Residual endotoxin induces primary graft dysfunction through ischemia/reperfusion-primed alveolar macrophages.

The Journal of Clinical Investigation
Mahzad AkbarpourAnkit Bharat

Abstract

Despite the widespread use of antibiotics, bacterial pneumonias in donors strongly predispose to the fatal syndrome of primary graft dysfunction (PGD) following lung transplantation. We report that bacterial endotoxin persists in human donor lungs after pathogen is cleared with antibiotics and is associated with neutrophil infiltration and PGD. In mouse models, depletion of tissue-resident alveolar macrophages (TRAMs) attenuated neutrophil recruitment in response to endotoxin as shown by compartmental staining and intravital imaging. Bone marrow chimeric mice revealed that neutrophils were recruited by TRAM through activation of TLR4 in a MyD88-dependent manner. Intriguingly, low levels of endotoxin, insufficient to cause donor lung injury, promoted TRAM-dependent production of CXCL2, increased neutrophil recruitment, and led to PGD, which was independent of donor NCMs. Reactive oxygen species (ROS) increased in human donor lungs starting from the warm-ischemia phase and were associated with increased transcription and translocation to the plasma membrane of TLR4 in donor TRAMs. Consistently, scavenging ROS or inhibiting their production to prevent TLR4 transcription/translocation or blockade of TLR4 or coreceptor CD14 on donor...Continue Reading

Citations

Dec 18, 2020·Frontiers in Immunology·Farideh OrdikhaniJordi Ochando

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Datasets Mentioned

BETA
GM-CSF
GSE122960
GSE135893

Methods Mentioned

BETA
bronchoalveolar lavage
PCR
RNA-Seq
flow cytometry
biopsies
scRNA-Seq
bronchoalveolar
lavage
flow
Assay

Software Mentioned

PRIMER
ImageWarp
GOrilla
GraphPad
R
EdgR
FeaturePlot
Zen
Seurat
Nexcelom

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