|
1
|
Choi EL, Taheri N, Tan E, Matsumoto K, Hayashi Y. The Crucial Role of the Interstitial Cells of Cajal in Neurointestinal Diseases. Biomolecules 2023; 13:1358. [PMID: 37759758 PMCID: PMC10526372 DOI: 10.3390/biom13091358] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2023] [Revised: 09/03/2023] [Accepted: 09/06/2023] [Indexed: 09/29/2023] Open
Abstract
Neurointestinal diseases result from dysregulated interactions between the nervous system and the gastrointestinal (GI) tract, leading to conditions such as Hirschsprung's disease and irritable bowel syndrome. These disorders affect many people, significantly diminishing their quality of life and overall health. Central to GI motility are the interstitial cells of Cajal (ICC), which play a key role in muscle contractions and neuromuscular transmission. This review highlights the role of ICC in neurointestinal diseases, revealing their association with various GI ailments. Understanding the functions of the ICC could lead to innovative perspectives on the modulation of GI motility and introduce new therapeutic paradigms. These insights have the potential to enhance efforts to combat neurointestinal diseases and may lead to interventions that could alleviate or even reverse these conditions.
Collapse
Affiliation(s)
- Egan L. Choi
- Enteric Neuroscience Program and Department of Physiology and Biomedical Engineering, Mayo Clinic College of Medicine and Science, Guggenheim 10, 200 1st Street SW, Rochester, MN 55905, USA; (E.L.C.); (N.T.)
- Gastroenterology Research Unit, Mayo Clinic College of Medicine and Science, Rochester, MN 55905, USA
| | - Negar Taheri
- Enteric Neuroscience Program and Department of Physiology and Biomedical Engineering, Mayo Clinic College of Medicine and Science, Guggenheim 10, 200 1st Street SW, Rochester, MN 55905, USA; (E.L.C.); (N.T.)
- Gastroenterology Research Unit, Mayo Clinic College of Medicine and Science, Rochester, MN 55905, USA
| | - Elijah Tan
- Enteric Neuroscience Program and Department of Physiology and Biomedical Engineering, Mayo Clinic College of Medicine and Science, Guggenheim 10, 200 1st Street SW, Rochester, MN 55905, USA; (E.L.C.); (N.T.)
- Gastroenterology Research Unit, Mayo Clinic College of Medicine and Science, Rochester, MN 55905, USA
| | - Kenjiro Matsumoto
- Laboratory of Pathophysiology, Faculty of Pharmaceutical Sciences, Doshisha Women’s College of Liberal Arts, Kyoto 610-0395, Japan;
| | - Yujiro Hayashi
- Enteric Neuroscience Program and Department of Physiology and Biomedical Engineering, Mayo Clinic College of Medicine and Science, Guggenheim 10, 200 1st Street SW, Rochester, MN 55905, USA; (E.L.C.); (N.T.)
- Gastroenterology Research Unit, Mayo Clinic College of Medicine and Science, Rochester, MN 55905, USA
| |
Collapse
|
|
2
|
Ma T, Xue X, Tian H, Zhou X, Wang J, Zhao Z, Wang M, Song J, Feng R, Li L, Jing C, Tian F. Effect of the gut microbiota and their metabolites on postoperative intestinal motility and its underlying mechanisms. J Transl Med 2023; 21:349. [PMID: 37237321 DOI: 10.1186/s12967-023-04215-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2023] [Accepted: 05/19/2023] [Indexed: 05/28/2023] Open
Abstract
Gut microbiota is closely related to human health and disease because, together with their metabolites, gut microbiota maintain normal intestinal peristalsis. The use of antibiotics or opioid anesthetics, or both, during surgical procedures can lead to dysbiosis and affect intestinal motility; however, the underlying mechanisms are not fully known. This review aims to discuss the effect of gut microbiota and their metabolites on postoperative intestinal motility, focusing on regulating the enteric nervous system, 5-hydroxytryptamine neurotransmitter, and aryl hydrocarbon receptor.
Collapse
Affiliation(s)
- TianRong Ma
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, China
| | - XiaoLei Xue
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, China
- Department of Pharmacy, The Second Affiliated Hospital of Shandong First Medical University, Taian, 271000, China
| | - Hui Tian
- Department of Gastroenterology, Liaocheng People's Hospital, Shandong First Medical University, Liaocheng, 252000, China
| | - XinXiu Zhou
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, China
| | - JunKe Wang
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, China
| | - ZhiWen Zhao
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, China
| | - MingFei Wang
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250021, China
| | - JiYuan Song
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250021, China
| | - RenXiang Feng
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250021, China
| | - Leping Li
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, China
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250021, China
| | - Changqing Jing
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, China.
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250021, China.
| | - Feng Tian
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, China.
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250021, China.
| |
Collapse
|
|
3
|
Friedmacher F, Rolle U. Interstitial cells of Cajal: clinical relevance in pediatric gastrointestinal motility disorders. Pediatr Surg Int 2023; 39:188. [PMID: 37101012 PMCID: PMC10133055 DOI: 10.1007/s00383-023-05467-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/03/2023] [Indexed: 04/28/2023]
Abstract
Interstitial cells of Cajal (ICCs) are pacemaker cells of gastrointestinal motility that generate and transmit electrical slow waves to smooth muscle cells in the gut wall, thus inducing phasic contractions and coordinated peristalsis. Traditionally, tyrosine-protein kinase Kit (c-kit), also known as CD117 or mast/stem cell growth factor receptor, has been used as the primary marker of ICCs in pathology specimens. More recently, the Ca2+-activated chloride channel, anoctamin-1, has been introduced as a more specific marker of ICCs. Over the years, various gastrointestinal motility disorders have been described in infants and young children in which symptoms of functional bowel obstruction arise from ICC-related neuromuscular dysfunction of the colon and rectum. The current article provides a comprehensive overview of the embryonic origin, distribution, and functions of ICCs, while also illustrating the absence or deficiency of ICCs in pediatric patients with Hirschsprung disease intestinal neuronal dysplasia, isolated hypoganglionosis, internal anal sphincter achalasia, and congenital smooth muscle cell disorders such as megacystis microcolon intestinal hypoperistalsis syndrome.
