Mitochondrial Dysfunction of Alveolar and Circulating Immune Cells During Acute Respiratory Distress Syndrome: Impact of Infectious Aggression and Alveolar Stretching as a Result of Mechanical Ventilation. (PNEUMOCHONDRIE)

Sepsis leads to a deregulated host response that can lead to organ failure. During sepsis, experimental and clinical data suggest the occurrence of mitochondrial dysfunctions, particularly in circulating muscle and monocytes, which may contribute to organ failure and death.

Lower respiratory infection is the leading cause of death from infectious causes. Mechanical ventilation (MV) is required in 20% of cases of bacterial pneumopathy with Streptococcus pneumoniae (S.p.) , with mortality reaching 50%. There are then frequently criteria for acute respiratory distress syndrome (ARDS), combining bilateral lung involvement and marked hypoxemia.

Cyclic stretching of lung cells induced by MV causes sterile inflammation and tissue damage (i.e. ventilator-induced lung injury [VILI]), which can cause cellular dysfunction that alter the immune response, particularly during ARDS. This is why the application of a so-called protective MV is then required. However, this does not prevent about one-third of patients from showing signs of alveolar overdistension, as evidenced by an increase in motor pressure (MP) (MP≥ 15 cmH2O), associated with an increase in mortality.

The deleterious effects of MV could be explained by the occurrence of mitochondrial abnormalities. Indeed, the cyclic stretching of lung cells leads to dysfunction in the respiratory chain and the production of free oxygen radicals (FOS), altering membrane permeability. These phenomena could promote VILI, facilitate the translocation of bacteria from the lung to the systemic compartment and lead to alterations in immune response.

In our model of S.p. pneumopathy in rabbits, animals on MV develop more severe lung disorders (lack of pulmonary clearance of bacteria, bacterial translocation in the blood, excess mortality), compared to animals on spontaneous ventilation (SV). Intracellular pulmonary mitochondrial DNA (mtDNA) concentrations, a reflection of the mitochondrial pool, are significantly decreased in ventilated rabbits compared to SV rabbits and in infected rabbits compared to uninfected rabbits. At the same time, the mitochondrial content of circulating cells decreased early (H8) in all infected rabbits, but was only restored in rabbits in SV, those who survived pneumonia (Blot et al, poster ECCMID 2015, submitted article). These data suggest an alteration in the mechanisms that restore mitochondrial homeostasis (mitochondrial biogenesis and mitophagy) during the dual infection/MV agression, which may explain the observed excess mortality. Other work by our team illustrates the importance of these phenomena by showing in a mouse model of polymicrobial infection that inhibition of mitophagia in macrophages promotes survival (Patoli et al, in preparation). Human data on this subject are non-existent.

The phenomena of mitochondrial dysfunction nevertheless deserve to be explored in humans during the combined MV/pneumopathy aggression in order to understand its possible impact on the effectiveness of the host's immune response. In a personalized medicine approach, these data would open up prospects for targeted therapies, capable of activating mitochondrial biogenesis and/or modulating mitophagia, to prevent organ dysfunction and mortality during severe CALs treated with antibiotic therapy.

Study Overview

• Status: Terminated
• Conditions: Lung Diseases; Mechanical Ventilation; Bronchoalveolar Lavage
• Intervention / Treatment: Biological: bronchoalveolar lavage fluid (BAL); Biological: Venous blood

• Study Type: Observational
• Enrollment (Actual): 28

Contacts and Locations

• Study Contact: Name: Mathieu Blot; Phone Number: +33 03 80 29 33 05; Email: mathieu.blot@chu-dijon.fr

Study Locations

• France
  • Dijon, France, 21000
    • Chu Dijon Bourogne

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Patients admited in the Intensive Care Unit and the Pneumology Intensive Care Unit of the CHU Dijon Bourgogne

Description

Inclusion Criteria:

• Patient who has given his non-opposition (or non-opposition obtained from close relative of ventilated patients, who will be informed as soon as possible).
• Adult patient

• Group 1: patient with:

  • Acute pneumonitis defined by: Signs and acute symptoms of pneumonia (new or worsening within the last 7 days), at least 2 of which are:

