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

Figures & data

Table 1 Agents Shown to Reduce ASM Mass

Therapy	Target	Effect on ASM Hypertrophy	References
Antibody to integrin αvβ5	TGF-β	Reduce remodeling	^11Tatler etal. J Immunol. 2011; 187(11):6094–6107.
Chloroquine and Quinine	Tas 2 receptors	Stimulate autophagy	^95Pan S, et al. Am J Physiol Lung Cell Mol Physiol 2017;313(1):L154–L165.
Compound SB239063	IL-1β, TNFα	Inhibit proliferation	^66Chung KF. Chest. 2011; 139(6)1470–1479.
Compound SKF96365	TRPC-1 and 3	Inhibit Ca^++ movement	^50Zhang X, et al. J Cell Biochem. 2018;119(7):6033–6044
Fevipiprant	Prostaglandin D2 receptor	Inhibit myofibroblast recruitment	^87Saunders R, et al. Eur Respir J 2017; 50(suppl 6):OA283.
Gallopamil	Calcium channels	Reduce airway passive stiffness	^97Girodet PO, et al. Am J Respir Crit Care Med; 2015; 191(8):876–883.
miR-485	TGF-β signaling	Reduce ASM cell proliferation, increase apoptosis	^100Wang J, et al. Cell Physiol Biochem. 2018;51(2):692–710.
MMP-9 inhibitor	MMP-9	Inhibit ASM cell migration and hypertrophy	^25Gueders MM, et al. Eur J Pharmacol. 2006; 533(1–3):133–144
Montelukast	Cysteinyl leukotrienes	Inhibit ASM cell migration and hypertrophy	^70Parameswaran K, et al. Am J Respir Crit Care Med; 2002; 166(5):738–742.
Phosphodiesterase inhibitor	Cyclic AMP	Inhibit ASM hypertrophy and proliferation	^86Wojcik-Pszczola K, et al. Int J Mol Sci. 2020; 21:4008
Simvastatin	Target unclear; possibly TH2 cells, HMG-CoA reductase	Stimulate autophagy	^93Gu W, et al. Respirology 2017; 22(3):533–541.
siRNA targeting ATPase protein	Calcium-dependent ATPase	Reduce airway passive stiffness	^103Mahn K, et al. Proc Natl Acad Sci USA 2009; 106(26):10,775–10,780.
Soluble epoxide hydrolase	Arachidonic acid CYP450	Reduce collagen, ECM	^104Jiang J-x, et al. Respir Res 2020; 21(1):22.
Sphingosine analogue	Mitochondrial SPHK-2	Reduce ASM oxidative metabolism	^92Gendron DR, et al. Front Pharmacol 2017; 8(78):78
Thermoplasty	Smooth muscle cells	Remove ASM cells and ECM	^110Pretolani M, et al. Am J Respir Crit Care Med 2014; 190(12):1452–1454.
tHGA	Akt phosphorylation	Inhibit ASM cell proliferation	^91Yap HM, et al. Sci Rep. 2018;8(1):16,640.
Tiotropium	Muscarinic receptors	Inhibit ASM hypertrophy	^72Lu JJ, et al. Resp Res. 2016; 17:25 ^105Ohta S, et al. Clin Exp Allergy 2010; 40(8):1266–1275 ^106Bos IS, et al. Eur Respir J 2007; 30(4):653–661.
Triptolide	Akt, NFkB	Inhibit ASM cell proliferation	^101He S, et al. Eur J Pharmacol. 2020;867:172,811.
WAY-200,070	ERβ	Inhibit ASM cell proliferation	^31Ambhore NS, et al. FASEB J. 2019; 33(12):13,935–13,950. ^32Ambhore NS, et al. Mol Cell Endocrinol. 2018;476:37–47.

Figure 1 A cut away view of the structure of a normal and an asthmatic bronchiole, revealing the ASM cell hypertrophy with a thicker cross-sectional area and wider extension of the muscle across the outer surface of the asthmatic bronchiole. The muscle layer itself exhibits increased thickness. The airway lumen of the asthmatic bronchiole is decreased by the edematous swollen pseudo-columnar epithelium and submucosa, increased and edematous extracellular matrix, and the increased ASM thickness. The mucous secretions in the airway are also increased, contributing to the resistance to air flow. Current asthma therapies reduce the tissue swelling and edema, but not the increased thickness of the ASM and ECM.

Figure 2 The increased ASM mass in asthma is driven by cell hypertrophy, increased cell migration, and increased cell proliferation. Activation of the airway epithelium by allergens causes the release of EGF, Eotaxin, PDGF, TGF-β, IL-8, and PGD2. Part of the response of these factors is recruitment of inflammatory cells into the airway ECM that release IL-4, IL-5 and IL-13. The factors from the epithelium and the inflammatory cells stimulate myofibroblast migration, proliferation, and hypertrophy, and increased production of ECM components. The epithelial and inflammatory cell-derived factors also stimulate additional production of soluble mediators from the ASM cells that further drive increased ASM mass.

Figure 3 The ASM in chronic asthma exhibits fixed stiffness and muscle spasticity that maintain a baseline increased airway tone with chronic tension. This exerts mechanical compressive forces on the underlying airway epithelium, and also stimulates TGF-β activity via αvβ5 integrin. Chronic inflammation further increases the basal airway tension and epithelial compression. The constant high level of airway spasticity and airway hyperreactivity create a fixed degree of mechanical obstruction.

Figure 4 The pathways and factors that create airway stiffness, ASM proliferation, migration, and hypertrophy, and dysregulated autophagy are summarized. Each panel illustrates how different signaling elements and pathways combine to stimulate remodeling of the airway. The autophagy panel illustrates the current dilemma over whether autophagy is increased or decreased in the development of ASM hypertrophy.

Figure 5 Increased ASM cell hypertrophy and migration, ASM cell proliferation and survival, biomechanical forces, and extracellular matrix are the conditions which can be therapeutically targeted to decrease the physical impact of airway remodeling in asthma. Causal factors are listed separately for each process, along with potential strategies to inhibit these factors. The causal factors include only those for which there is good evidence that they stimulate the specific process. The listed potential remedies include only those shown to antagonize one or more of the causal factors in that column. Some causal factors and potential remedies are listed in more than one column, indicating that some factors are involved in more than one process. This figure should be examined in combination with the Table 1, which lists the treatments shown to affect the named process.