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Effects of Hypoxia and Inflammation on Citrulline Synthesis by Ornithine Transcarbamylase in Human Enterocytes (HYPOCITRE)

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ClinicalTrials.gov Identifier: NCT02820064
Recruitment Status : Unknown
Verified December 2016 by University Hospital, Grenoble.
Recruitment status was:  Recruiting
First Posted : June 30, 2016
Last Update Posted : December 6, 2016
AGIR à Dom
Information provided by (Responsible Party):
University Hospital, Grenoble

Brief Summary:

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.

Condition or disease Intervention/treatment Phase
Hypoxia Inflammation Chronic Obstructive Pulmonary Disease Procedure: duodenal biopsy during gastroduodenal endoscopy Not Applicable

Detailed Description:

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 30 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Basic Science
Official Title: Effects of Hypoxia and Inflammation on Citrulline Synthesis by Ornithine Transcarbamylase in Human Enterocytes
Study Start Date : January 2016
Estimated Primary Completion Date : January 2017
Estimated Study Completion Date : January 2017

Arm Intervention/treatment
only one arm
Patients for who and esophagogastroduodenoscopy in order to diagnose is performed. 8 duodenal biopsy specimens will be removed.
Procedure: duodenal biopsy during gastroduodenal endoscopy
Patients for who and esophagogastroduodenoscopy in order to diagnose is performed. 8 duodenal biopsy specimens will be removed.

Primary Outcome Measures :
  1. OCT activity in biopsy specimens [ Time Frame: OCT activity in biopsies after incubation ]
    OCT activity in duodenal biopsy specimens will be measured at the end of the incubation period and compared between the 4 different groups (standard/inflammatory/hypoxic:inflammatory+hypoxic conditions)

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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.

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02820064

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Contact: Eric FONTAINE, Professor efontaine@chu-grenoble.fr

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Grenoble University Hospital Recruiting
Grenoble, France, 38043
Principal Investigator: Eric Fontaine, Professor         
Sub-Investigator: Patrick Tuvignon, MD         
Sub-Investigator: Eyraud Pierre Yves, MD         
Sub-Investigator: Mathieu Nicolas, MD         
Sub-Investigator: Picot Audrey, MD         
Sponsors and Collaborators
University Hospital, Grenoble
AGIR à Dom
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Principal Investigator: Eric Fontaine, Professor Division of clinical Nutrition-Grenoble University Hospital
The economic burden of lung disease. European white lung book 2013:16-27.
Antonione R. Nutrition in cardiac and pulmonary disease. In Basic in clinical nutrition. Sobotka L. ed. Galen, 4th ed. 485-493.
Jonker R. and al. Whole body de novo ARG production and NO synthesis are reduced in COPD patients. Clin.Nutr. 2013;32(S1):S5-S6.
Heresbach D, Napoléon B. Delchier J.C. and al. Consensus en endoscopie digestive. Acta endo (2009) 39 :206-2011.
Prat F. Recommandations de la SFED 2005 : De la pratique des biopsies oeso-gastro-duodénales.
Boustière C. Endoscopie digestive, antigoagulants, antiagrégants : faut-il encore modifier nos pratiques en 2013 ? Acta endo (2013) 43 :260-265.
Recommandations de bonnes pratiques sur les antiagrégants plaquettaires: prise en compte des risques thrombotique et hémorragique en cas de geste endoscopique HAS-SFED, oct 2012.

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Responsible Party: University Hospital, Grenoble
ClinicalTrials.gov Identifier: NCT02820064    
Other Study ID Numbers: 38RC15.303
First Posted: June 30, 2016    Key Record Dates
Last Update Posted: December 6, 2016
Last Verified: December 2016
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Additional relevant MeSH terms:
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Lung Diseases, Obstructive
Pulmonary Disease, Chronic Obstructive
Pathologic Processes
Lung Diseases
Respiratory Tract Diseases
Signs and Symptoms, Respiratory