J Neurogastroenterol Motil 2024; 30(2): 129-130  https://doi.org/10.5056/jnm24045
How Does Esophageal Smooth Muscle Change After Denervation in Achalasia?
Yu Kyung Cho
Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
Correspondence to: *Yu Kyung Cho, MD
Division of Gastroenterology and Hepatology, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul 06591, Korea
Tel: +82-2-2258-6024, E-mail: ykcho@catholic.ac.kr

Article: Altered esophageal smooth muscle phenotype in achalasia
Rodrigues DM, Lourenssen SR, Kataria J, Paterson WG, Blennerhassett MG, Bechara R
(J Neurogastroenterol Motil 2024;30:166-176)
Received: March 15, 2024; Accepted: March 25, 2024; Published online: April 30, 2024
© The Korean Society of Neurogastroenterology and Motility. All rights reserved.

cc This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Achalasia is a primary esophageal motor disorder, characterized by impaired lower esophageal sphincter (LES) relaxation during swallowing and abnormal peristalsis. On conventional manometry, achalasia is classified into classical achalasia and vigorous achalasia. On the high-resolution manometry, achalasia is sub-grouped into type 1, aperistalsis of esophageal body; type 2, pan esophageal pressurization; and type 3, spastic contraction. Type 1 and type 2 achalasia have similar clinical relevance, however, type 3 or vigorous achalasia may overlap with diffuse esophageal spasm. The repetitive hypertonic contraction in spastic achalasia may change to hypotonic contraction or aperistalsis after a long duration of the disease.1,2

Achalasia is a multifactorial disease. The etiologies are unknown. The main pathophysiology of achalasia is loss of inhibitory myenteric plexus neurons and neuronal degeneration. The histopathology is characterized by degeneration of the esophageal myenteric plexus, and reduction in interstitial cells of Cajal, particularly in LES. As the results of denervation, the functional or structural change will occur in the esophageal smooth muscle including hypertrophy or atrophy, and hypercontractility or hypocontractbility.3 Some studies reported achalasia or diffuse esophageal spasm are associated with smooth muscle hypertrophy and hypercontractility above the level of obstruction.4 How the histology or phenotypes of esophageal smooth muscle change are not known.

The etiologies are not identified, although variable factors such as viral infection, immune disorders, inheritance, and gastrointestinal hormones are suggested.4 Most of all, it has been proposed that autoimmune-mediated inflammatory responses drive inhibitory neuronal degeneration in achalasia. Mast cells may play a main role in the development of achalasia by mediating neurodegenerative responses.5 Mast cell acts as a main regulator in physiological and immunological response. Patients with achalasia had increased infiltration of mast cells in their LES muscle, which was associated with loss of interstitial cells of Cajal, neuronal degeneration, the type of achalasia, and a history of autoimmune disease or viral infection.6 Mast cells can cause esophageal muscle cells to proliferate and differentiate into a more contractile phenotype, and mediators released by degranulating mast cells such as tryptase and histamine can activate smooth muscle contraction pathways. Thus, activated mast cells in the esophageal muscle might cause esophageal motility abnormalities, including the failure of LES relaxation in typical achalasia.7 Recently, Rodrigues et al8 investigated the changes in the contractile phenotype and innervation of the esophageal circular smooth muscle (CSM), as well as inflammatory status, and correlated these with patient’s parameters in achalasia. They used the esophageal CSM tissue obtained by per oral endoscopic myotomy. They found that the CSM layer is thickened and largely denervated. The drop in axon density over controls did not differ among subtypes of achalasia. The denervated esophageal CSM cells were not actively proliferating. The authors interpreted that proliferation occurs very early in the disease process or that hyperplasia is not part of the pathogenesis of achalasia. There was a significant increase in collagen in the tissue samples and this may be an important contributor to the thickening CSM and fibrosis. The significant upregulation in α-smooth muscle actin and smoothelin expression in the CSM of achalasia samples suggests aberrant contractile smooth muscle marker expression, which may contribute to abnormal function. The increased α-smooth muscle actin and smoothelin expression in the achalasia biopsies correlated with the duration of symptoms.8

The changes in the intestinal smooth muscle of rat colitis models following an autoimmunity-driven inflammatory response may be similar to that of achalasia in the initial stage. In that model, inflammation changes the phenotype of the intestinal smooth muscle, causes the proliferation of intestinal smooth muscle cells, and promotes fibro-stenotic stricture formation such as Crohn’s disease. Smooth muscle cells showed an impaired phenotype associated with increased expression of epigenetic regulatory enzymes.9 In the rat colitis model, intestinal inflammation causes initial axonal degeneration and neuronal death, as well as the proliferation of intestinal smooth muscle cells at early stages. However, subsequently, the axon regrows by surviving myenteric neurons into the surrounding tissues and returns to innervation density to control levels.10 Compared with the rat colitis model, the thickened CSM in achalasia is largely denervated, then glial cell line-derived neurotrophic factor expression increased in the esophageal CSM cell, however, on the contrary, the recovery of innervation does not occur, the denervation persists. Therefore, it proposes that inflammation-induced destruction of myenteric neurons is ongoing. Some study suggests that bolus transport in a partially obstructed esophagus due to stricture or achalasia may cause smooth muscle stress and activate the immune system, leading to muscle hypertrophy and hypercontractility. It may be the cause of ongoing immune activation. Mechanical stress by labored bolus transport through fibro stenotic segment or achalasia cause immune inflammation. The mucosal inflammation may cause mechanical stress on the smooth muscle, initiating mast cell-medicated immune inflammation, which leads to muscle hypertrophy.4

The results of this study showed aberrant phenotypes of denervated smooth muscle. The study suggested the possibility of persisting immune activation to the denervated smooth muscle. Those results will help to explain the pathophysiology of achalasia and establish a target treatment strategy.

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