TY - JOUR
T1 - Blocking hyaluronan synthesis alleviates acute lung allograft rejection
AU - Imani, Jewel
AU - Liu, Kaifeng
AU - Cui, Ye
AU - Assaker, Jean Pierre
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
N1 - Funding Information:
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.
Publisher Copyright:
© 2021, Imani et al.
PY - 2021/11/22
Y1 - 2021/11/22
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.
AB - 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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U2 - 10.1172/jci.insight.142217
DO - 10.1172/jci.insight.142217
M3 - Article
C2 - 34665782
AN - SCOPUS:85120310963
VL - 6
JO - JCI insight
JF - JCI insight
SN - 2379-3708
IS - 22
M1 - e142217
ER -