Targeting Airway Smooth Muscle Hypertrophy in Asthma: An Approach Whose Time Has Come

Overview

Journal J Asthma Allergy

Publisher Dove Medical Press

Date 2021 Jun 3

PMID 34079293

Citations 11

Authors

Anne Chetty

Heber C Nielsen

Affiliations

Soon will be listed here.

Abstract

Airway smooth muscle (ASM) cell dysfunction is an important component of several obstructive pulmonary diseases, particularly asthma. External stimuli such as allergens, dust, air pollutants, and change in environmental temperatures provoke ASM cell hypertrophy, proliferation, and migration without adequate mechanistic controls. ASM cells can switch between quiescent, migratory, and proliferative phenotypes in response to extracellular matrix proteins, growth factors, and other soluble mediators. While some aspects of airway hypertrophy and remodeling could have beneficial effects, in many cases these contribute to a clinical phenotype of difficult to control asthma. In this review, we discuss the factors responsible for ASM hypertrophy and proliferation in asthma, focusing on cytokines, growth factors, and ion transporters, and discuss existing and potential approaches that specifically target ASM hypertrophy to reduce the ASM mass and improve asthma symptoms. The goal of this review is to highlight strategies that appear ready for translational investigations to improve asthma therapy.

Citing Articles

Integrative Roles of Pro-Inflammatory Cytokines on Airway Smooth Muscle Structure and Function in Asthma.

Ford M, Reza M, Ruwanpathirana A, Sathish V, Britt Jr R Immunol Rev. 2025; 330(1):e70007.

PMID: 39991781 PMC: 11848829. DOI: 10.1111/imr.70007.

Targeting cytoskeletal biomechanics to modulate airway smooth muscle contraction in asthma.

McCullough M, Joshi I, Pereira N, Fuentes N, Krishnan R, Druey K J Biol Chem. 2024; 301(1):108028.

PMID: 39615690 PMC: 11721269. DOI: 10.1016/j.jbc.2024.108028.

Fisetin reduces ovalbumin-triggered airway remodeling by preventing phenotypic switching of airway smooth muscle cells.

Liu Y, Yin Q, Liu B, Lu Z, Liu M, Meng L Respir Res. 2024; 25(1):370.

PMID: 39402516 PMC: 11479573. DOI: 10.1186/s12931-024-03005-8.

Multifaceted roles of mitochondria in asthma.

Zhang W, Zhang C, Zhang Y, Zhou X, Dong B, Tan H Cell Biol Toxicol. 2024; 40(1):85.

PMID: 39382744 PMC: 11464602. DOI: 10.1007/s10565-024-09928-8.

WISP1 and Macrophage Migration Inhibitory Factor in Respiratory Inflammation: Novel Insights and Therapeutic Potentials for Asthma and COPD.

Christopoulou M, Aletras A, Papakonstantinou E, Stolz D, Skandalis S Int J Mol Sci. 2024; 25(18).

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References

Paw M, Wnuk D, Kadziolka D, Sek A, Lasota S, Czyz J . Fenofibrate Reduces the Asthma-Related Fibroblast-To-Myofibroblast Transition by TGF-Β/Smad2/3 Signaling Attenuation and Connexin 43-Dependent Phenotype Destabilization. Int J Mol Sci. 2018; 19(9). PMC: 6163263. DOI: 10.3390/ijms19092571. View

Chakir J, Haj-Salem I, Gras D, Joubert P, Beaudoin E, Biardel S . Effects of Bronchial Thermoplasty on Airway Smooth Muscle and Collagen Deposition in Asthma. Ann Am Thorac Soc. 2015; 12(11):1612-8. DOI: 10.1513/AnnalsATS.201504-208OC. View

Girodet P, Dournes G, Thumerel M, Begueret H, Santos P, Ozier A . Calcium channel blocker reduces airway remodeling in severe asthma. A proof-of-concept study. Am J Respir Crit Care Med. 2015; 191(8):876-83. DOI: 10.1164/rccm.201410-1874OC. View

Bardin P, Kanniess F, Gauvreau G, Bredenbroker D, Rabe K . Roflumilast for asthma: Efficacy findings in mechanism of action studies. Pulm Pharmacol Ther. 2015; 35 Suppl:S4-10. DOI: 10.1016/j.pupt.2015.08.006. View

