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 TRAMs prevented neutrophil recruitment in response to endotoxin and ameliorated PGD. Our studies demonstrate that residual endotoxin after successful treatment of donor bacterial pneumonia promotes PGD through ischemia/reperfusion-primed donor TRAMs.
Original language | English (US) |
---|---|
Pages (from-to) | 4456-4469 |
Number of pages | 14 |
Journal | Journal of Clinical Investigation |
Volume | 140 |
Issue number | 8 |
DOIs | |
State | Published - Aug 3 2020 |
Funding
This work was supported by NIH grants HL145478, HL147290, and HL147575 (to AB), NIH grants P01 AG049665 and P01 HL071643 and Department of the Army grant W81XWH-15-1-0215 (to GRSB and AVM), and NIH grants 5P01AG049665 and 5P01HL071643 (to NSC). The Northwestern University Flow Cytometry Core Facility is supported by a Cancer Center Support Grant (NCI CA060553). We thank Suchitra Swaminathan, director of the flow cytometry core facility, for providing professional technical assistance and Elena Susan for administrative assistance and submission of the manuscript.
ASJC Scopus subject areas
- General Medicine