Blocking hyaluronan synthesis alleviates acute lung allograft rejection
Jewel Imani, … , Gary Visner, Souheil El-Chemaly
Jewel Imani, … , Gary Visner, Souheil El-Chemaly
Published October 19, 2021
Citation Information: JCI Insight. 2021;6(22):e142217. https://doi.org/10.1172/jci.insight.142217.
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Research Article Pulmonology

Blocking hyaluronan synthesis alleviates acute lung allograft rejection

Abstract

Lung allograft rejection results in the accumulation of low–molecular weight hyaluronic acid (LMW-HA), which further propagates inflammation and tissue injury. We have previously shown that therapeutic lymphangiogenesis in a murine model of lung allograft rejection reduced tissue LMW-HA and was associated with improved transplant outcomes. Herein, we investigated the use of 4-Methylumbelliferone (4MU), a known inhibitor of HA synthesis, to alleviate acute allograft rejection in a murine model of lung transplantation. We found that treating mice with 4MU from days 20 to 30 after transplant was sufficient to significantly improve outcomes, characterized by a reduction in T cell–mediated lung inflammation and LMW-HA content and in improved pathology scores. In vitro, 4MU directly attenuated activation, proliferation, and differentiation of naive CD4+ T cells into Th1 cells. As 4MU has already been demonstrated to be safe for human use, we believe examining 4MU for the treatment of acute lung allograft rejection may be of clinical significance.

Authors

Jewel Imani, Kaifeng Liu, Ye Cui, Jean-Pierre Assaker, Junwen Han, Auyon J. Ghosh, Julie Ng, Shikshya Shrestha, Anthony M. Lamattina, Pierce H. Louis, Anne Hentschel, Anthony J. Esposito, Ivan O. Rosas, Xiaoli Liu, Mark A. Perrella, Jamil Azzi, Gary Visner, Souheil El-Chemaly

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Figure 1

Treatment with 4MU ameliorates lung transplant rejection.

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Treatment with 4MU ameliorates lung transplant rejection. Left lungs fro...
Left lungs from donor BALB/c mice were orthotopically transplanted into recipient C57BL/6 mice on day 0 (A). Starting at day 20 after transplant, the recipient mice were gavaged daily with 4MU (450 mg/kg, 1% Arabic gum in PBS). On day 30 after transplant, the recipient mice were sacrificed, and tissues were collected for analysis. Schematic diagram of the transplant and treatment procedure (A). Representative gross pathology of control (n = 6), untreated allograft transplanted (n = 6), or 4MU-treated allografts (n = 8). Transplanted grafts are depicted on the left side of each lung block (B). Representative images from donor left lung sections stained with H&E and imaged at 200× magnification. Scale bar: 200 μm (C). Acute cellular rejection scores of vehicle (n = 5) and 4MU-treated mice (n = 7) (D). Heatmap of lung pathology scores (E). Representative images of TUNEL+ apoptotic cells (pink) from donor left lungs. Scale bar: 20 μm (F). Quantitative analysis of TUNEL+ apoptotic cells from 5 random high-power fields from control (n = 5), vehicle-treated (n = 5), and 4MU-treated (n = 5) mice (G). Data are represented as mean ± SEM and analyzed using 1-way ANOVA followed by Tukey’s post hoc test for multiple comparisons (*P < 0.05) or 2-tailed Student’s t test (**P < 0.01).