Ignite Creation Date:
2024-05-06 @ 1:11 PM
Last Modification Date:
2024-10-26 @ 1:10 PM
Study NCT ID:
NCT03955887
Status:
TERMINATED
Last Update Posted:
2023-11-13
First Post:
2019-05-16
Brief Title:
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
Sponsor:
Centre Hospitalier Universitaire Dijon
Organization:
Centre Hospitalier Universitaire Dijon
Study Overview
Official Title:
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:
TERMINATED
Status Verified Date:
2023-11
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
technical difficulties
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
PNEUMOCHONDRIE
Brief 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 Sp 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 ie 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 Sp 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 infectionMV 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 MVpneumopathy aggression in order to understand its possible impact on the effectiveness of the hosts immune response In a personalized medicine approach these data would open up prospects for targeted therapies capable of activating mitochondrial biogenesis andor modulating mitophagia to prevent organ dysfunction and mortality during severe CALs treated with antibiotic therapy
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 Sp 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 ie 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 Sp 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 infectionMV 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 MVpneumopathy aggression in order to understand its possible impact on the effectiveness of the hosts immune response In a personalized medicine approach these data would open up prospects for targeted therapies capable of activating mitochondrial biogenesis andor modulating mitophagia to prevent organ dysfunction and mortality during severe CALs treated with antibiotic therapy
Detailed Description:
None
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None