Translational neuropharmacology: the use of human isolated gastrointestinal tissues

Sanger, Gareth J.; Broad, John; Kung, Victor; Knowles, CH

doi:10.1111/j.1476-5381.2012.02198.x

Cited by 34 publications

(48 citation statements)

References 104 publications

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“…Extrapolation of data from animal models is complicated by the many human‐specific signalling pathways involved in the regulation of human intestinal functions (Sanger et al . ).…”

Section: Introductionmentioning

confidence: 97%

Neural influences on human intestinal epithelium in vitro

Krueger

Michel

Zeller³

et al. 2015

The Journal of Physiology

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Key pointsr We present the first systematic and, up to now, most comprehensive evaluation of the basic features of epithelial functions, such as basal and nerve-evoked secretion, as well as tissue resistance, in over 2200 surgical specimens of human small and large intestine.r We found no evidence for impaired nerve-evoked epithelial secretion or tissue resistance with age or disease pathologies (stomach, pancreas or colon cancer, polyps, diverticulitis, stoma reversal). This indicates the validity of future studies on epithelial secretion or resistance that are based on data from a variety of surgical specimens.r ACh mainly mediated nerve-evoked and basal secretion in the small intestine, whereas vasoactive intestinal peptide and nitric oxide were the primary pro-secretory transmitters in the large intestine.r The results of the present study revealed novel insights into regional differences in nerve-mediated secretion in the human intestine and comprise the basis by which to more specifically target impaired epithelial functions in the diseased gut.Abstract Knowledge on basic features of epithelial functions in the human intestine is scarce. We used Ussing chamber techniques to record basal tissue resistance (R-basal) and short circuit currents (I SC; secretion) under basal conditions (I SC -basal) and after electrical field stimulation (I SC -EFS) of nerves in 2221 resectates from 435 patients. I SC -EFS was TTX-sensitive and of comparable magnitude in the small and large intestine. I SC -EFS or R-basal were not influenced by the patients' age, sex or disease pathologies (cancer, polyps, diverticulitis). Ion substitution, bumetanide or adenylate cyclase inhibition studies suggested that I SC -EFS depended on epithelial cAMP-driven chloride and bicarbonate secretion but not on amiloride-sensitive sodium absorption. Although atropine-sensitive cholinergic components prevailed for I SC -EFS of the duodenum, jejunum and ileum, PG97-269-sensitive [vasoactive intestinal peptide (VIP) receptor 1 antagonist] VIPergic together with L-NAME-sensitive nitrergic components dominated the I SC -EFS in colonic preparations. Differences in numbers of cholinergic or VIPergic neurons, sensitivity of epithelial muscarinic or VIP receptors, or stimulus frequency-dependent transmitter release were not responsible for the region-specific transmitter contribution to I SC -EFS. Instead, the low atropine-sensitivity of I SC -EFS in the colon was the result of high cholinesterase activity because neostigmine revealed cholinergic components. Colonic I SC -EFS remained unchanged after tachykinin, P2X, P2Y or A1 and A2 receptor blockade. R-basal was smaller and I SC -basal was higher in the small intestine. TTX and bumetanide decreased I SC -basal in all regions, suggesting nerve-dependent secretory tone. I SC -basal was atropine-sensitive in the small intestine and PG97-269-sensitive in the large intestine. This comprehensive study reveals novel insights into region-specific nerve-mediated secretion in the human small and large intestine.

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“…Extrapolation of data from animal models is complicated by the many human‐specific signalling pathways involved in the regulation of human intestinal functions (Sanger et al . ).…”

Section: Introductionmentioning

confidence: 97%

Neural influences on human intestinal epithelium in vitro

Krueger

Michel

Zeller³

et al. 2015

The Journal of Physiology

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“…Although the basic functions of the gastrointestinal tract are similar between human and animals, there are significant anatomical and functional differences. Results from animal studies should not be assumed to translate directly into human tissue (40,41).…”

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confidence: 99%

Neurally mediated propagating discrete clustered contractions superimposed on myogenic ripples in ex vivo segments of human ileum

