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TGF-?1-induced phospholamban expression alters esophageal smooth muscle cell contraction in patients with eosinophilic esophagitis.

ABSTRACT: Eosinophilic esophagitis (EoE) is a chronic antigen-mediated disease characterized by esophageal eosinophilia, remodeling, and fibrosis. TGF-?1 is a central regulator of EoE remodeling and increases esophageal smooth muscle (ESM) cell contraction.In this study we aimed to understand the molecular mechanisms by which TGF-?1 could induce ESM cell contraction.We used primary human ESM cells and esophageal myofibroblasts (EMFs) to assess the mechanisms of TGF-?1-induced contraction. We analyzed the expression, phosphorylation, and function of phospholamban (PLN), a sarcoendoplasmic reticulum regulatory protein induced by TGF-?1. Expression of PLN, phospho-PLN, and its regulatory pathway was analyzed in the ESM of biopsy specimens from patients with EoE and control subjects. Gene silencing in EMFs from patients with EoE was used to understand the role of PLN in contraction.TGF-?1 induced and phosphorylated PLN in primary human ESM cells and EMFs from patients with EoE. PLN and phospho-PLN levels were increased in smooth muscle from patients with EoE compared with that seen in smooth muscle from control subjects in vivo. PLN inhibition significantly diminished TGF-?1-induced EMF contraction in patients with EoE. PLN expression and ESM/EMF contraction depended on TGF-? receptor I signals.We describe a previously unrecognized mechanism for ESM cell contraction that depends on TGF-?1, its receptors, and PLN. Because PLN levels are increased in smooth muscle from patients with EoE and PLN silencing diminishes contraction, we provide a novel potential mechanistic framework and therapeutic target for ESM dysfunction in patients with EoE.

SUBMITTER: Beppu LY

PROVIDER: S-EPMC4231011 | biostudies-literature | 2014 Nov

REPOSITORIES: biostudies-literature

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TGF-β1-induced phospholamban expression alters esophageal smooth muscle cell contraction in patients with eosinophilic esophagitis.

Beppu Lisa Y LY Anilkumar Arjun A AA Newbury Robert O RO Dohil Ranjan R Broide David H DH Aceves Seema S SS

The Journal of allergy and clinical immunology 20140513 5

<h4>Background</h4>Eosinophilic esophagitis (EoE) is a chronic antigen-mediated disease characterized by esophageal eosinophilia, remodeling, and fibrosis. TGF-β1 is a central regulator of EoE remodeling and increases esophageal smooth muscle (ESM) cell contraction.<h4>Objective</h4>In this study we aimed to understand the molecular mechanisms by which TGF-β1 could induce ESM cell contraction.<h4>Methods</h4>We used primary human ESM cells and esophageal myofibroblasts (EMFs) to assess the mecha ...[more]

PMID: 24835503

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Project description:Background & aimsAn association of eosinophilic esophagitis (EoE) with esophageal dysmotility has been described, however, the related mechanism remains unclear. We aimed to evaluate clinical and physiologic characteristics, including esophageal distensibility, associated with secondary peristalsis in patients with EoE.MethodsA total of 199 consecutive adult patients with EoE (age, 18-78 y; 32% female) who completed a 16-cm functional luminal imaging probe (FLIP) during endoscopy were evaluated in a cross-sectional study. FLIP panometry contractile response (CR) patterns were classified as normal CR or borderline CR if antegrade contractions were present, and abnormal CRs included impaired/disordered CR, absent CR, or spastic-reactive CR. The distensibility plateau of the esophageal body and esophagogastric junction distensibility was measured with FLIP.ResultsFLIP CR patterns included 68 (34%) normal CR, 65 (33%) borderline CR, 44 (22%) impaired/disordered CR, 16 (8%) absent CR, and 6 (3%) spastic-reactive CR. Compared with normal CRs, abnormal CRs more frequently had reduced esophageal distensibility (distensibility plateau <17 mm in 56% vs 32%), greater total EoE reference scores (median, 5; interquartile range [IQR], 3-6 vs median, 4; IQR, 3-5) with more severe ring scores, and a greater duration of symptoms (median, 10 y; IQR, 4-23 y vs median, 7 y; IQR, 3-15 y). Mucosal eosinophil density, however, was similar between abnormal CRs and normal CRs (median, 34 eosinophils/high-power field [hpf]; IQR, 14-60 eosinophils/hpf vs median, 25 eosinophils/hpf; IQR, 5-50 eosinophils/hpf).ConclusionsAlthough normal secondary peristalsis was observed frequently in this EoE cohort, abnormal esophageal CRs were related to EoE disease severity, especially features of fibrostenosis. This study evaluating secondary peristalsis in EoE suggests that esophageal wall remodeling, rather than eosinophilic inflammatory intensity, was associated with esophageal dysmotility in EoE.

Dataset Information

TGF-?1-induced phospholamban expression alters esophageal smooth muscle cell contraction in patients with eosinophilic esophagitis.

Publications

TGF-β1-induced phospholamban expression alters esophageal smooth muscle cell contraction in patients with eosinophilic esophagitis.

Similar Datasets

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