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

Chronic Obstructive Pulmonary Disease Clinical Trial

— HYPOCITRE  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT02820064
• Other study ID #: 38RC15.303
• Status: Recruiting
• Phase: N/A
• First received: June 28, 2016
• Last updated: December 5, 2016
• Start date: January 2016
• Est. completion date: January 2017

Study information

• Verified date: December 2016
• Source: University Hospital, Grenoble
• Contact: Eric FONTAINE, Professor
• Email: efontaine[@]chu-grenoble.fr
• Is FDA regulated: No
• Health authority: France: Committee for the Protection of PersonnesFrance: Agence Nationale de Sécurité du Médicament et des produits de santé
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 30
• Est. completion date: January 2017
• Est. primary completion date: January 2017
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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 Design

Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Basic Science

Related Conditions & MeSH terms

• Anoxia
• Chronic Obstructive Pulmonary Disease
• Hypoxia
• Inflammation
• Lung Diseases
• Lung Diseases, Obstructive
• Pulmonary Disease, Chronic Obstructive

Intervention

Procedure:
• duodenal biopsy during gastroduodenal endoscopy
Patients for who and esophagogastroduodenoscopy in order to diagnose is performed. 8 duodenal biopsy specimens will be removed.

Locations

Country	Name	City	State
France	Grenoble University Hospital	Grenoble

Sponsors (2)

Lead Sponsor	Collaborator
University Hospital, Grenoble	AGIR à Dom

Country where clinical trial is conducted

France, 

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* Note: There are 31 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	OCT activity in biopsy specimens	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	No