Kuizenga

Sia

Dodds

et al. 2015

American Journal of Physiology-Gastrointestinal and Liver Physi

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Kuizenga MH, Sia TC, Dodds KN, Wiklendt L, Arkwright JW, Thomas A, Brookes SJ, Spencer NJ, Wattchow DA, Dinning PG, Costa M. Neurally mediated propagating discrete clustered contractions superimposed on myogenic ripples in ex vivo segments of human ileum. Am J Physiol Gastrointest Liver Physiol 308: G1-G11, 2015. First published November 13, 2014; doi:10.1152/ajpgi.00230.2014.-Narrow muscle strips have been extensively used to study intestinal contractility. Larger specimens from laboratory animals have provided detailed understanding of mechanisms that underlie patterned intestinal motility. Despite progress in animal tissue, investigations of motor patterns in large, intact specimens of human gut ex vivo have been sparse. In this study, we tested whether neurally dependent motor patterns could be detected in isolated specimens of intact human ileum. Specimens (n ϭ 14; 7-30 cm long) of terminal ileum were obtained with prior informed consent from patients undergoing colonic surgery for removal of carcinomas. Preparations were set up in an organ bath with an array of force transducers, a fiberoptic manometry catheter, and a video camera. Spontaneous and distension-evoked motor activity was recorded, and the effects of lidocaine, which inhibits neural activity, were studied. Myogenic contractions (ripples) occurred in all preparations (6.17 Ϯ 0.36/min). They were of low amplitude and formed complex patterns by colliding and propagating in both directions along the specimen at anterograde velocities of 4.1 Ϯ 0.3 mm/s and retrogradely at 4.9 Ϯ 0.6 mm/s. In five specimens, larger amplitude clusters of contractions were seen (discrete clustered contractions), which propagated aborally at 1.05 Ϯ 0.13 mm/s and orally at 1.07 Ϯ 0.09 mm/s. These consisted of two to eight phasic contractions that aligned with ripples. These motor patterns were abolished by addition of lidocaine (0.3 mM). The ripples continued unchanged in the presence of this neural blocking agent. These results demonstrate that both myogenic and neurogenic motor patterns can be studied in isolated specimens of human small intestine. small intestine; motor patterns; enteric nervous system; myogenic; neurogenic PROPULSION AND MIXING OF INTESTINAL CONTENTS along the digestive tract are essential for normal digestion. The motor patterns underlying these functions are due to the coordinated contractions and relaxations of the smooth muscle layers of the intestine. The internal circular smooth muscle layer and the external longitudinal smooth muscle layer are controlled by two main mechanisms. Myogenic activity is driven by the nonneural pacemaker cells, the interstitial cells of Cajal. Neurogenic control is mediated by circuits in the enteric nervous system. These two types of activity combine to generate the motor patterns that mix and propel luminal content (14,29). Most of our understanding of these mechanisms has been derived from animal studies. Although the basic functions of the gastrointestinal tract are similar between human and animals, there are si...

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“…An in vitro mouse model measuring colonic peristaltic motor activity and the standard rodent charcoal meal GI transit model were found to be poor predictors of the expected motility changes associated with diarrhea or constipation observed in the clinic. Taken together, differences in functional and molecular pathways controlling GI function between rodents and human potentially compromise the translational value of drug effects from laboratory animals to humans (Sanger et al 2011(Sanger et al , 2013. Therefore, there is a need to develop preclinical model(s) with better predictive value for early screening of GI motility liability of novel compounds in development (Keating et al 2014).…”

Section: Gastrointestinal Motility and Transitmentioning

confidence: 97%

“…Isolated human tissue resected at the time of operation can be used immediately or after storage overnight at 4 C in an appropriate solution without significant changes in the viability of the specimen (Bennett and Whitney 1966;Al-Saffar and Hellstr€ om 2001). However, experiments with fresh human tissue are relatively uncommon because access to human tissue can be limited and researchers have to confront issues like ethical, legal age, gender, life style, genetic background, and disease (Sanger et al 2011(Sanger et al , 2013. Furthermore, the use of anesthetic drugs and preoperative medications and the impact of ischemia on removed tissues for use in research are also considerations.…”

Section: In Vitro Modelsmentioning

confidence: 98%

Gastrointestinal Safety Pharmacology in Drug Discovery and Development

Al‐Saffar

Costa²,

Delaunois³

et al. 2015

Principles of Safety Pharmacology

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Although the basic structure of the gastrointestinal tract (GIT) is similar across species, there are significant differences in the anatomy, physiology, and biochemistry between humans and laboratory animals, which should be taken into account when conducting a gastrointestinal (GI) assessment. Historically, the percentage of cases of drug attrition associated with GI-related adverse effects is small; however, this incidence has increased over the last few years. Drug-related GI effects are very diverse, usually functional in nature, and not limited to a single pharmacological class. The most common GI signs are nausea and vomiting, diarrhea, constipation, and gastric ulceration. Despite being generally not life-threatening, they can greatly affect patient compliance and quality of life. There is therefore a real need for improved and/or more extensive GI screening of candidate drugs in preclinical development, which may help to better predict clinical effects. Models to identify drug effects on GI function cover GI motility, nausea and emesis liability, secretory function (mainly gastric secretion), and absorption aspects. Both in vitro and in vivo assessments are described in this chapter. Drug-induced effects on GI function can be assessed in stand-alone safety pharmacology studies or as endpoints integrated into toxicology studies. In silico approaches are also being developed, such as the gut-on-a-chip model, but await further optimization and validation before routine use in drug development. GI injuries are still in their infancy with regard to biomarkers, probably due to their greater diversity. Nevertheless, several potential blood, stool, and breath biomarkers have been investigated. However, additional validation studies are necessary to assess the relevance of these biomarkers and their predictive value for GI injuries.

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Translational neuropharmacology: the use of human isolated gastrointestinal tissues

Cited by 34 publications

References 104 publications

Neural influences on human intestinal epithelium in vitro

Neural influences on human intestinal epithelium in vitro

Neurally mediated propagating discrete clustered contractions superimposed on myogenic ripples in ex vivo segments of human ileum

Gastrointestinal Safety Pharmacology in Drug Discovery and Development

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