Depleted interstitial cells of Cajal and fibrosis in the pylorus: Novel features of gastroparesis

Moraveji, Sharareh; Bashashati, Mohammad; Elhanafi, Sherif; Sunny, Joseph; Sarosiek, Irene; Davis, Brian R.; Torabi, Alireza; McCallum, Richard W.

doi:10.1111/nmo.12806

Cited by 61 publications

(50 citation statements)

References 28 publications

(79 reference statements)

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“…This study and previous studies by the same authors have found similar ICC loss in gastric antrum in patients with GP and GLS [9]. As pointed out by Wang et al, an older study in dogs demonstrated antral contractile forces open the pylorus [13,14].…”

Section: Interstitial Cells Of Cajalsupporting

confidence: 89%

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Understanding the Differences Between Gastroparesis and Gastroparesis-Like Syndrome: Filling a GaPing Hole?

Gotfried

Schey

2017

Dig Dis Sci

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Section: Interstitial Cells Of Cajalsupporting

confidence: 89%

“…Significant heterogeneity exists among studies examining the number of ICC in the gastric antrum. Few studies have investigated ICC networks in the pylorus, with only one other human study to date (conducted by the current study's author) [9][10][11].…”

Section: Interstitial Cells Of Cajalmentioning

confidence: 99%

Understanding the Differences Between Gastroparesis and Gastroparesis-Like Syndrome: Filling a GaPing Hole?

Gotfried

Schey

2017

Dig Dis Sci

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“…; Bashashati & McCallum, ; Farrugia, ; Moraveji et al . ). It has also been shown that different splice variants of Ano1 exist in patients with diabetic gastroparesis and that these variants alter the electrophysiological properties of this ion channel, including sensitivity to intracellular Ca 2+ and CaCC inhibitors (Mazzone et al .…”

Section: Discussionmentioning

confidence: 97%

Differential sensitivity of gastric and small intestinal muscles to inducible knockdown of anoctamin 1 and the effects on gastrointestinal motility

Hwang

Pardo

Zheng

et al. 2019

The Journal of Physiology

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Key pointsr Electrical pacemaking in gastrointestinal muscles is generated by specialized interstitial cells of Cajal that produce the patterns of contractions required for peristalsis and segmentation in the gut.r The calcium-activated chloride conductance anoctamin-1 (Ano1) has been shown to be responsible for the generation of pacemaker activity in GI muscles, but this conclusion is established from studies of juvenile animals in which effects of reduced Ano1 on gastric emptying and motor patterns could not be evaluated.r Knocking down Ano1 expression using Cre/LoxP technology caused dramatic changes in in gastric motor activity, with disrupted slow waves, abnormal phasic contractions and delayed gastric emptying; modest changes were noted in the small intestine.r Comparison of the effects of Ano1 antagonists on muscles from juvenile and adult small intestinal muscles suggests that conductances in addition to Ano1 may develop with age and contribute to pacemaker activity.Abstract Interstitial cells of Cajal (ICC) generate slow waves and transduce neurotransmitter signals in the gastrointestinal (GI) tract, facilitating normal motility patterns. ICC express a Ca 2+ -activated Cl − conductance (CaCC), and constitutive knockout of the channel protein Sung Jin Hwang received his others J Physiol 597.9anoctamin-1 leads to loss of slow waves in gastric and intestinal muscles. These knockout experiments were performed on juvenile mice. However, additional experiments demonstrated significant differences in the sensitivity of gastric and intestinal muscles to antagonists of anoctamin-1 channels. Furthermore, the significance of anoctamin-1 and the electrical and mechanical behaviours facilitated by this conductance have not been evaluated on the motor behaviours of adult animals. Cre/loxP technology was used to generate cell-specific knockdowns of anoctamin-1 in ICC (Kit CreERT2/+ ;Ano1 tm2jrr/+ ) in GI muscles. The recombination efficiency of Kit CreERT was evaluated with an eGFP reporter, molecular techniques and immunohistochemistry. Electrical and contractile experiments were used to examine the consequences of anoctamin-1 knockdown on pacemaker activity, mechanical responses, gastric motility patterns, gastric emptying and GI transit. Reduced anoctamin-1 caused loss of gastric, but not intestinal slow waves. Irregular spike complexes developed in gastric muscles, leading to uncoordinated antral contractions, delayed gastric emptying and increased total GI transit time. Slow waves in intestinal muscles of juvenile mice were more sensitive to anoctamin-1 antagonists than slow waves in adult muscles. The low susceptibility to anoctamin-1 knockdown and weak efficacy of anoctamin-1 antagonists in inhibiting slow waves in adult small intestinal muscles suggest that a conductance in addition to anoctamin-1 may develop in small intestinal ICC with ageing and contribute to pacemaker activity.

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“…In addition, loss of ICC and smooth muscle fibrosis is more common in the pylorus than in the antrum of patients with refractory GP. 23 The advent of the endoscopic functional luminal imaging probe (EndoFLIP) has allowed for the evaluation of pyloric dysfunction in DMGP. Symptoms of early satiety and postprandial fullness are inversely correlated with the diameter and cross-sectional area of the pyloric sphincter.…”

Section: Introductionmentioning

confidence: 99%

Diabetic gastroparesis: current challenges and future prospects

Avalos¹,

Sarosiek²,

Loganathan³

et al. 2018

CEG

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Diabetic gastroparesis (DMGP) is a condition of delayed gastric emptying after gastric outlet obstruction has been excluded. Symptoms of nausea, vomiting, early satiety, bloating, and abdominal pain are associated with DMGP. Uncontrolled symptoms can lead to overall poor quality of life and financial burdens on the healthcare system. A combination of antiemetics and prokinetics is used in symptom control; metoclopramide is the main prokinetic available for clinical use and is the only U.S. Food and Drug Administration-approved agent in the United States. However, a black box warning in 2009 reporting its association with tardive dyskinesia and recommending caution in chronically using this agent beyond 3 months has decreased its role in clinical practice. There is an unmet need for new prokinetics with good efficacy and safety profiles. Currently, there are several new drugs with different mechanisms of action in the pipeline that are under investigation and show promising preliminary results. Surgically combining gastric electrical stimulation with pyloroplasty is considered “gold” standard. Advances in therapeutic endoscopic intervention with gastric per-oral endoscopic pyloromyotomy have also been shown to improve gastric emptying and gastroparesis (GP) symptoms. In this review, we will comment on the challenges encountered when managing patients with DMGP and provide an update on advances in drug development and endoscopic and surgical interventions.

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Depleted interstitial cells of Cajal and fibrosis in the pylorus: Novel features of gastroparesis

Cited by 61 publications

References 28 publications

Understanding the Differences Between Gastroparesis and Gastroparesis-Like Syndrome: Filling a GaPing Hole?

Understanding the Differences Between Gastroparesis and Gastroparesis-Like Syndrome: Filling a GaPing Hole?

Differential sensitivity of gastric and small intestinal muscles to inducible knockdown of anoctamin 1 and the effects on gastrointestinal motility

Diabetic gastroparesis: current challenges and future prospects

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