airway smooth muscle cells from asthmatic donors activate more TGF-β in response to contraction agonists than cells isolated from non-asthmatic donors (Tatler et al 2011).Taken together these findings suggest an important role for αVβ5 integrins in mediating airway remodelling in asthma, however, definitive proof that broncho-constriction in asthma leads to αVβ5-mediated TGF-β activation and airway remodelling is still needed.

Currently used in vivo models of asthma require relatively large numbers of animals, especially when testing potential therapeutics and treatments where drugs and their respective vehicle controls are used. Airway remodelling changes are most often assessed using immunohistochemistry, which cannot be performed on animals that have undergone whole body plethysmography to assess lung function due to the possibility that the forced respiratory manoevers cause tissue artificats . Therefore, the ability to image the lungs and measure lung function, on the same animal would lead to a considerable reduction in animal usage in airway remodelling experiments.

The primary aim of these studies is to test the hypothesis that enhanced contraction of airway smooth muscle in asthma leads to airway remodelling via an αVβ5-mediated TGF-β activation pathway. My proposal will investigate the role of bronchoconstriction-induced TGF-β activation in the development of airway remodelling in asthma, while concurrently refining lung slice and imaging techniques to allow for the reduction of animal use, as well as accurately assessing structural changes associated with airway remodelling. This will be achieved by addressing the following specific aims.

Use molecular and biochemical techniques using human cells isolated from both diseased and non-diseased donors, and murine cells from knockout mice, to determine whether there is an increase in RhoA signalling and contraction in asthma, and whether this contributes to airway remodelling via αVβ5-mediated TGF-β activation.

  1. Investigate whether bronchoconstriction can induce αVβ5-mediated TGF-β activation  and matrix synthesis ex vivo using a precision cut lung slice model, and whether increased force of contraction and/or repeated contraction leads to increased TGF-β activation and matrix synthesis.
  2. Refine newly emerging, non-invasive imaging techniques such as fMRI and HR-CT to assess to development of airway remodelling and changes in lung function in situ over time during an in vivo asthma model.

Tatler AL, Barnes J, Habgood A, Goodwin A, McAnulty RJ, Jenkins G (2016). Caffeine inhibits TGFβ activation in epithelial cells, interrupts fibroblast responses to TGFβ, and reduces established fibrosis in ex vivo precision-cut lung slices. Thorax 71(6): 565-7. doi: 10.1136/thoraxjnl-2015-208215. 

Tatler AL, Habgood A, Porte J, John AE, Stavrou A, Hodge E, Kerama-Likoko C, Violette SM, Weinreb PH, Knox AJ, Laurent G, Parfrey H, Wolters PJ, Wallace W, Alberti S, Nordheim A, Jenkins G (2016). Reduced Ets domain-containing protein Elk1 promotes pulmonary fibrosis via increased Integrin αvβ6 expression. J Biol Chem 291(18): 9540-53. doi: 10.1074/jbc.M115.692368. 

Tatler AL, Jenkins G (2015). Sphingosine-1-phosphate metabolism: can its enigmatic lyase promote the autophagy of fibrosis? Thorax 70(12): 1106-7. doi: 10.1136/thoraxjnl-2015-207974. 

Lilburn DM, Tatler AL, Six JS, Lesbats C, Habgood A, Porte J, Hughes-Riley T, Shaw DE, Jenkins G, Meersmann T (2015). Investigating lung responses with functional hyperpolarized xenon-129 MRI in an ex vivo rat model of asthma. Magn Reson Med 2015 Oct 28. doi: 10.1002/mrm.26003. 

Tatler AL, Jenkins G (2015). Reducing affinity of αvβ8 interactions with latent TGFβ: dialling down fibrosis. Ann Transl Med 3(Suppl 1): S31. doi: 10.3978/j.issn.2305-5839.2015.02.18.

Clifford RL, Patel JK, John AE, Tatler AL, Mazengarb L, Brightling CE, Knox AJ (2015). CXCL8 histone H3 acetylation is dysfunctional in airway smooth muscle in asthma: regulation by BET.  Am J Physiol Lung Cell Mol Physiol 308(9): L962-72. doi: 10.1152/ajplung.00021.2015. 

Noble PB, Pascoe CD, Lan B, Ito S, Kistemaker LE, Tatler AL, Pera T, Brook BS, Gosens R, West AR (2014). Airway smooth muscle in asthma: linking contraction and mechanotransduction to disease pathogenesis and remodelling. Pulm Pharmacol Ther 29(2): 96-107. doi: 10.1016/j.pupt.2014.07.005. 

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Fellowship

Status:

Closed

Principal investigator

Dr Amanda Tatler

Institution

University of Nottingham

Grant reference number

NC/K500501/1

Award date:

Nov 2012 - Oct 2015

Grant amount

£195,000