Chetty A, Cao G, Nielsen H . Insulin-like Growth Factor-I signaling mechanisms, type I collagen and alpha smooth muscle actin in human fetal lung fibroblasts. Pediatr Res. 2006; 60(4):389-94. DOI: 10.1203/01.pdr.0000238257.15502.f4. View

James A, Maxwell P, Elliot J, Carroll N . The relationship of reticular basement membrane thickness to airway wall remodeling in asthma. Am J Respir Crit Care Med. 2002; 166(12 Pt 1):1590-5. DOI: 10.1164/rccm.2108069. View

Halayko A, Tran T, Ji S, Yamasaki A, Gosens R . Airway smooth muscle phenotype and function: interactions with current asthma therapies. Curr Drug Targets. 2006; 7(5):525-40. DOI: 10.2174/138945006776818728. View

Grainge C, Lau L, Ward J, Dulay V, Lahiff G, Wilson S . Effect of bronchoconstriction on airway remodeling in asthma. N Engl J Med. 2011; 364(21):2006-15. DOI: 10.1056/NEJMoa1014350. View

Bonta P, dHooghe J, Sterk P, Bel E, Annema J . Reduction of airway smooth muscle mass after bronchial thermoplasty: are we there yet?. Am J Respir Crit Care Med. 2015; 191(10):1207-8. DOI: 10.1164/rccm.201502-0334LE. View

10.

Post S, Heijink I, Petersen A, de Bruin H, van Oosterhout A, Nawijn M . Protease-activated receptor-2 activation contributes to house dust mite-induced IgE responses in mice. PLoS One. 2014; 9(3):e91206. PMC: 3961228. DOI: 10.1371/journal.pone.0091206. View

11.

Khan M . Inflammation signals airway smooth muscle cell proliferation in asthma pathogenesis. Multidiscip Respir Med. 2013; 8(1):11. PMC: 3568740. DOI: 10.1186/2049-6958-8-11. View

12.

Seow C . Passive stiffness of airway smooth muscle: the next target for improving airway distensibility and treatment for asthma?. Pulm Pharmacol Ther. 2012; 26(1):37-41. DOI: 10.1016/j.pupt.2012.06.012. View

13.

Salter B, Pray C, Radford K, Martin J, Nair P . Regulation of human airway smooth muscle cell migration and relevance to asthma. Respir Res. 2017; 18(1):156. PMC: 5559796. DOI: 10.1186/s12931-017-0640-8. View

14.

Meurs H, Dekkers B, Maarsingh H, Halayko A, Zaagsma J, Gosens R . Muscarinic receptors on airway mesenchymal cells: novel findings for an ancient target. Pulm Pharmacol Ther. 2012; 26(1):145-55. DOI: 10.1016/j.pupt.2012.07.003. View

15.

Yap H, Lee Y, Harith H, Tham C, Cheema M, Shaari K . The geranyl acetophenone tHGA attenuates human bronchial smooth muscle proliferation via inhibition of AKT phosphorylation. Sci Rep. 2018; 8(1):16640. PMC: 6226528. DOI: 10.1038/s41598-018-34847-0. View

16.

Thomson R, Bramley A, Schellenberg R . Airway muscle stereology: implications for increased shortening in asthma. Am J Respir Crit Care Med. 1996; 154(3 Pt 1):749-57. DOI: 10.1164/ajrccm.154.3.8810615. View

17.

Parameswaran K, Cox G, Radford K, Janssen L, Sehmi R, OByrne P . Cysteinyl leukotrienes promote human airway smooth muscle migration. Am J Respir Crit Care Med. 2002; 166(5):738-42. DOI: 10.1164/rccm.200204-291OC. View

18.

Li P, Lang X, Xia S . Elevated expression of microRNA-378 in children with asthma aggravates airway remodeling by promoting the proliferation and apoptosis resistance of airway smooth muscle cells. Exp Ther Med. 2019; 17(3):1529-1536. PMC: 6364182. DOI: 10.3892/etm.2018.7141. View

19.

Tatler A, John A, Jolly L, Habgood A, Porte J, Brightling C . Integrin αvβ5-mediated TGF-β activation by airway smooth muscle cells in asthma. J Immunol. 2011; 187(11):6094-107. PMC: 3242066. DOI: 10.4049/jimmunol.1003507. View

20.

Brightling C, Berry M, Amrani Y . Targeting TNF-alpha: a novel therapeutic approach for asthma. J Allergy Clin Immunol. 2007; 121(1):5-10. PMC: 3992375. DOI: 10.1016/j.jaci.2007.10.028. View