Effects of Hypoxia and Inflammation on Citrulline Synthesis by Ornithine Transcarbamylase in Human Enterocytes
NCT ID: NCT02820064
Last Updated: 2016-12-06
Study Results
Results pending
The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.
Basic Information
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Recruitment Status
UNKNOWN
Clinical Phase
NA
Total Enrollment
30 participants
Study Classification
INTERVENTIONAL
Study Start Date
2016-01-31
Study Completion Date
2017-01-31
Brief Summary
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Chronic Obstructive Pulmonary Disease (COPD) is characterized by chronic systemic hypoxia and low-grade inflammation as well as by an alteration of arginine (ARG) metabolism. As ARG is synthetized from circulating citrulline (CIT), an alteration of CIT homeostasis, particularly its production by ornithine transcarbamylase (OCT) in small intestine could be involved. We hypothesized that hypoxia +/- inflammation, classically associated to COPD, has effects on OCT regulation in enterocytes.
This study aims at exploring the effects of hypoxia and inflammation on the production of citrulline by ornithine transcarbamylase (OTC) activity in enterocytes from explant cultures of duodenal tissue.
This study aims at exploring the effects of hypoxia and inflammation on the production of citrulline by ornithine transcarbamylase (OTC) activity in enterocytes from explant cultures of duodenal tissue.
Detailed Description
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Citrulline is an amino-acid almost exclusively released by the small intestine after its synthesis from glutamine by the OTC in enterocytes. Citrulline from the small intestine is released into the portal vena and, because it does not enter hepatocytes, it reaches the systemic circulation to be metabolized in arginine by kidneys. By this way, is an important source of endogenous ARG. Moreover, evidence suggests that circulating citrulline could have a direct action on the regulation of muscle protein synthesis. Therefore, the administration of citrulline might be an interesting nutritional strategy to preserve or restore muscle mass and function. Muscle mass is a determinant of respiratory function and muscle weakness explains for a large part morbidity and mortality in patients suffering from Chronic Obstructive Pulmonary Disease (COPD).
Evidence suggests that citrulline plasmatic levels would be lower in several states involving systemic inflammation and hypoxia. Indeed, it has been observed in rats that hypoxia leads to a sharp decline in plasma CIT concentration and also in human (hypocitrullinemia has been observed in Intensive Care Unit patients and in subjects suffering from sepsis and trauma) but the cause of relationship is not yet established. Therefore, it may be supposed that a decreased plasma CIT level could be responsible for a decrease in de novo ARG synthesis leading to an impairment of NO production (endothelial dysfunction) in these pathological situations.
Because chronic hypoxia and systemic inflammation are both systemic traits of patients suffering from COPD, the fact that hypoxia and/or systemic inflammation might directly affect OCT, decreasing intestinal citrulline production which, in turn, could contribute to endothelial dysfunction and muscle weakness is considered.
In order to explore this hypothesis, the potential consequences of hypoxia and inflammation (alone or in association) on citrulline synthesis by the OCT in human enterocytes will be determined, thanks to an "explant" culture model of duodenal tissue. Duodenal biopsies will be removed during oesophago-gastro-duodenoscopies performed in the Hepato-gastro-enterology unit of Grenoble University Hospital, among patients expected to undergo a gastroscopy for any diagnostic purpose. 30 patients will be selected during a period of 6 months. After complete information and written agreement, 8 biopsy specimens will be removed from the duodenum of each patient and processed for organ culture.
Then, duodenal biopsies will be incubated in the presence or not of cytokines and exposed or not to hypoxia. Indeed, 4 groups will be constituted: a control group (no stimulus), a group exposed to hypoxic conditions, a group exposed to inflammatory conditions (cytokines) and a group exposed to both hypoxic an inflammatory conditions.
As primary endpoint, for each group, the OTC activity and the citrulline production in the culture medium will be studied.
Evidence suggests that citrulline plasmatic levels would be lower in several states involving systemic inflammation and hypoxia. Indeed, it has been observed in rats that hypoxia leads to a sharp decline in plasma CIT concentration and also in human (hypocitrullinemia has been observed in Intensive Care Unit patients and in subjects suffering from sepsis and trauma) but the cause of relationship is not yet established. Therefore, it may be supposed that a decreased plasma CIT level could be responsible for a decrease in de novo ARG synthesis leading to an impairment of NO production (endothelial dysfunction) in these pathological situations.
Because chronic hypoxia and systemic inflammation are both systemic traits of patients suffering from COPD, the fact that hypoxia and/or systemic inflammation might directly affect OCT, decreasing intestinal citrulline production which, in turn, could contribute to endothelial dysfunction and muscle weakness is considered.
In order to explore this hypothesis, the potential consequences of hypoxia and inflammation (alone or in association) on citrulline synthesis by the OCT in human enterocytes will be determined, thanks to an "explant" culture model of duodenal tissue. Duodenal biopsies will be removed during oesophago-gastro-duodenoscopies performed in the Hepato-gastro-enterology unit of Grenoble University Hospital, among patients expected to undergo a gastroscopy for any diagnostic purpose. 30 patients will be selected during a period of 6 months. After complete information and written agreement, 8 biopsy specimens will be removed from the duodenum of each patient and processed for organ culture.
