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.

  • STATUS
    Recruiting
  • End date
    Jan 15, 2023
  • participants needed
    51
  • sponsor
    Centre Hospitalier Universitaire Dijon
Updated on 15 February 2021
antibiotics
chest x-ray
dyspnea
x-rays
respiratory distress
FIO2
assisted ventilation
polymicrobial infection

Summary

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.

Details
Condition Pulmonary Disease, Bronchoalveolar Lavage, Artificial respiration, Lung Disease, pulmonary diseases, lung diseases, pulmonary disorders, mechanical ventilation
Treatment bronchoalveolar lavage fluid (BAL), Venous blood
Clinical Study IdentifierNCT03955887
SponsorCentre Hospitalier Universitaire Dijon
Last Modified on15 February 2021

Eligibility

Yes No Not Sure

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 < 35C or 38C 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 37.8C)
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
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