Pathogenesis of airway disease

Specialists

This is the main focus of the laboratory-based research on the Glenfield site within the Adult Respiratory group (Amrani, Bradding, Brightling, Cousins, Siddiqui, Wardlaw), in collaboration with the Paediatric Airways group (Gaillard, Pandya), the Cell Physiologists/Biologists based on the main site (Challiss, Leyland, Tobin, Vial, Willars) and Genetics (Tobin, Wain).

Adult Respiratory

• Amrani
• Bradding
• Brightling
• Cousins
• Siddiqui
• Wardlaw

Cell Physiolgists and Biologists

• Challiss
• Leyland
• Tobin
• Vial
• Willars

Genetics

• Tobin
• Wain

Paediatric Airways

• Gaillard
• Pandya

Main research areas

• Leucocyte biology, including mast cells in relation to airway inflammation particularly around cell migration and ion channels
• Airway smooth muscle biology
• Airway remodelling
• Immunology of Asthma

Highlights

The relationship between airway inflammation and obesity in severe asthma is poorly understood, so our researchers sought to determine the relationship between sputum mediator profiles and the distribution of eosinophilic inflammation and obesity in people with severe asthma. Our research found that Sputum IL-5 and submucosal eosinophils, but not sputum eosinophils, are elevated in obese people with severe asthma. Whether specific antieosinophilic therapy is beneficial, or improved diet and lifestyle in obese asthma has antiinflammatory effects beyond weight reduction, requires further study.

Elevated sputum interleukin-5 and submucosal eosinophilia in obese individuals with severe asthma. Desai D, Newby C, Symon FA, Haldar P, Shah S, Gupta S, Bafadhel M, Singapuri A, Siddiqui S, Woods J, Herath A, Anderson IK, Bradding P, Green R, Kulkarni N, Pavord I, Marshall RP, Sousa AR, May RD, Wardlaw AJ, Brightling CE. Am J Respir Crit Care Med. 2013 Sep 15;188(6):657-63.

Influx of extracellular Ca(2+) into human lung mast cells (HLMCs) is essential for the FcεRI-dependent release of preformed granule-derived mediators and newly synthesized autacoids and cytokines. However, the identity of the ion channels underlying this Ca(2+) influx is unknown. The recently discovered members of the CRACM/Orai ion channel family that carries the Ca(2+) release-activated Ca(2+) current are candidates. Our researchers found the presence of CRACM channels, a CRACM-like current, and functional inhibition of HLMC Ca(2+) influx, mediator release, and allergen-induced bronchial smooth muscle contraction by CRACM-channel blockers supports a role for CRACM channels in FcεRI-dependent HLMC secretion. CRACM channels are therefore a potential therapeutic target in the treatment of asthma and related allergic diseases.

CRACM/Orai ion channel expression and function in human lung mast cells. Ashmole I, Duffy SM, Leyland ML, Morrison VS, Begg M, Bradding P.  J Allergy Clin Immunol. 2012 Jun;129(6):1628-35.e2.

Asthma is characterized by disordered airway physiology as a consequence of increased airway smooth muscle contractility. The underlying cause of this hypercontractility is poorly understood. Our researchers sought to investigate whether the burden of oxidative stress in airway smooth muscle in asthma is heightened and mediated by an intrinsic abnormality promoting hypercontractility. The findings support a critical role for NOX4 overexpression in asthma in the promotion of oxidative stress and consequent airway smooth muscle hypercontractility. This implicates NOX4 as a potential novel target for asthma therapy.

Increased nicotinamide adenine dinucleotide phosphate oxidase 4 expression mediates intrinsic airway smooth muscle hypercontractility in asthma. Sutcliffe A, Hollins F, Gomez E, Saunders R, Doe C, Cooke M, Challiss RA, Brightling CE. Am J Respir Crit Care Med. 2012 Feb 1;185(3):267-74. doi: 10.1164/rccm.201107-1281OC.

