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Residual endotoxin induces primary graft dysfunction through ischemia/reperfusion-primed alveolar macrophages
Mahzad Akbarpour, … , G.R. Scott Budinger, Ankit Bharat
Mahzad Akbarpour, … , G.R. Scott Budinger, Ankit Bharat
Published May 19, 2020
Citation Information: J Clin Invest. 2020;130(8):4456-4469. https://doi.org/10.1172/JCI135838.
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Research Article Immunology Transplantation

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

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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.

Authors

Mahzad Akbarpour, Emilia Lecuona, Stephen F. Chiu, Qiang Wu, Melissa Querrey, Ramiro Fernandez, Félix L. Núñez-Santana, Haiying Sun, Sowmya Ravi, Chitaru Kurihara, James M. Walter, Nikita Joshi, Ziyou Ren, Scott C. Roberts, Alan Hauser, Daniel Kreisel, Wenjun Li, Navdeep S. Chandel, Alexander V. Misharin, Thalachallour Mohanakumar, G.R. Scott Budinger, Ankit Bharat

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Figure 3

Influx of neutrophils into LPS-treated lung is abrogated by selective depletion of TRAMs.

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Influx of neutrophils into LPS-treated lung is abrogated by selective de...
(A) CXCL2 chemokine levels in BALF of LPS-treated mice injected with PBS-lip or Clo-lip i.t. (n = 5–6). (B) Quantification of neutrophil infiltration into lungs in TRAM-depleted compared with PBS-lip control mice 24 hours after LPS administration (n = 6–11). Neutrophils were gated as live CD45+Ly6G+CD11b+CD24+SSChi cells. (C) Representative intravital 2-photon microscopy images of control PBS-lip– or Clo-lip–treated lungs 4 hours after LPS administration in B6 LysM-GFP mice (also refer to Supplemental Videos 1 and 2). Q-dots (655-nm nontargeted) were injected 5 minutes before imaging to label the vessels red (n = 3). (D) Quantification of total GFP+ neutrophils from C (n = 3). (E) Quantification of neutrophil infiltration into lungs in LPS-treated mice previously injected with IgG or an antibody against CXCL2 (n = 3–4). (F) Quantification of neutrophil infiltration into lungs in LPS-treated mice in WT (WT) compared with Cxcr2–/– (Cxcr2.KO) mice (n = 3–6). Scale bar: 30 μm. All graphs show mean ± SD. Graphs were analyzed by unpaired t test. *P < 0.05; **P < 0.01; ***P < 0.001.

Copyright © 2023 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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