Collapse
Affiliation(s)
- Florian Friedmacher
- Department of Paediatric Surgery and Paediatric Urology, University Hospital Frankfurt, Goethe University Frankfurt, Theodor-Stern-Kai 7, 60590, Frankfurt, Germany
| | - Udo Rolle
- Department of Paediatric Surgery and Paediatric Urology, University Hospital Frankfurt, Goethe University Frankfurt, Theodor-Stern-Kai 7, 60590, Frankfurt, Germany.
| |
Collapse
|
|
4
|
Pan W, Goldstein AM, Hotta R. Opportunities for novel diagnostic and cell-based therapies for Hirschsprung disease. J Pediatr Surg 2022; 57:61-68. [PMID: 34852916 PMCID: PMC9068833 DOI: 10.1016/j.jpedsurg.2021.10.049] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2021] [Revised: 10/17/2021] [Accepted: 10/28/2021] [Indexed: 12/26/2022]
Abstract
Despite significant progress in our understanding of the etiology and pathophysiology of Hirschsprung disease (HSCR), early and accurate diagnosis and operative management can be challenging. Moreover, long-term morbidity following surgery, including fecal incontinence, constipation, and Hirschsprung-associated enterocolitis (HAEC), remains problematic. Recent advances applying state-of-the art imaging for visualization of the enteric nervous system and utilizing neuronal stem cells to replace the missing enteric neurons and glial cells offer the possibility of a promising new future for patients with HSCR. In this review, we summarize recent research advances that may one day offer novel approaches for the diagnosis and management of this disease.
Collapse
Affiliation(s)
- Weikang Pan
- Department of Pediatric Surgery, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, 185 Cambridge St, CPZN 6-215, Boston, MA 02114, USA; Department of Pediatric Surgery, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710004, China
| | - Allan M Goldstein
- Department of Pediatric Surgery, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, 185 Cambridge St, CPZN 6-215, Boston, MA 02114, USA
| | - Ryo Hotta
- Department of Pediatric Surgery, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, 185 Cambridge St, CPZN 6-215, Boston, MA 02114, USA.
| |
Collapse
|
|
5
|
Hong M, Li X, Li Y, Zhou Y, Li Y, Chi S, Cao G, Li S, Tang S. Hirschsprung's disease: key microRNAs and target genes. Pediatr Res 2022; 92:737-747. [PMID: 34880446 DOI: 10.1038/s41390-021-01872-1] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Revised: 11/01/2021] [Accepted: 11/13/2021] [Indexed: 12/11/2022]
Abstract
BACKGROUND This study aimed to identify key microRNAs (miRNAs), pathways, and target genes mediating Hirschsprung's disease (HSCR) pathogenesis and identify the diagnostic potential of miRNAs. METHODS The Gene Expression Omnibus database and reverse transcription-quantitative PCR were used to compare miRNA expression between ganglionic and aganglionic colon tissues of children with HSCR, and the TAM 2.0 database was used to identify colon tissue-specific miRNAs. The StarBase database, TargetScan database, luciferase reporter, and western blot assays were used to analyze miRNA-messenger RNA interactions. OmicShare was used to perform functional and pathway enrichment analyses of the target genes. Migration assays were performed to validate the functions of the miRNAs. RESULTS The TAM 2.0 database analysis and reverse transcription-quantitative PCR showed that hsa-miR-192-5p, hsa-miR-200a-3p, and hsa-miR-200b-3p were colon tissue-specific and upregulated in aganglionic colon tissue compared to paired ganglionic colon tissue. These three miRNAs effectively reduced cell viability and migration. Luciferase reporter and western blot assays verified the direct interaction between these three miRNAs and the target genes of ZEB2 and FNDC3B. Furthermore, the plasma levels of these miRNAs were higher in HSCR patients than in non-HSCR patients. CONCLUSIONS Three plasma miRNAs (hsa-miR-192-5p, hsa-miR-200a-3p, and hsa-miR-200b-3p) are potential peripheral HSCR biomarkers. IMPACT The molecular mechanisms underlying HSCR are unclear. HSCR is most accurately diagnosed using rectal biopsy samples, and no consensus has been reached on the use of blood-based tests for HSCR diagnosis. Circulating miRNAs may be candidate diagnostic HSCR biomarkers because they are typically easily detectable, stable, and tissue-specific. Three plasma miRNAs (miR-200a-3p, miR-192-5p, and miR-200b-3p) are potential peripheral HSCR biomarkers.
Collapse
Affiliation(s)
- Mei Hong
- Department of Pediatric Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiangyang Li
- Department of Pediatric Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yuan Li
- Department of Pediatric Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yun Zhou
- Department of Pediatric Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yibo Li
- Department of Pediatric Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Shuiqing Chi
- Department of Pediatric Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Guoqing Cao
- Department of Pediatric Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Shuai Li
- Department of Pediatric Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Shaotao Tang
- Department of Pediatric Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
| |
Collapse
|
|
6
|
Verkuijl SJ, Friedmacher F, Harter PN, Rolle U, Broens PMA. Persistent bowel dysfunction after surgery for Hirschsprung’s disease: A neuropathological perspective. World J Gastrointest Surg 2021; 13:822-833. [PMID: 34512906 PMCID: PMC8394380 DOI: 10.4240/wjgs.v13.i8.822] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/12/2021] [Revised: 05/12/2021] [Accepted: 07/05/2021] [Indexed: 02/06/2023] Open
Abstract
Hirschsprung’s disease (HD) is a congenital disorder, characterized by aganglionosis in the distal part of the gastrointestinal tract. Despite complete surgical resection of the aganglionic segment, both constipation and fecal incontinence persist in a considerable number of patients with limited treatment options. There is growing evidence for structural abnormalities in the ganglionic bowel proximal to the aganglionosis in both humans and animals with HD, which may play a role in persistent bowel dysfunction. These abnormalities include: (1) Histopathological abnormalities of enteric neural cells; (2) Imbalanced expression of neurotransmitters and neuroproteins; (3) Abnormal expression of enteric pacemaker cells; (4) Abnormalities of smooth muscle cells; and (5) Abnormalities within the extracellular matrix. Hence, a better understanding of these previously unrecognized neuropathological abnormalities may improve follow-up and treatment in patients with HD suffering from persistent bowel dysfunction following surgical correction. In the long term, further combination of clinical and neuropathological data will hopefully enable a translational step towards more individual treatment for HD.
