On the origin of rhythmic contractile activity of the esophagus in early achalasia, a clinical case study

Chen, Jihong; Wang, Xuan-Yu; Liu, Louis W. C.; Yu, Wenzhen; Yu, Yuanjie; Zhao, Liang; Huizinga, Jan D.

doi:10.3389/fnins.2013.00077

Cited by 13 publications

(20 citation statements)

References 70 publications

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“…This process allows for the passage of gut contents and is essential for muscle relaxation during peristalsis [14,15]. Decreased nitrergic innervation has been observed in idiopathic achalasia (inability of the sphincter to relax) and is considered an important factor in its pathogenesis [21][22]. Here, we found decreased nitrergic innervation in infected individuals with megaesophagus.…”

Section: Resultssupporting

confidence: 52%

“…It is well known that, like other cells, the number of ICCs is controlled by several factors that regulate proliferation and death and that ICCs continuously undergo apoptosis in the GI tract of healthy individuals [12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31]. Because neurons produce Stem Cell Factor (SCF), which activates the c-kit receptor and stimulates the proliferation, survival…”

Section: Resultsmentioning

confidence: 99%

“…Decreased nitrergic innervation and loss of ICCs have been observed in idiopathic achalasia and those factors, in conjunction, have been considered to be implicated in such pathological process [21,22]. Previous studies of individuals with the digestive form of Chagas disease, have reported a decrease of ICCs density in the esophagus and colon that were associated with megaesophagus and megacolon, respectively [23,24].…”

Section: Patients and Tissue Samplesmentioning

confidence: 98%

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Decrease of Nitrergic Innervation in the Esophagus of Patients with Chagas Disease: Correlation with Loss of Interstitial Cells of Cajal

Nascimento¹,

Martins²,

Duarte³

et al. 2017

Int J Pathol Clin Res

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The pathogenesis of megaesophagus in chronic Chagas disease, which is caused by infection with the parasite Trypanosoma cruzi is compelling. Individuals with megaesophagus often present achalasia and disturbances of peristalsis and neuronal loss. Esophageal samples were obtained from 6 T. cruzi infected individuals with megaesophagus, 6 T. cruzi infected individuals without megaesophagus, and 6 noninfected individuals who underwent necropsy procedures. Using one antibody specific for neuronal Nitric Oxide Synthase (nNOS) and another specific for Protein Gene Product 9.5 (PGP-9.5), which is a pan-neuronal marker, we demonstrated the relative area of nitrergic innervation. Additionally, we analysed the area occupied by Interstitial Cells of Cajal (ICCs) with antibody specific anti-CD117. The analyses presented here show that the relative area of nitrergic innervation is reduced in T. cruzi infected individuals with megaesophagus. Furthermore, we demonstrated reduced CD117-immunostained areas in the esophagus of T. cruzi infected individuals. Statistical analyses revealed a positive correlation between the relative area of nitrergic innervation and the density of ICCs in the same infected individuals. Considering data from the literature, we raised the hypothesis that the loss of nitrergic nerve fibers and ICCs could be view as an interdependent phenomenon occurring in the esophagus of T. cruzi infected individuals and that it could contribute to peristalsis disturbances, to achalasia and to megaesophagus development.

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Section: Resultssupporting

confidence: 52%

Section: Resultsmentioning

confidence: 99%

Section: Patients and Tissue Samplesmentioning

confidence: 98%

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Decrease of Nitrergic Innervation in the Esophagus of Patients with Chagas Disease: Correlation with Loss of Interstitial Cells of Cajal

Nascimento¹,

Martins²,

Duarte³

et al. 2017

Int J Pathol Clin Res

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“…A deficiency in nNOS neurons has been noted in other GI motility disorders like achalasia in the esophagus, where nNOS is characteristically deficient with the loss of myenteric ganglion cells in the lower esophageal sphincter. 36 No obvious change in ICC was observed in early achalasia despite a segmental loss of nitrergic nerves with aperistalsis, 37 which may be also applicable to our cases. How NOS neurons are selectively lost is unclear.…”

Section: Involvementmentioning

confidence: 81%

Molecular and Cellular Characteristics of the Colonic Pseudo-obstruction in Patients With Intractable Constipation

