Review The regulation of fibrosis in airway remodeling in asthma Simon G. Royce a , Victor Cheng a , Chrishan S. Samuel b , Mimi L.K. Tang a,⇑ a Department of Allergy and Immunology, Murdoch Children’s Research Institute, The Royal Children’s Hospital, Melbourne 3052, Australia b Department of Pharmacology, Monash University, Melbourne, Australia article info Article history: Received 19 December 2011 Accepted 4 January 2012 Available online 14 January 2012 Keywords: Asthma Fibrosis Relaxin Airway remodeling Therapy abstract Fibrosis is one of the key pathological features of airway remodeling in asthma. In the normal airway the amount of collagen and other extracellular matrix components is kept in equilibrium by regulation of synthesis and degradation. In asthma this homeostasis is disrupted due to genetic and environmental fac- tors. In the airways of patients with the disease there is increased extracellular matrix deposition, partic- ularly in the reticular basement membrane region, lamina propria and submucosa. Fibrosis is important as it can occur early in the pathogenesis of asthma, be associated with severity and resistant to therapy. In this review we will discuss current knowledge of relaxin and other key regulators of fibrosis in the airway including TGFb, Smad2/3 and matrix metalloproteinases. As fibrosis is not directly targeted or effectively treated by current asthma drugs including corticosteroids, characterization of airway fibrosis and how it is regulated will be essential for the development of novel therapies for asthma. Ó 2012 Elsevier Ireland Ltd. All rights reserved. Contents 1. Definition of asthma .................................................................................................. 167 2. Epidemiology of asthma ............................................................................................... 168 3. Etiology of asthma .................................................................................................... 168 4. Current treatment .................................................................................................... 169 5. Airway remodeling .................................................................................................... 169 6. Reticular basement membrane fibrosis ................................................................................... 169 7. Transforming growth factor-b (TGFb1) and Smads .......................................................................... 170 8. Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) ............................................ 170 9. Relaxin – a novel regulator of airway remodeling ........................................................................... 172 10. Receptors for relaxin .................................................................................................. 172 11. Therapeutic targeting of fibrosis in asthma ................................................................................ 172 12. Conclusion .......................................................................................................... 173 References ........................................................................................................... 173 1. Definition of asthma Asthma is a chronic inflammatory disorder of the airways characterized by spontaneous, widespread, but variable broncho- constriction and airflow obstruction in response to a wide variety of environmental and endogenous stimuli (Holgate, 2008a,b). The clinical manifestations of asthma are episodic and can include wheezing, coughing, dyspnoea and chest tightness (AIHW Australian Centre for Asthma Monitoring, 2005). Due to the heter- ogeneous nature of the disorder, the severity of these manifesta- tions can vary greatly between asthma sufferers, but in the majority of cases, asthma sufferers are asymptomatic between epi- sodes, so asthma is widely considered to be a reversible condition, spontaneously or through treatment (Pascual and Peters, 2005). Severe asthma, on the other hand, refers to forms of therapy- resistant, potentially fatal asthma. Although severe asthma is 0303-7207/$ - see front matter Ó 2012 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.mce.2012.01.007 Abbreviations: AAD, allergic airways disease; ASM, airway smooth muscle; ECM, extracellular matrix; EMTU, epithelial–mesenchymal trophic unit; GR, glucocorti- coid receptor; MMP, matrix metalloproteinase; OVA, ovalbumin; p-Smad2, phospho-Smad2; RBM, reticular basement membrane; RXFP1, relaxin family peptide receptor-1; TGFb, transforming growth factor-b; TIMP, tissue inhibitors of metalloproteinase. ⇑ Corresponding author. Tel.: +61 3 9345 5733; fax: +61 3 9345 6348. E-mail address: mimi.tang@rch.org.au (M.L.K. Tang). Molecular and Cellular Endocrinology 351 (2012) 167–175 Contents lists available at SciVerse ScienceDirect Molecular and Cellular Endocrinology journal homepage: www.elsevier.com/locate/mce