Collapse
Affiliation(s)
- Sanne J Verkuijl
- Department of Pediatric Surgery, University Hospital Frankfurt, Goethe University Frankfurt, Frankfurt 60590, Germany
- Neurological Institute (Edinger-Institute), University Hospital Frankfurt, Goethe University Frankfurt, Frankfurt 60528, Germany
- Department of Surgery, Division of Pediatric Surgery, University of Groningen, University Medical Center Groningen, Groningen 9700 RB, Netherlands
| | - Florian Friedmacher
- Department of Pediatric Surgery, University Hospital Frankfurt, Goethe University Frankfurt, Frankfurt 60590, Germany
| | - Patrick N Harter
- Neurological Institute (Edinger-Institute), University Hospital Frankfurt, Goethe University Frankfurt, Frankfurt 60528, Germany
| | - Udo Rolle
- Department of Pediatric Surgery, University Hospital Frankfurt, Goethe University Frankfurt, Frankfurt 60590, Germany
| | - Paul MA Broens
- Department of Surgery, Division of Pediatric Surgery, University of Groningen, University Medical Center Groningen, Groningen 9700 RB, Netherlands
| |
Collapse
|
|
7
|
Yu B, Zhu X, Yang X, Jin L, Xu J, Ma T, Yang H. Plumbagin Prevents Secretory Diarrhea by Inhibiting CaCC and CFTR Channel Activities. Front Pharmacol 2019; 10:1181. [PMID: 31649543 PMCID: PMC6795057 DOI: 10.3389/fphar.2019.01181] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2019] [Accepted: 09/13/2019] [Indexed: 12/12/2022] Open
Abstract
Secretory diarrhea, which primarily originates through intestinal pathogens and viruses, is a health burden in many regions worldwide. Enterocyte Cl− channels, as the final step in enterotoxin-induced fluid secretion, constitute an attractive class of targets for diarrhea therapy. Chloride channel inhibitors have become a new class of candidates for antisecretion and anti-intestinal motility agents. In the present study, we identified plumbagin as a transmembrane protein 16A (TMEM16A) inhibitor in a cell-based fluorescence-quenching assay, and the IC50 value was ∼12.46 µM. Short-circuit current measurements showed that plumbagin reversibly inhibited the Eact-induced Cl− current on the apical side of TMEM16A-transfected Fischer rat thyroid (FRT) cells with no significant effect on cytoplasmic Ca2+ signaling. Notably, plumbagin also inhibited the activity of intestinal epithelial calcium-activated chloride channel (CaCC) and cystic fibrosis transmembrane conductance regulator (CFTR) in both HT-29 cells and mouse colons, but had no effects on the activity of the Na+-K+ ATPase or K+ channels. In in vivo experiments, the administration of plumbagin reduced both Escherichia coli heat-stable enterotoxin (STa)- and cholera toxin (CT)-induced intestinal fluid secretion. In neonatal mouse models of CT- and rotavirus infection-induced diarrhea, 0.4 µg plumbagin inhibited secretory diarrhea by >40% and 50%, respectively, without affecting intestinal epithelial integrity or the rotaviral infection. In addition, plumbagin exerted inhibitory effects on the vasoactive intestinal peptide (VIP)-, prostaglandin E2 (PGE2)-, and 5-hydroxytryptamine (5-HT)-stimulated Cl− currents. In the evaluations of intestinal motility, plumbagin significantly delayed intestinal motility and inhibited intestinal smooth muscle contractility without an evident impact on contractive frequency. Collectively, our results indicate that plumbagin inhibits both Ca2+- and cAMP-activated Cl− channels, accounting for the mechanisms of plumbagin inhibition of chloride secretion and intestinal motility. Thus, plumbagin can be a lead compound in the treatment of CT-induced, Traveler’s, and rotaviral diarrhea, as well as other types of secretory diarrhea that result from excessive intestinal fluid secretion and increased intestinal peristalsis.
