Dexmedetomidine attenuates sepsis-associated acute lung injury by regulating macrophage efferocytosis through the ROS/ADAM10/AXL pathway.
Int Immunopharmacol
; 142(Pt A): 112832, 2024 Dec 05.
Article
in En
| MEDLINE
| ID: mdl-39362816
ABSTRACT
BACKGROUND:
The lungs are highly susceptible to damage during sepsis, with severe lung injury potentially progressing to acute respiratory distress syndrome and even fatal sepsis. Effective efferocytosis of apoptotic cells is crucial in alleviating inflammation and tissue injury.METHODS:
We established a septic lung injury mouse model via intraperitoneal injection of lipopolysaccharide. Lung injury was assessed by histology, immunofluorescence, neutrophil immunohistochemistry staining, and cytokine detection. We extracted alveolar macrophages by bronchoalveolar lavage and primary macrophages from mouse bone marrow to investigate the regulatory effects of Dexmedetomidine (DEX) on efferocytosis. We further validated the molecular mechanisms underlying the regulation of macrophage efferocytosis by DEX through knockdown of AXL expression. Additionally, we examined the efferocytic ability of monocytes isolated from patients.RESULTS:
We discovered that DEX treatment effectively alleviated pulmonary injury and inflammation. Lipopolysaccharide reduced macrophage efferocytosis and AXL expression which were reversed by DEX. We also found DEX inhibited the increased activation of A Disintegrin And Metalloproteinase 10 (ADAM10) and the production of soluble AXL. Moreover, our findings demonstrated that DEX decreased the elevated ROS production linked to higher ADAM10 activation. Blocking AXL negated DEX's benefits on efferocytosis and lung protection. Efferocytosis in monocytes from septic lung injury patients was notably lower than in healthy individuals.CONCLUSION:
Our findings demonstrated that DEX treatment effectively reduces septic lung injury by promoting macrophage efferocytosis through ROS/ADAM10/AXL signaling pathwway.Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Phagocytosis
/
Lipopolysaccharides
/
Proto-Oncogene Proteins
/
Reactive Oxygen Species
/
Receptor Protein-Tyrosine Kinases
/
Sepsis
/
Dexmedetomidine
/
Acute Lung Injury
/
ADAM10 Protein
/
Axl Receptor Tyrosine Kinase
Limits:
Animals
/
Humans
/
Male
Language:
En
Journal:
Int Immunopharmacol
/
Int. immunopharmacol
/
International immunopharmacology
Journal subject:
ALERGIA E IMUNOLOGIA
/
FARMACOLOGIA
Year:
2024
Document type:
Article
Affiliation country:
China
Country of publication:
Netherlands