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Updated: Jul 16, 2026
Mouse Model of Alloimmune-induced Vascular Rejection and Transplant Arteriosclerosis
Published on: May 17, 2015
Residual endotoxin induces primary graft dysfunction through ischemia/reperfusion-primed alveolar macrophages
Mahzad Akbarpour1, Emilia Lecuona1, Stephen F Chiu1
1Division of Thoracic Surgery.
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.
Insights
Residual endotoxin in donor lungs after antibiotic treatment promotes primary graft dysfunction (PGD) by activating tissue-resident alveolar macrophages (TRAMs), leading to neutrophil infiltration and lung injury post-transplant.
Area of Science:
- Immunology
- Transplantation Biology
- Pulmonary Medicine
Background:
- Bacterial pneumonia in lung donors increases the risk of primary graft dysfunction (PGD).
- Antibiotic treatment clears pathogens but may leave residual bacterial endotoxin.
- Endotoxin is a potent activator of inflammatory responses.
Purpose of the Study:
- To investigate the role of residual endotoxin in donor lungs in promoting PGD.
- To elucidate the mechanisms by which endotoxin triggers PGD.
- To identify potential therapeutic targets for preventing PGD.
Main Methods:
- Analysis of human donor lungs for endotoxin and inflammatory markers.
- Mouse models of lung transplantation with endotoxin challenge.
- Depletion of tissue-resident alveolar macrophages (TRAMs).
- Intravital imaging and compartmental staining for neutrophil recruitment.
- Bone marrow chimeric mice studies.
- Assessment of reactive oxygen species (ROS) and Toll-like receptor 4 (TLR4) expression.
Main Results:
- Residual endotoxin in donor lungs correlates with neutrophil infiltration and PGD.
- TRAMs are critical for endotoxin-induced neutrophil recruitment via TLR4/MyD88 signaling.
- Low-dose endotoxin primes TRAMs to promote PGD.
- Ischemia/reperfusion increases ROS, leading to TLR4 activation on TRAMs.
- Scavenging ROS or blocking TLR4/CD14 on TRAMs ameliorates PGD.
Conclusions:
- Residual endotoxin in donor lungs, even after antibiotic treatment, is a key driver of PGD.
- Ischemia/reperfusion primes donor TRAMs to respond to endotoxin, initiating PGD.
- Targeting TRAM activation, ROS, or TLR4 signaling offers potential therapeutic strategies for PGD prevention.