Collapse
Affiliation(s)
- Bo Yu
- School of Life Sciences, Liaoning Provincial Key Laboratory of Biotechnology and Drug Discovery, Liaoning Normal University, Dalian, China
| | - Xiaojuan Zhu
- School of Life Sciences, Liaoning Provincial Key Laboratory of Biotechnology and Drug Discovery, Liaoning Normal University, Dalian, China
| | - Xinyu Yang
- School of Life Sciences, Liaoning Provincial Key Laboratory of Biotechnology and Drug Discovery, Liaoning Normal University, Dalian, China
| | - Lingling Jin
- College of Basic Medical Sciences, Dalian Medical University, Dalian, China
| | - Jia Xu
- School of Life Sciences, Liaoning Provincial Key Laboratory of Biotechnology and Drug Discovery, Liaoning Normal University, Dalian, China
| | - Tonghui Ma
- School of Life Sciences, Liaoning Provincial Key Laboratory of Biotechnology and Drug Discovery, Liaoning Normal University, Dalian, China
| | - Hong Yang
- School of Life Sciences, Liaoning Provincial Key Laboratory of Biotechnology and Drug Discovery, Liaoning Normal University, Dalian, China
| |
Collapse
|
|
8
|
Hu B, Cao L, Wang XY, Li L. Downregulation of microRNA-431-5p promotes enteric neural crest cell proliferation via targeting LRSAM1 in Hirschsprung's disease. Dev Growth Differ 2019; 61:294-302. [PMID: 31037734 DOI: 10.1111/dgd.12606] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2018] [Revised: 02/18/2019] [Accepted: 03/04/2019] [Indexed: 12/28/2022]
Abstract
BACKGROUND Hirschsprung's disease (HSCR) is characterized by missing of enteric neurons in the terminal areas of the whole gut, which is causally related to poor proliferation of enteric neural crest cells (ENCCs). Our aim is to explore how miR-431-5p interacts with its target gene in regulation of proliferation of ENCCs in HSCR. METHODS Mouse model of HSCR was established by Benzalkonium chloride (BAC) treatment. Quantitative Real-time PCR and western blotting were performed to determine the miR-431-5p and the LRSAM1 expression in colon tissues of the HSCR group (n = 8) and the control group (n = 8) and in ENCCs isolated from colon tissues. CCK-8 assay was performed to detect the proliferation of ENCCs of HSCR. ENCCs after transfection with miR-431-5p mimics or miR-431-5p inhibitor. Luciferase reporter assay was conducted to clarify the connections between miR-431-5p and LRSAM1. RESULTS Upregulation of miR-431-5p and downregulation of LRSAM1 were found in ENCCs of HSCR. Downregulation of miR-431-5p could promote cell proliferation of ENCCs. LRSAM1 was proved to be the target gene of miR-431-5p by luciferase reporter assay. Moreover, proliferation of ENCCs was increased in the miR-431-5p inhibitor group and was suppressed after knocking down LRSAM1. CONCLUSION Downregulation of miR-431-5p promoted proliferation of ENCCs via targeting LRSAM1, which provides an innovative and candidate target for treatment of HSCR.
Collapse
Affiliation(s)
- Bo Hu
- Department of Pediatric Surgery, Tianjin Medical University General Hospital, Tianjin, China
| | - Lei Cao
- Department of General Surgery, Tianjin Union Medical Center, Tianjin, China
| | - Xiao-Ye Wang
- Department of Pediatric Surgery, Tianjin Medical University General Hospital, Tianjin, China
| | - Long Li
- Department of General Surgery, Capital Institute of Pediatrics Children's Hospital, Beijing, China
| |
Collapse
|
|
9
|
Liu W, Zhang L, Wu R. Enteric Neural Stem Cells Expressing Insulin-Like Growth Factor 1: A Novel Cellular Therapy for Hirschsprung's Disease in Mouse Model. DNA Cell Biol 2018; 37:642-648. [PMID: 29792527 DOI: 10.1089/dna.2017.4060] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Affiliation(s)
- Wei Liu
- Department of Pediatric Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China
| | - Lijuan Zhang
- Department of Pediatric Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China
| | - Rongde Wu
- Department of Pediatric Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China
| |
Collapse
|
|
10
|
Yang H, Ma T. Luminally Acting Agents for Constipation Treatment: A Review Based on Literatures and Patents. Front Pharmacol 2017; 8:418. [PMID: 28713271 PMCID: PMC5491688 DOI: 10.3389/fphar.2017.00418] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2017] [Accepted: 06/13/2017] [Indexed: 12/11/2022] Open
Abstract
Constipation is one of the most frequently reported gastrointestinal (GI) disorders that negatively impacts quality of life and is associated with a significant economic burden to the patients and society. Traditional treatments including lifestyle modification and laxatives are often ineffective in the more severe forms of constipation and over the long term. New medications targeting at intestinal chloride channels and colonic serotonin receptors have been demonstrated effective in recent years. Emerging agents focusing on improving intestinal secretion and/or colonic motility have been shown effective in animal models and even in clinical trials. Recognization of the role of cystic fibrosis transmembrane regulator (CFTR) and calcium-activated chloride channels (CaCCs) in intestine fluid secretion and motility modulation makes CFTR and CaCCs promising molecule targets for anti-constipation therapy. Although there are multiple choices for constipation treatment, there is still a recognized need for new medications in anti-constipation therapy. The present review covers the discovery of luminally acting agents for constipation treatment described in both patents (2011–present) and scientific literatures.
Collapse
Affiliation(s)
- Hong Yang
- Liaoning Provincial Key Laboratory of Biotechnology and Drug Discovery, School of Life Sciences, Liaoning Normal UniversityDalian, China
| | - Tonghui Ma
- Institute of Traditional Chinese Medicine, Nanjing University of Chinese MedicineNanjing, China
| |
Collapse
|
|
11
|
Touré AM, Charrier B, Pilon N. Male-specific colon motility dysfunction in the TashT mouse line. Neurogastroenterol Motil 2016; 28:1494-507. [PMID: 27278627 DOI: 10.1111/nmo.12847] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2016] [Accepted: 04/10/2016] [Indexed: 02/08/2023]
Abstract
BACKGROUND In Hirschsprung disease (HSCR), the absence of myenteric neural ganglia in the distal bowel prevents motility and thereby causes functional intestinal obstruction. Although surgical resection of the aganglionic segment allows HSCR children to survive this condition, a number of patients still suffer from impaired motility despite having myenteric ganglia in their postoperative distal bowel. Such phenomenon is also observed in patients suffering from other enteric neuropathies and, in both cases, colonic dysmotility is believed to result from abnormalities of myenteric ganglia and/or associated interstitial cells of Cajal (ICC). To better understand this, we used a recently described HSCR mouse model called TashT. METHODS Intestinal motility parameters were assessed and correlated with extent of aganglionosis and with neuronal density in ganglionated regions. The neural composition of the myenteric plexus and the status of ICC networks was also evaluated using immunofluorescence. KEY RESULTS TashT(Tg/Tg) mice display a strong male bias in the severity of both colonic aganglionosis and hypoganglionosis, which are associated with male-specific reduced colonic motility. TashT(Tg/Tg) male mice also exhibit a specific increase in nNos(+) neurons that is restricted to the most distal ganglionated regions. In contrast, Calretinin(+) myenteric neurons, Sox10(+) myenteric glial cells, and cKit(+) ICC are not affected in TashT(Tg/Tg) mice. CONCLUSIONS AND INFERENCES Male-specific impairment of colonic motility in TashT(Tg/Tg) mice is associated with both severe hypoganglionosis and myenteric neuronal imbalance. Considering these parameters in the clinic might be important for the management of postoperative HSCR patients.
