Abstract
Rationale Exaggerated release of neutrophil extracellular traps (NET) along with decreased NET clearance and inability to remove apoptotic cells (efferocytosis) may contribute to sustained inflammation in Acute respiratory distress syndrome (ARDS). Recent studies in experimental models of ARDS have revealed the crosstalk between AMPK and HMGB1 which may contribute to effectiveness of efferocytosis, therefore reducing inflammation and ARDS severity.
Methods We investigated neutrophil and NET clearance by macrophages from control and ARDS patients and examined how bronchoalveolar lavage (BAL) fluids from control and ARDS patients could affect NET formation and efferocytosis. Metformin, an AMPK activator, and neutralizing antibody against HMGB1 were applied to improve efferocytosis and NET clearance.
Main results Neutrophils from ARDS showed a significantly reduced apoptosis. Conversely, NET formation was significantly enhanced in ARDS. Exposure of neutrophils to ARDS BAL fluid promoted NETs production, while control BALs have no effects. Macrophage engulfment of NETs and apoptotic neutrophils was diminished in ARDS patients. Notably, activation of AMPK in macrophages or neutralization of HMGB1 in BAL fluids improved efferocytosis and NET clearance.
Conclusions Restoration of AMPK activity with metformin or specific neutralization of HMGB1 in BALs fluids represent promising therapeutic strategies to decrease sustained lung inflammation during ARDS.
Footnotes
This manuscript has recently been accepted for publication in the European Respiratory Journal. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article.
Conflict of interest: Dr. Gregoire has nothing to disclose.
Conflict of interest: Dr. Uhel has nothing to disclose.
Conflict of interest: Dr. Lesouhaitier has nothing to disclose.
Conflict of interest: Dr. Gacouin has nothing to disclose.
Conflict of interest: Dr. Guirriec has nothing to disclose.
Conflict of interest: Dr. Mourcin has nothing to disclose.
Conflict of interest: Dr. Dumontet has nothing to disclose.
Conflict of interest: Dr. Chalin has nothing to disclose.
Conflict of interest: Dr. Samson has nothing to disclose.
Conflict of interest: Dr. Berthelot has nothing to disclose.
Conflict of interest: Dr. Tissot has nothing to disclose.
Conflict of interest: Dr. Kerjouan has nothing to disclose.
Conflict of interest: Dr. Jouneau has nothing to disclose.
Conflict of interest: Dr. Le Tulzo has nothing to disclose.
Conflict of interest: Dr. Tarte has nothing to disclose.
Conflict of interest: Dr. Zmijewski has nothing to disclose.
Conflict of interest: Dr. Tadié has nothing to disclose.
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