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

December 5, 2016 updated by: University Hospital, Grenoble

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.

Study Overview

Status

Unknown

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Anticipated)

30

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Locations

  • France
      • Grenoble, France, 38043
        • Recruiting
        • Grenoble University Hospital
        • 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

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Basic Science
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Other: 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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)
OCT activity in biopsies after incubation

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University Hospital, Grenoble

Collaborators

AGIR à Dom

Investigators

  • Principal Investigator: Eric Fontaine, Professor, Division of clinical Nutrition-Grenoble University Hospital

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

January 1, 2016

Primary Completion (Anticipated)

January 1, 2017

Study Completion (Anticipated)

January 1, 2017

Study Registration Dates

First Submitted

June 28, 2016

First Submitted That Met QC Criteria

June 28, 2016

First Posted (Estimate)

June 30, 2016

Study Record Updates

Last Update Posted (Estimate)

December 6, 2016

Last Update Submitted That Met QC Criteria

December 5, 2016

Last Verified

December 1, 2016

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 38RC15.303

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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