Collapse
Affiliation(s)
- A M Touré
- Molecular Genetics of Development Laboratory, Department of Biological Sciences and BioMed Research Center, Faculty of Sciences, University of Quebec at Montreal (UQAM), Montreal, Canada
| | - B Charrier
- Molecular Genetics of Development Laboratory, Department of Biological Sciences and BioMed Research Center, Faculty of Sciences, University of Quebec at Montreal (UQAM), Montreal, Canada
| | - N Pilon
- Molecular Genetics of Development Laboratory, Department of Biological Sciences and BioMed Research Center, Faculty of Sciences, University of Quebec at Montreal (UQAM), Montreal, Canada.
| |
Collapse
|
|
12
|
Neves Romaneli MTD, Ribeiro AF, Bustorff-Silva JM, Carvalho RBD, Lomazi EA. Hirschsprung's disease – Postsurgical intestinal dysmotility. REVISTA PAULISTA DE PEDIATRIA (ENGLISH EDITION) 2016. [PMID: 26979103 PMCID: PMC5178128 DOI: 10.1016/j.rppede.2016.05.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Affiliation(s)
| | - Antonio Fernando Ribeiro
- Faculdade de Ciências Médicas, Universidade Estadual de Campinas (Unicamp), Campinas, SP, Brasil.
| | | | - Rita Barbosa de Carvalho
- Faculdade de Ciências Médicas, Universidade Estadual de Campinas (Unicamp), Campinas, SP, Brasil
| | - Elizete Aparecida Lomazi
- Faculdade de Ciências Médicas, Universidade Estadual de Campinas (Unicamp), Campinas, SP, Brasil.
| |
Collapse
|
|
13
|
Laparoscopic-assisted pull-through operation for Hirschsprung's disease: a systematic review and meta-analysis. Pediatr Surg Int 2016; 32:751-7. [PMID: 27369964 DOI: 10.1007/s00383-016-3910-5] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 06/18/2016] [Indexed: 12/21/2022]
Abstract
PURPOSE In the last two decades, laparoscopic-assisted pull-through (LAPT) has gained much popularity in the treatment of Hirschsprung's disease. The aim of this meta-analysis was to determine the long-term outcome of patients treated laparoscopically. METHODS A systematic literature-based search for relevant cohorts was performed using the terms "Hirschsprung's disease and Laparoscopy", "Laparoscopic-assisted pull-through outcome", "Laparoscopic-assisted Soave pull-through" "Laparoscopic-assisted Swenson pull-through" and Laparoscopic-assisted Duhamel pull-through. The relevant cohorts of laparoscopic operated HD were systematically searched for outcome regarding continence, constipation, secondary surgery related to the laparoscopic approach and enterocolitis. Pooled incidence rates and odds ratios (ORs) with 95 % confidence intervals (CI) were calculated using standardized statistical methodology. RESULTS Sixteen studies met defined inclusion criteria, reporting a total of 820 patients. All studies were retrospective case series, with variability in outcome assessment quality and length of follow-up. The median cohort size consisted of 28 patients (range 15-218). In the long-term follow-up, 97 patients (11.14 %) experienced constipation (OR 0.06, 95 % CI 0.05-0.08, p < 0.00001), 53 (6.46 %) incontinence/soiling (OR 0.01 95 % CI 0.01-0.01, p < 0.00001), 75 (9.14 %) recurrent enterocolitis (OR 0.02 95 % CI 0.01-0.02, p < 0.00001) and 69 (8.4 %) developed complications requiring secondary surgery (OR 0.01 95 % CI 0.01-0.02, p < 0.00001). Overall events in long-term follow-up occurred in 225 (27.5 %) patients (OR 0.24 95 % CI 0.20-0.30, p < 0.00001). CONCLUSIONS This meta-analysis shows that nearly one-third of the patients continue to have long-term bowel problems, such as constipation, soiling and recurrent enterocolitis following LAPT. Many patients treated by LAPT require secondary surgery. Large randomized studies with long-term follow-up are necessary to determine the difference in outcome between LAPT and completely transanal pull-through operation.
Collapse
|
|
14
|
Neves Romaneli MTD, Ribeiro AF, Bustorff-Silva JM, Carvalho RBD, Lomazi EA. Hirschsprung's disease - Postsurgical intestinal dysmotility. REVISTA PAULISTA DE PEDIATRIA 2016; 34:388-92. [PMID: 26979103 DOI: 10.1016/j.rpped.2015.12.008] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/13/2015] [Revised: 10/29/2015] [Accepted: 12/22/2015] [Indexed: 11/28/2022]
Abstract
OBJECTIVE To describe the case of an infant with Hirschsprung's disease presenting as total colonic aganglionosis, which, after surgical resection of the aganglionic segment persisted with irreversible functional intestinal obstruction; discuss the difficulties in managing this form of congenital aganglionosis and discuss a plausible pathogenetic mechanism for this case. CASE DESCRIPTION The diagnosis of Hirschsprung's disease presenting as total colonic aganglionosis was established in a two-month-old infant, after an episode of enterocolitis, hypovolemic shock and severe malnutrition. After colonic resection, the patient did not recover intestinal motor function that would allow enteral feeding. Postoperative examination of remnant ileum showed the presence of ganglionic plexus and a reduced number of interstitial cells of Cajal in the proximal bowel segments. At 12 months, the patient remains dependent on total parenteral nutrition. COMMENTS Hirschsprung's disease presenting as total colonic aganglionosis has clinical and surgical characteristics that differentiate it from the classic forms, complicating the diagnosis and the clinical and surgical management. The postoperative course may be associated with permanent morbidity due to intestinal dysmotility. The numerical reduction or alteration of neural connections in the interstitial cells of Cajal may represent a possible physiopathological basis for the condition.
