Blocking hyaluronan synthesis alleviates acute lung allograft rejection

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

doi:10.1172/jci.insight.142217

Blocking hyaluronan synthesis alleviates acute lung allograft rejection

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^*

^*Corresponding author for this work

Medicine, Pulmonary Division

Research output: Contribution to journal › Article › peer-review

6 Scopus citations

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.

Original language	English (US)
Article number	e142217
Journal	JCI Insight
Volume	6
Issue number	22
DOIs	https://doi.org/10.1172/jci.insight.142217
State	Published - Nov 22 2021

Funding

These works were supported by NIH R01 HL130275 (SEC). We thank Ehab Ayaub for technical assistance with fluorescence imaging. Imaging was performed in the Neurobiology Imaging Facility at Harvard Medical School. This facility is supported in part by the HMS/BCH CENTER FOR NEUROSCIENCE RESEARCH as part of an NINDS P30 Core Center grant NS072030.

ASJC Scopus subject areas

General Medicine

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Cite this

Imani, J., Liu, K., Cui, Y., Assaker, J. P., Han, J., Ghosh, A. J., Ng, J., Shrestha, S., Lamattina, A. M., Louis, P. H., Hentschel, A., Esposito, A. J., Rosas, I. O., Liu, X., Perrella, M. A., Azzi, J., Visner, G., & El-Chemaly, S. (2021). Blocking hyaluronan synthesis alleviates acute lung allograft rejection. JCI Insight, 6(22), Article e142217. https://doi.org/10.1172/jci.insight.142217

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title = "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.",

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

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AU - Liu, Kaifeng

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AU - Han, Junwen

AU - Ghosh, Auyon J.

AU - Ng, Julie

AU - Shrestha, Shikshya

AU - Lamattina, Anthony M.

AU - Louis, Pierce H.

AU - Hentschel, Anne

AU - Esposito, Anthony J.

AU - Rosas, Ivan O.

AU - Liu, Xiaoli

AU - Perrella, Mark A.

AU - Azzi, Jamil

AU - Visner, Gary

AU - El-Chemaly, Souheil

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N2 - 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.

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Blocking hyaluronan synthesis alleviates acute lung allograft rejection

Abstract

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ASJC Scopus subject areas

UN SDGs

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