Then, duodenal biopsies will be incubated in the presence or not of cytokines and exposed or not to hypoxia. Indeed, 4 groups will be constituted: a control group (no stimulus), a group exposed to hypoxic conditions, a group exposed to inflammatory conditions (cytokines) and a group exposed to both hypoxic an inflammatory conditions.
As primary endpoint, for each group, the OTC activity and the citrulline production in the culture medium will be studied.
Conditions
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Hypoxia
Inflammation
Chronic Obstructive Pulmonary Disease
Study Design
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Allocation Method
NA
Intervention Model
SINGLE_GROUP
Primary Study Purpose
BASIC_SCIENCE
Blinding Strategy
NONE
Study Groups
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only one arm
Patients for who and esophagogastroduodenoscopy in order to diagnose is performed. 8 duodenal biopsy specimens will be removed.
Group Type
OTHER
duodenal biopsy during gastroduodenal endoscopy
Intervention Type
PROCEDURE
Patients for who and esophagogastroduodenoscopy in order to diagnose is performed. 8 duodenal biopsy specimens will be removed.
Interventions
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duodenal biopsy during gastroduodenal endoscopy
Patients for who and esophagogastroduodenoscopy in order to diagnose is performed. 8 duodenal biopsy specimens will be removed.
Intervention Type
PROCEDURE
Eligibility Criteria
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Inclusion Criteria
* Digestive disease known or suspected which justify an oeso-gastro-endoscopy with digestive biopsies, excepted a disease with duodenal localization known or strongly suspected.
* Gastroscopy performed under general anaesthesia
* Patient's written agreement obtained
Non inclusion-criteria:
* Age \< 18
* Therapeutical endoscopy (that is to say when a therapeutical act will be performed as balloon dilation, digestive or biliary prosthesis, drainage, diverticulotomy, polypectomy, variceal ligation...) either expected or
* Duodenal pathology (known or strongly suspected with the clinical and biological elements)
* Duodenal biopsies are not allowed to be performed: vascular lesions, digestive haemorrhage, clotting disorder.
* Antiplatelet drug and anticoagulant drug
* Lack of written agreement
* Subjects hospitalized in an emergency state or without agreement
* Subjects who cannot be contacted in emergency.
* Gastroscopy performed under general anaesthesia
* Patient's written agreement obtained
Non inclusion-criteria:
* Age \< 18
* Therapeutical endoscopy (that is to say when a therapeutical act will be performed as balloon dilation, digestive or biliary prosthesis, drainage, diverticulotomy, polypectomy, variceal ligation...) either expected or
* Duodenal pathology (known or strongly suspected with the clinical and biological elements)
* Duodenal biopsies are not allowed to be performed: vascular lesions, digestive haemorrhage, clotting disorder.
* Antiplatelet drug and anticoagulant drug
* Lack of written agreement
* Subjects hospitalized in an emergency state or without agreement
* Subjects who cannot be contacted in emergency.
Exclusion Criteria
subjects will be excluded from the study:
* if an unexpected therapeutic act has to be performed during the endoscopy
* if duodenal duodenal atrophy or lesions are discovered during the endoscopy
* if duodenal lesions are discoverd at the histological examination
* if an unexpected therapeutic act has to be performed during the endoscopy
* if duodenal duodenal atrophy or lesions are discovered during the endoscopy
* if duodenal lesions are discoverd at the histological examination
Minimum Eligible Age
18 Years
Eligible Sex
ALL
Accepts Healthy Volunteers
No
Sponsors
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AGIR à Dom
OTHER
Sponsor Role
collaborator
University Hospital, Grenoble
OTHER
Sponsor Role
lead
Responsible Party
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Responsibility Role
SPONSOR
Principal Investigators
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Eric Fontaine, Professor
Role: PRINCIPAL_INVESTIGATOR
Division of clinical Nutrition-Grenoble University Hospital
Locations
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Grenoble University Hospital
Grenoble, , France
Site Status
RECRUITING
Countries
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France
Central Contacts
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References
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Windmueller HG, Spaeth AE. Source and fate of circulating citrulline. Am J Physiol. 1981 Dec;241(6):E473-80. doi: 10.1152/ajpendo.1981.241.6.E473.
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BACKGROUND
Breuillard C, Cynober L, Moinard C. Citrulline and nitrogen homeostasis: an overview. Amino Acids. 2015 Apr;47(4):685-91. doi: 10.1007/s00726-015-1932-2. Epub 2015 Feb 13.
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Osowska S, Moinard C, Neveux N, Loi C, Cynober L. Citrulline increases arginine pools and restores nitrogen balance after massive intestinal resection. Gut. 2004 Dec;53(12):1781-6. doi: 10.1136/gut.2004.042317.
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Osowska S, Duchemann T, Walrand S, Paillard A, Boirie Y, Cynober L, Moinard C. Citrulline modulates muscle protein metabolism in old malnourished rats. Am J Physiol Endocrinol Metab. 2006 Sep;291(3):E582-6. doi: 10.1152/ajpendo.00398.2005. Epub 2006 Apr 11.
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Faure C, Raynaud-Simon A, Ferry A, Dauge V, Cynober L, Aussel C, Moinard C. Leucine and citrulline modulate muscle function in malnourished aged rats. Amino Acids. 2012 Apr;42(4):1425-33. doi: 10.1007/s00726-011-0841-2. Epub 2011 Feb 23.
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Other Identifiers
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38RC15.303
Identifier Type: -
Identifier Source: org_study_id