Collapse
Affiliation(s)
| | - Antonio Fernando Ribeiro
- Faculdade de Ciências Médicas, Universidade Estadual de Campinas (Unicamp), Campinas, SP, Brasil.
| | | | - Rita Barbosa de Carvalho
- Faculdade de Ciências Médicas, Universidade Estadual de Campinas (Unicamp), Campinas, SP, Brasil
| | - Elizete Aparecida Lomazi
- Faculdade de Ciências Médicas, Universidade Estadual de Campinas (Unicamp), Campinas, SP, Brasil.
| |
Collapse
|
|
15
|
Uyttebroek L, Shepherd IT, Vanden Berghe P, Hubens G, Timmermans JP, Van Nassauw L. The zebrafish mutant lessen: an experimental model for congenital enteric neuropathies. Neurogastroenterol Motil 2016; 28:345-57. [PMID: 26685876 DOI: 10.1111/nmo.12732] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2015] [Accepted: 10/22/2015] [Indexed: 02/08/2023]
Abstract
BACKGROUND Congenital enteric neuropathies of the distal intestine (CEN) are characterized by the partial or complete absence of enteric neurons. Over the last decade, zebrafish has emerged as a leading model organism in experimental research. Our aim was to demonstrate that the mutant zebrafish, lessen, expressing CEN characteristics, is an equally valuable animal model alongside mammalian models for CEN, by studying its enteric phenotype. METHODS The effect of the lessen mutation on the development of the enteric nervous system (ENS), interstitial cells of Cajal (ICC), and intestinal motility in each intestinal region of mutant and wild-type (wt) zebrafish embryos at 3-6 dpf, was analyzed by immunofluorescent detection of neurochemical markers and motility assays. KEY RESULTS Development of intestinal motility in the mutant was delayed and the majority of the observed contractions were disturbed. A significant disturbance in ENS development resulted in a distal intestine that was almost free of neuronal elements, in reduced neuronal density in the proximal and mid-intestine, and in a defect in the expression of neurochemical markers. Furthermore, markedly disturbed development of ICC gave rise to a less dense network of ICC. CONCLUSIONS & INFERENCES The observed alterations in intestinal motility, intrinsic innervation and ICC network of the mutant in comparison with the wt zebrafish, are similar to those seen in the oligo- and aganglionic regions of the intestine of CEN patients. It is concluded that the zebrafish mutant lessen is an appropriate animal model to investigate CEN.
Collapse
Affiliation(s)
- L Uyttebroek
- Laboratory of Human Anatomy and Embryology, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerpen, Belgium
| | - I T Shepherd
- Department of Biology, Emory University, Atlanta, GA, USA
| | - P Vanden Berghe
- Laboratory for Enteric NeuroScience (LENS), Translational Research in GastroIntestinal Disorders (TARGID), Department of Clinical and Experimental Medicine, University of Leuven, Leuven, Belgium
| | - G Hubens
- Laboratory of Human Anatomy and Embryology, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerpen, Belgium
| | - J-P Timmermans
- Laboratory of Cell Biology and Histology, Department of Veterinary Sciences, University of Antwerp, Antwerpen, Belgium
| | - L Van Nassauw
- Laboratory of Human Anatomy and Embryology, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerpen, Belgium
| |
Collapse
|
|
16
|
Zhou Y, Besner G. Transplantation of amniotic fluid-derived neural stem cells as a potential novel therapy for Hirschsprung's disease. J Pediatr Surg 2016; 51:87-91. [PMID: 26597391 DOI: 10.1016/j.jpedsurg.2015.10.016] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2015] [Accepted: 10/07/2015] [Indexed: 01/13/2023]
Abstract
BACKGROUND/PURPOSE We have previously shown that embryonic enteric neural stem cells (NSCs) isolated from the intestine colonize aganglionic intestine upon transplantation, but posttransplantation cell survival limits efficacy. The aims of this study were to investigate whether transplantation of amniotic fluid (AF)-derived NSCs could improve survival of the engrafted cells and promote functional recovery of the diseased colon. METHODS AF cells were induced into NSCs with neurogenic medium, and further differentiated into neurons and glial cells. Ednrb knockout mice received an intestinal intramuscular injection of 20,000 AF-derived NSCs into the aganglionic colon. Engrafted cells were visualized and characterized by immunohistochemistry for GFP, neuronal, and glial cell markers. Colonic motility was quantified by colonic bead expulsion time. RESULTS AF-derived NSCs had increased expression levels of the NSC marker Nestin and the glial cell marker GFAP compared to enteric NSCs. Transplanted AF-derived NSCs had decreased apoptosis and increased survival compared to enteric NSCs. Colonic motility was significantly improved in Ednrb knockout mice transplanted with AF-derived NSCs, as demonstrated by significantly decreased colonic bead expulsion time. CONCLUSION AF-derived NSCs have enhanced survival upon transplantation into a defective enteric nervous system. Transplantation of AF-derived NSCs may represent a potential novel future therapy for the treatment of Hirschsprung's disease.