Thymic stromal lymphopoietin (TSLP) is a cytokine implicated in the pathophysiology of asthma through 2 distinct pathways: a TSLP-OX40 ligand (OX40L)-T cell axis and a TSLP-mast cell axis. Whether these pathways are active in human asthma is unknown. Our researchers sought to investigate whether mucosal TSLP protein expression relates to asthma severity and distinct immunologic pathways. They found TSLP expression is increased in a subset of patients with severe asthma in spite of high-dose inhaled or oral corticosteroid therapy. Targeting TSLP might only be efficacious in the subset of asthma characterized by increased TSLP expression and T(H)2 inflammation.

Increased expression of immunoreactive thymic stromal lymphopoietin in patients with severe asthma. Shikotra A, Choy DF, Ohri CM, Doran E, Butler C, Hargadon B, Shelley M, Abbas AR, Austin CD, Jackman J, Wu LC, Heaney LG, Arron JR, Bradding P. J Allergy Clin Immunol. 2012 Jan;129(1):104-11.e1-9.

A collaboration between the adult and paediatric groups showed for the first time that bronchial epithelial cilial damage is a feature of severe asthma.

Ciliary dysfunction and ultrastructural abnormalities are features of severe asthma. Thomas B, Rutman A, Hirst RA, Haldar P, Wardlaw AJ, Bankart J, Brightling CE, O'Callaghan C. J Allergy Clin Immunol. 2010.

In terms of airway remodelling we have shown for the first time that fibrocytes can migrate into the airway smooth muscle and this may be a mechanism for the increased muscle bulk characteristic of severe asthma.

Fibrocyte localization to the airway smooth muscle is a feature of asthma. Saunders R, Siddiqui S, Kaur D, Doe C, Sutcliffe A, Hollins F, Bradding P, Wardlaw A, Brightling CE. J Allergy Clin Immunol. 2009;123:376-384.

We have shown that we can measure eosinophilic inflammation by assessing the extent to which macrophages take up eosinophils and this has revealed that eosinophilic inflammation may be more extensive than previously considered.

Eosinophil protein in airway macrophages: a novel biomarker of eosinophilic inflammation in patients with asthma. Kulkarni NS, Hollins F, Sutcliffe A, Saunders R, Shah S, Siddiqui S, Gupta S, Haldar P, Green R, Pavord I, Wardlaw A, Brightling C. J Allergy Clin Immunol. 2010;126:61-69 e63.

Emphasising the increasingly close links between the Leicester and Nottingham research groups Martin Tobin and Ian Hall have led a consortium to discover genes related to lung function which has identified a number of candidates and opened up a new programme of research.

Genome-wide association study identifies five loci associated with lung function. Repapi E, Sayers I, Wain LV, Burton PL, Johnson T, Obeidat M, Zhao JH, Ramasamy A, Zhai G, Vitart V, Huffman JE, Igl W, Albrecht E, Deloukas P, Hernderson J, Granell R, McArdle WL, Rudnicka AR, Barroso I, Loos RJF, Wareham NJ, Mustelin L, Rantanen T, Surakka I, Imboden M, Wichmann HE, Grkovic I, Jankovic S, Zgaga L, Hartikainen AL, Paltonen L, Gyllensten U, Jonansson Å, Zaboli G, Campbell H, Wild SH, Wilson JF, Gläser S, Homuth G, Völzke H, Mangino M, Soranzo N, Spector TD, Polašek O, Rudan I, Wright AF, Heliövaara M, Rippatti S, Pouta A, Naluai ÅT, Olin AC, Torén K, Cooper MN, James AL, Palmer LJ, Hingorani AD, Wannamethee SG, Whincup PH, Smith GD, Ebrahim S, McKeever TM, Pavord ID, MacLeod AK, Morris AD, Porteous DJ, Cooper C, Dennison E, Shaheen S, Karrasch S, Shchnabel E, Schulz H, Grallert H, Bouatia-Naji N, Delplanque J, Froguel P, Blakey JD, Britton JR, Morris RW, Holloway JW, Lawlor DA, Hui J, Nyberg F, Jarvelin MR, Jackson C, Kähönen M, Kaprio J, Probst-Hensch NM, Koch B, Hayward C, Evans DM, Elliott P, Strachan DP, Hall IP, Tobin MD. Nat Genet. 2010;42:36-44.