    • Coughing
    • Purulent sputum
    • Dyspnea
    • Chest pain
    • Temperature < 35°C or ≥ 38°C And a new pulmonary radiological infiltrate (x-ray or CT scan on admission)
  • Not acquired under mechanical ventilation
  • Complicated from ARDS according to the new Berlin definition, Chest x-ray finding bilateral parenchymal opacities not fully explained by pleural effusions, nodules or atelectasis. Respiratory distress not explained by cardiac dysfunction or overfilling. An echocardiogram will be performed in case of diagnostic uncertainty. PaO2/FiO2 report < 300 and PEP ≥ 5 cmH2O
  • Requiring the use of MV.
  • With a diagnostic BAL performed within 72 hours of the start of the MV

• Group 2: Patients:

  • No fever during the last 15 days (reported or measured ≥ 37.8°C).
  • Not under MV,
  • Undergoing BAL for a reason other than acute infection (e.g. chronic interstitial syndrome, nodule or lung mass).

Exclusion Criteria:

• Patient not affiliated to the national health insurance system
• Major under judicial protection
• Pregnant, parturient or breastfeeding woman
• Known primary or secondary immune deficiency (radiotherapy, chemotherapy, immunosuppressive therapy or systemic corticosteroid therapy (>10mg/day prednisone equivalent for more than 7 days) within 6 months before inclusion, HIV infection, primary cellular immune deficiency)
• Patients with treatment known to modulate mitochondrial function, biogenesis and/or mitophagia (chloroquine, hydroxychloroquine, rapamycin, carbamazepine, resveratrol, metformin, sildenafil)
• Patients with pulmonary fibrosis or cystic fibrosis known to be associated with mitochondrial alterations

Study Plan

How is the study designed?

Design Details

• Observational Models: Case-Control
• Time Perspectives: Prospective

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Experimental; Patients with severe acute lung disease requiring mechanical ventilation	Biological: bronchoalveolar lavage fluid (BAL); Recovery of a 10 mL volume of BAL fluid, performed as part of patient care; Biological: Venous blood; Collection of 3 additional blood tubes (12 ml) during a blood sample taken as part of patient care
Control; Patients receiving routine bronchoalveolar lavage for a pathology not suspected of acute infection	Biological: bronchoalveolar lavage fluid (BAL); Recovery of a 10 mL volume of BAL fluid, performed as part of patient care; Biological: Venous blood; Collection of 3 additional blood tubes (12 ml) during a blood sample taken as part of patient care

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Active mitochondria content of alveolar macrophages	Through study completion, an average of 19 months

Collaborators and Investigators

• Sponsor: Centre Hospitalier Universitaire Dijon

Publications and helpful links

General Publications

• Blot M, Jacquier M, Aho Glele LS, Beltramo G, Nguyen M, Bonniaud P, Prin S, Andreu P, Bouhemad B, Bour JB, Binquet C, Piroth L, Pais de Barros JP, Masson D, Quenot JP, Charles PE; Pneumochondrie study group. CXCL10 could drive longer duration of mechanical ventilation during COVID-19 ARDS. Crit Care. 2020 Nov 2;24(1):632. doi: 10.1186/s13054-020-03328-0. Erratum In: Crit Care. 2021 Apr 13;25(1):143.

Study record dates

Study Major Dates

• Study Start (Actual): June 11, 2019
• Primary Completion (Actual): May 7, 2020
• Study Completion (Actual): May 7, 2020

Study Registration Dates

• First Submitted: May 16, 2019
• First Submitted That Met QC Criteria: May 16, 2019
• First Posted (Actual): May 20, 2019

Study Record Updates

• Last Update Posted (Estimated): November 13, 2023
• Last Update Submitted That Met QC Criteria: November 9, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Behavioral Symptoms; Respiratory Tract Diseases; Respiration Disorders; Infant, Newborn, Diseases; Lung Injury; Infant, Premature, Diseases; Aggression; Lung Diseases; Respiratory Distress Syndrome; Respiratory Distress Syndrome, Newborn; Acute Lung Injury; Molecular Mechanisms of Pharmacological Action; Chelating Agents; Sequestering Agents; Dimercaprol
• Other Study ID Numbers: BLOT MSD-APJ 2018

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No