Collapse
Affiliation(s)
- Yu Zhou
- The Center for Perinatal Research, The Research Institute at Nationwide Children's Hospital, Department of Pediatric Surgery, The Ohio State University College of Medicine, Columbus, OH, United States
| | - Gail Besner
- The Center for Perinatal Research, The Research Institute at Nationwide Children's Hospital, Department of Pediatric Surgery, The Ohio State University College of Medicine, Columbus, OH, United States.
| |
Collapse
|
|
17
|
Serotonin abnormalities in Engrailed-2 knockout mice: New insight relevant for a model of Autism Spectrum Disorder. Neurochem Int 2015; 87:34-42. [DOI: 10.1016/j.neuint.2015.05.004] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2014] [Revised: 04/02/2015] [Accepted: 05/14/2015] [Indexed: 12/14/2022]
|
|
18
|
Gfroerer S, Rolle U. Interstitial cells of Cajal in the normal human gut and in Hirschsprung disease. Pediatr Surg Int 2013; 29:889-97. [PMID: 23917331 DOI: 10.1007/s00383-013-3364-y] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Hirschsprung disease (HD) is the most prevalent congenital gastrointestinal motility disorder. The pathogenesis of HD is defined as a functional intestinal obstruction resulting from a defect in the intrinsic innervation of the distal bowel. In addition to the enteric nervous system, the interstitial cells of Cajal (ICC) play an important role in the generation of coordinated gastrointestinal peristalsis. The major function of the ICCs is the generation of slow waves that allow these cells to act as specialised pacemaker cells within various tissues. ICCs have additional functions in the gastrointestinal tract as regulators of mechanical activity and neurotransmission. Due to the central role of ICCs in gastrointestinal peristalsis, it has been suggested that defects or impairments of the ICCs may contribute to motility dysfunction in several gastrointestinal motility disorders. This review describes the distribution and functions of ICCs in the normal gut and in Hirschsprung disease.
Collapse
Affiliation(s)
- Stefan Gfroerer
- Department of Paediatric Surgery, University Hospital, Goethe University Frankfurt/M, 60596 Frankfurt/M, Germany,
| | | |
Collapse
|
|
19
|
Bernardini N, Segnani C, Ippolito C, De Giorgio R, Colucci R, Faussone-Pellegrini MS, Chiarugi M, Campani D, Castagna M, Mattii L, Blandizzi C, Dolfi A. Immunohistochemical analysis of myenteric ganglia and interstitial cells of Cajal in ulcerative colitis. J Cell Mol Med 2012; 16:318-27. [PMID: 21426484 PMCID: PMC3823295 DOI: 10.1111/j.1582-4934.2011.01298.x] [Citation(s) in RCA: 83] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Ulcerative colitis (UC) is an inflammatory bowel disease with alterations of colonic motility, which influence clinical symptoms. Although morpho-functional abnormalities in the enteric nervous system have been suggested, in UC patients scarce attention has been paid to possible changes in the cells that control colonic motility, including myenteric neurons, glial cells and interstitial cells of Cajal (ICC). This study evaluated the neural-glial components of myenteric ganglia and ICC in the colonic neuromuscular compartment of UC patients by quantitative immunohistochemical analysis. Full-thickness archival samples of the left colon were collected from 10 patients with UC (5 males, 5 females; age range 45–62 years) who underwent elective bowel resection. The colonic neuromuscular compartment was evaluated immunohistochemically in paraffin cross-sections. The distribution and number of neurons, glial cells and ICC were assessed by anti-HuC/D, -S100β and -c-Kit antibodies, respectively. Data were compared with findings on archival samples of normal left colon from 10 sex- and age-matched control patients, who underwent surgery for uncomplicated colon cancer. Compared to controls, patients with UC showed: (i) reduced density of myenteric HuC/D+ neurons and S100β+ glial cells, with a loss over 61% and 38%, respectively, and increased glial cell/neuron ratio; (ii) ICC decrease in the whole neuromuscular compartment. The quantitative variations of myenteric neuro-glial cells and ICC indicate considerable alterations of the colonic neuromuscular compartment in the setting of mucosal inflammation associated with UC, and provide a morphological basis for better understanding the motor abnormalities often observed in UC patients.
Collapse
Affiliation(s)
- Nunzia Bernardini
- Department of Human Morphology and Applied Biology, University of Pisa, Pisa, Italy.
| | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
20
|
Nah SA, de Coppi P, Kiely EM, Curry JI, Drake DP, Cross K, Spitz L, Eaton S, Pierro A. Duhamel pull-through for Hirschsprung disease: a comparison of open and laparoscopic techniques. J Pediatr Surg 2012; 47:308-12. [PMID: 22325381 DOI: 10.1016/j.jpedsurg.2011.11.025] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2011] [Accepted: 11/10/2011] [Indexed: 02/08/2023]
Abstract
PURPOSE Various pull-through techniques, both open and laparoscopic, have been performed for Hirschsprung disease. Our study compares open and laparoscopic Duhamel pull-through. METHODS After ethical approval, we reviewed all children (n = 181) with Hirschsprung disease admitted to our institution between 1999 and 2009. We excluded total colonic aganglionosis (n = 14), previous pull-through done elsewhere (n = 33), or follow-up performed abroad (n = 58). Open and laparoscopic pull-through were done in the same period according to surgeon preference. Data were analyzed using χ(2) or Mann-Whitney U test. RESULTS Seventy-six children had a Duhamel pull-through for rectosigmoid aganglionosis. Operative time, time to full feeds, and length of hospital stay were similar in each group. OPEN (N = 41): Fifteen children (37%) required 33 further procedures. Fourteen had procedures for persistent constipation, including redo Duhamel (n = 2), stoma formation (n = 2), spur division (n = 2), and dilatation/stretch/Botox/rectal biopsy/manual evacuation (n = 23). Three children had other procedures (adhesiolysis [n = 2] and incisional hernia repair [n = 1]). LAPAROSCOPIC (N = 35): Fourteen children (40%) required 30 further procedures. Eleven had procedures for persistent constipation, including redo Duhamel (n = 1), stoma formation (n = 4), spur division (n = 9), and dilatation/stretch/rectal biopsy (n = 8). Three children had other procedures (adhesiolysis [n = 1] and incisional hernia repair [n = 2]). There were 4 conversions. CONCLUSION Open and laparoscopic Duhamel pull-through have similar outcomes. We show that the techniques have comparable operative times and hospital stay.