Suh

Myung

Kwak

et al. 2015

J Neurogastroenterol Motil

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Background/AimsChronic intestinal pseudo-obstruction (CIPO) is a disorder characterized by recurrent symptoms suggestive of obstruction such as abdominal pain, proximal distension with extremely suppressed motility in the absence of lumen-occluding lesion, whose etiology/pathophysiology is poorly understood. In this study we investigated a functionally obstructive lesion that could underlie symptoms of CIPO. MethodsWe studied colons surgically removed from 13 patients exhibiting clinical/pathological features of pseudo-obstruction but were unresponsive to standard medical treatments. The colons were characterized morphologically, functionally and molecularly, which were compared between regions and to 28 region-matched controls obtained from colon cancer patients. ResultsThe colons with pseudo-obstruction exhibited persistent luminal distension proximally, where the smooth muscle was hypertrophied with changes in the cell phenotypes. Distinct luminal narrowing was observed near the distal end of the dilated region, close to the splenic flexure, previously referred to as the "transition zone (TZ)" between the dilated and non-dilated loops. Circular muscles from the TZ responded less to depolarization and cholinergic stimulation, which was associated with downregulation of L-type calcium channel expression. Smooth muscle contractile protein was also downregulated. Myenteric ganglia and neuronal nitric oxide synthase (nNOS) positive cells were deficient, more severely in the TZ region. Interstitial cells of Cajal was relatively less affected. 561 ConclusionsThe TZ may be the principal site of functional obstruction, leading to proximal distension and smooth muscle hypertrophy, in which partial nNOS depletion could play a key role. The neuromuscular abnormalities probably synergistically contributed to the extremely suppressed motility observed in the colonic pseudo-obstruction.(J Neurogastroenterol Motil 2015;21:560-570)

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“…This involves well‐regulated motility which requires both excitatory and inhibitory neurotransmission as part of intricate neuronal programs. Nitric oxide (NO) plays a role as the dominant inhibitory neurotransmitter in addition to its role in the overall programing of peristaltic contractions . Nitric oxide was also shown to be essential for rhythmic electrical depolarizations in the canine colon likely involving both enteric neurons and ICC .…”

Section: Discussionmentioning

confidence: 99%

Cell‐specific effects of nitric oxide on the efficiency and frequency of long distance contractions in murine colon

Beck

Voussen

Reigl

et al. 2019

Neurogastroenterology Motil

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Background Nitric oxide (NO) mediates inhibitory neurotransmission and is a critical component of neuronal programs that generate propulsive contractions. NO acts via its receptor NO‐sensitive guanylyl cyclase (NO‐GC) which is expressed in smooth muscle cells (SMC) and interstitial cells of Cajal (ICC). Organ bath studies with colonic rings from NO‐GC knockout mice (GCKO) have indicated NO‐GC to modulate spontaneous contractions. The cell‐specific effects of NO‐GC on the dominant pan‐colonic propulsive contraction, the long distance contractions (LDCs), of whole colon preparations have not yet been described. Methods Contractions of whole colon preparations from wild type (WT), global, and cell‐specific GCKO were recorded. After transformation into spatiotemporal maps, motility patterns were analyzed. Simultaneous perfusion of the colon enabled the correlation of outflow with LDCs to analyze contraction efficiency. Key Results Deletion of NO‐GC in both ICC and SMC (ie, in GCKO and SMC/ICC‐GCKO) caused loss of typical LDC activity and instead generated high‐frequency LDC‐like contractions with inefficient propulsive activity. Frequency was also increased in WT, SMC‐GCKO, and ICC‐GCKO colon in the presence of L‐NAME to block neuronal NO synthase. LDC efficiency was dependent on NO‐GC in SMC as it was reduced in GCKO, SMC‐GCKO, and ICC/SMC‐GCKO colon; LDC efficiency was decreased in all genotypes in the presence of L‐NAME. Conclusions and Inferences NO/cGMP signaling is critical for normal peristaltic movements; as NO‐GC in both SMC and ICC is essential, both cell types appear to work in synchrony. The efficiency of contractions to expel fluid is particularly influenced by NO‐GC in SMC.

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On the origin of rhythmic contractile activity of the esophagus in early achalasia, a clinical case study

Cited by 13 publications

References 70 publications

Decrease of Nitrergic Innervation in the Esophagus of Patients with Chagas Disease: Correlation with Loss of Interstitial Cells of Cajal

Decrease of Nitrergic Innervation in the Esophagus of Patients with Chagas Disease: Correlation with Loss of Interstitial Cells of Cajal

Molecular and Cellular Characteristics of the Colonic Pseudo-obstruction in Patients With Intractable Constipation

Cell‐specific effects of nitric oxide on the efficiency and frequency of long distance contractions in murine colon

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