Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
  • Clinical Research and Public Health
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Video Abstracts
  • Reviews
    • View all reviews ...
    • Pancreatic Cancer (Jul 2025)
    • Complement Biology and Therapeutics (May 2025)
    • Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)
    • Microbiome in Health and Disease (Feb 2025)
    • Substance Use Disorders (Oct 2024)
    • Clonal Hematopoiesis (Oct 2024)
    • Sex Differences in Medicine (Sep 2024)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Clinical Research and Public Health
    • Research Letters
    • Letters to the Editor
    • Editorials
    • Commentaries
    • Editor's notes
    • Reviews
    • Viewpoints
    • 100th anniversary
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Video Abstracts
  • In-Press Preview
  • Clinical Research and Public Health
  • Research Letters
  • Letters to the Editor
  • Editorials
  • Commentaries
  • Editor's notes
  • Reviews
  • Viewpoints
  • 100th anniversary
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
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.
View: Text | PDF
Research Article Immunology Article has an altmetric score of 34

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

  • Text
  • PDF
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

×

Figure 7

TRAMs exposed to ischemia/reperfusion have increased TLR4 transcription and translocation to the plasma membrane.

Options: View larger image (or click on image) Download as PowerPoint
TRAMs exposed to ischemia/reperfusion have increased TLR4 transcription ...
(A) Heatmap of selected TLR4 pathway genes expressed in murine donor TRAMs exposed to ischemia/reperfusion (n = 3–5). (B) Tlr4 and Cd14 mRNA expression in TRAMs harvested from BALF before and after ischemia at 24 hours was assessed by qPCR (n = 3). (C) Expression level of Tlr4 mRNA in TRAMs harvested from BALF before ischemia and 1 hour, 4 hours, and 24 hours after ischemia, assessed by qPCR (n = 3–5). (D) Protein expression of TLR4 at the plasma membrane in TRAMs harvested as in C, assessed by flow cytometry (n = 3–5). (E) Immunocytochemistry for TLR4 of TRAMs harvested as described in C. (F) WT C57BL/6 donor mice were treated with low-dose i.t. LPS (0.5 μg/g BW) alone or in combination with TLR4 antagonist (TAK-242; 1 μg/g BW, i.v.) or IAXO-101 (3 μg/g BW, i.t.) and neutrophil recruitment was assessed 24 hours after ischemia. Neutrophils were gated as live CD45+Ly6G+CD11b+CD24+SSChi cells (n = 4–5). (B) Graph was analyzed by unpaired t test. (C, D, and F) Graphs were analyzed by 1-way ANOVA followed by Tukey’s post hoc test. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001. Scale bar: 10 μm. Arrow points to TLR4 at the plasma membrane.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts

Picked up by 2 news outlets
Posted by 21 X users
22 readers on Mendeley
See more details