Collapse
Affiliation(s)
- Shireen A Nah
- Department of General Surgery, Great Ormond Street Hospital and UCL Institute of Child Health, London, UK
| | | | | | | | | | | | | | | | | |
Collapse
|
|
21
|
Araujo SEA, Dumarco RB, Rawet V, Seid VE, Bocchini SF, Nahas SC. Depopulation of interstitial cells of cajal in chagasic megacolon: towards tailored surgery? ABCD-ARQUIVOS BRASILEIROS DE CIRURGIA DIGESTIVA 2010. [DOI: 10.1590/s0102-67202010000200004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
BACKGROUND: The mechanism of constipation in patients with Chagasic megacolon remains partially explained. In these patients, it was recently demonstrated a reduction in the population of interstitial cells of Cajal. AIM: To evaluate density of Cajal cells in the surgically resected colon of Chagasic patients in comparison to control patients, and to verify possible association between preoperative and postoperative bowel function of Chagasic patients and colonic cell count. METHOD: Sixteen patients with Chagasic megacolon were operated on. Clinical pre- and post-operative evaluation using the Cleveland Clinic Constipation Score was undertaken. Resected colons were examined. Cajal cells were identified by immunohistochemistry using anti-CD117 antibody. The mean cell number was compared to resected colons from 16 patients with non-obstructive sigmoid cancer. Association between pre-and post-operative constipation scores and cell count for megacolon patients was evaluated using the Pearson coefficient correlation test (r). RESULTS: A reduced number of Cajal cells [cells per field: 2.84 (0-6.6) vs. 9.68 (4.3-13) - p<0.001] was observed in the resected colon of Chagasic patients when compared to colon cancer patients. No correlation between constipation score before (r=-0.205; p=0.45) or after surgery (r=0,291; p=0.28) and cell count for megacolon patients was observed. CONCLUSIONS: Patients with Chagasic megacolon display marked reduction of interstitial cells of Cajal when compared to non-Chagasic patients. An association of constipation severity and Cajal cells depopulation in Chagasic megacolon could not be demonstrated.
Collapse
|
|
22
|
Medhus AW, Bjørnland K, Emblem R, Husebye E. Motility of the oesophagus and small bowel in adults treated for Hirschsprung's disease during early childhood. Neurogastroenterol Motil 2010; 22:154-60, e49. [PMID: 19735477 DOI: 10.1111/j.1365-2982.2009.01397.x] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
BACKGROUND Dysmotility of the upper gastrointestinal (GI) tract has been reported in children with Hirschsprung's disease (HD). In the present study, motility of the oesophagus and the small bowel was studied in adults treated for HD during early childhood to elucidate whether there are alterations in motility of the upper GI tract in this patient group. [Correction added after online publication 15 Sep: The preceding sentence has been rephrased for better clarity.] METHODS Ambulatory small bowel manometry with recording sites in duodenum/jejunum was performed in 16 adult patients with surgically treated HD and 17 healthy controls. In addition, oesophageal manometry was performed with station pull-through technique. KEY RESULTS The essential patterns of small bowel motility were recognized in all patients and controls. During fasting, phase III of the migrating motor complex (MMC) was more prominent in patients with HD than in controls when accounting for duration and propagation velocity (P = 0.006). Phase I of the MMC was of shorter duration (P = 0.008), and phase II tended to be of longer duration (P = 0.05) in the patients. During daytime fasting, propagated clustered contractions (PCCs) were more frequent in the patients (P = 0.01). Postprandially, the patients demonstrated a higher contractile frequency (P = 0.02), a shorter duration of contractions (P = 0.008) and more frequent PCCs (P < 0.001). The patients had normal oesophageal motility. CONCLUSIONS & INFERENCES This study demonstrates that adult patients with HD have preserved essential patterns of oesophageal and small bowel motility. However, abnormalities mainly characterized by increased contractile activity of the small bowel during fasting and postprandially are evident. These findings indicate alterations in neuronal control of motility and persistent involvement of the upper GI tract in this disease.
Collapse
Affiliation(s)
- A W Medhus
- Department of Gastroenterology, Oslo University Hospital, Ullevål, Oslo, Norway.
| | | | | | | |
Collapse
|
|
23
|
Abstract
PURPOSE OF REVIEW Disorders of colonic motor and sensory function are common among children and adults and pose significant diagnostic and therapeutic challenges; the purpose of this review, therefore, was to critically assess the recent literature on this topic. RECENT FINDINGS Considerable progress has been made at the ultrastructural, molecular and electrophysiological level in understanding the normal functions of the muscles, nerves and interstitial cells that generate and control colonic motility. Furthermore, abnormalities in these cell types and in the interstitial cells of Cajal, in particular, have been identified in a number of disease states. Testing of colonic motor and sensory function in clinical practice continues to be a challenge due, in part, not only to the technical issues presented by accessing the organ but also to the intrinsic variability of its physiology. These have not been auspicious times for advances in the therapy of disturbed colonic motility; new agents or new applications for 'old' agents continue to be explored as are more innovative approaches such as those based on neural stimulation and cell therapy. SUMMARY Considerable progress has been made in understanding the basic pathophysiology of colonic dysmotility; clinical diagnostics and therapeutics continue to lag behind.
Collapse
|
|
24
|
Abstract
The mature enteric nervous system (ENS) is composed of many different neuron subtypes and enteric glia, which all arise from the neural crest. How this diversity is generated from neural crest-derived cells is a central question in neurogastroenterology, as defects in these processes are likely to underlie some paediatric motility disorders. Here we review the developmental appearance (the earliest age at which expression of specific markers can be localized) and birthdates (the age at which precursors exit the cell cycle) of different enteric neuron subtypes, and their projections to some targets. We then focus on what is known about the mechanisms underlying the generation of enteric neuron diversity and axon pathfinding. Finally, we review the development of the ENS in humans and the etiologies of a number of paediatric motility disorders.
Collapse
Affiliation(s)
- Marlene M Hao
- Department of Anatomy & Cell Biology, University of MelbourneParkville, Victoria, Australia
| | - Heather M Young
- Department of Anatomy & Cell Biology, University of MelbourneParkville, Victoria, Australia
| |
Collapse
|