PMID- 31036697
OWN - NLM
STAT- In-Data-Review
LR  - 20190610
IS  - 1754-8411 (Electronic)
IS  - 1754-8403 (Linking)
VI  - 12
IP  - 5
DP  - 2019 May 15
TI  - Adenosine and hyaluronan promote lung fibrosis and pulmonary hypertension in
      combined pulmonary fibrosis and emphysema.
LID - dmm038711 [pii]
LID - 10.1242/dmm.038711 [doi]
AB  - Combined pulmonary fibrosis and emphysema (CPFE) is a syndrome that predominantly
      affects male smokers or ex-smokers and it has a mortality rate of 55% and a
      median survival of 5 years. Pulmonary hypertension (PH) is a frequently fatal
      complication of CPFE. Despite this dismal prognosis, no curative therapies exist 
      for patients with CPFE outside of lung transplantation and no therapies are
      recommended to treat PH. This highlights the need to develop novel treatment
      approaches for CPFE. Studies from our group have demonstrated that both adenosine
      and its receptor ADORA2B are elevated in chronic lung diseases. Activation of
      ADORA2B leads to elevated levels of hyaluronan synthases (HAS) and increased
      hyaluronan, a glycosaminoglycan that contributes to chronic lung injury. We
      hypothesize that ADORA2B and hyaluronan contribute to CPFE. Using isolated CPFE
      lung tissue, we characterized expression levels of ADORA2B and HAS. Next, using a
      unique mouse model of experimental lung injury that replicates features of CPFE, 
      namely airspace enlargement, PH and fibrotic deposition, we investigated whether 
      4MU, a HAS inhibitor, was able to inhibit features of CPFE. Increased protein
      levels of ADORA2B and HAS3 were detected in CPFE and in our experimental model of
      CPFE. Treatment with 4MU was able to attenuate PH and fibrosis but not airspace
      enlargement. This was accompanied by a reduction of HAS3-positive macrophages. We
      have generated pre-clinical data demonstrating the capacity of 4MU, an
      FDA-approved drug, to attenuate features of CPFE in an experimental model of
      chronic lung injury.This article has an associated First Person interview with
      the first author of the paper.
CI  - (c) 2019. Published by The Company of Biologists Ltd.
FAU - Collum, Scott D
AU  - Collum SD
AUID- ORCID: http://orcid.org/0000-0001-5510-7356
AD  - Department of Biochemistry and Molecular Biology, McGovern Medical School,
      University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
FAU - Molina, Jose G
AU  - Molina JG
AD  - Department of Biochemistry and Molecular Biology, McGovern Medical School,
      University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
FAU - Hanmandlu, Ankit
AU  - Hanmandlu A
AD  - Department of Biochemistry and Molecular Biology, McGovern Medical School,
      University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
FAU - Bi, Weizhen
AU  - Bi W
AD  - Department of Biochemistry and Molecular Biology, McGovern Medical School,
      University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
FAU - Pedroza, Mesias
AU  - Pedroza M
AD  - Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA.
FAU - Mertens, Tinne C J
AU  - Mertens TCJ
AD  - Department of Biochemistry and Molecular Biology, McGovern Medical School,
      University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
FAU - Wareing, Nancy
AU  - Wareing N
AD  - Department of Biochemistry and Molecular Biology, McGovern Medical School,
      University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
FAU - Wei, Wang
AU  - Wei W
AD  - Department of Biochemistry and Molecular Biology, McGovern Medical School,
      University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
FAU - Wilson, Cory
AU  - Wilson C
AUID- ORCID: http://orcid.org/0000-0003-3948-3831
AD  - Department of Biochemistry and Molecular Biology, McGovern Medical School,
      University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
FAU - Sun, Wenchao
AU  - Sun W
AD  - Biomaterials and Advanced Drug Delivery Lab, Stanford University School of
      Medicine, Stanford, CA 94304, USA.
FAU - Rajadas, Jayakumar
AU  - Rajadas J
AUID- ORCID: http://orcid.org/0000-0001-6520-3923
AD  - Biomaterials and Advanced Drug Delivery Lab, Stanford University School of
      Medicine, Stanford, CA 94304, USA.
FAU - Bollyky, Paul L
AU  - Bollyky PL
AD  - Division of Infectious Diseases, Department of Medicine, Stanford University
      School of Medicine, Stanford, CA 94305, USA.
FAU - Philip, Kemly M
AU  - Philip KM
AUID- ORCID: http://orcid.org/0000-0002-7749-9781
AD  - Department of Biochemistry and Molecular Biology, McGovern Medical School,
      University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
FAU - Ren, Dewei
AU  - Ren D
AD  - Houston Methodist DeBakey Transplant Center, Houston Methodist Hospital, Houston,
      TX 77030, USA.
FAU - Thandavarayan, Rajarajan A
AU  - Thandavarayan RA
AD  - Houston Methodist DeBakey Transplant Center, Houston Methodist Hospital, Houston,
      TX 77030, USA.
FAU - Bruckner, Brian A
AU  - Bruckner BA
AD  - Houston Methodist DeBakey Transplant Center, Houston Methodist Hospital, Houston,
      TX 77030, USA.
FAU - Xia, Yang
AU  - Xia Y
AD  - Department of Biochemistry and Molecular Biology, McGovern Medical School,
      University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
FAU - Blackburn, Michael R
AU  - Blackburn MR
AUID- ORCID: http://orcid.org/0000-0002-1394-9966
AD  - Department of Biochemistry and Molecular Biology, McGovern Medical School,
      University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
FAU - Karmouty-Quintana, Harry
AU  - Karmouty-Quintana H
AUID- ORCID: http://orcid.org/0000-0003-4753-9823
AD  - Department of Biochemistry and Molecular Biology, McGovern Medical School,
      University of Texas Health Science Center at Houston, Houston, TX 77030, USA
      harry.karmouty@uth.tmc.edu.
LA  - eng
PT  - Journal Article
DEP - 20190515
PL  - England
TA  - Dis Model Mech
JT  - Disease models & mechanisms
JID - 101483332
PMC - PMC6550050
OTO - NOTNLM
OT  - Adenosine
OT  - Airspace enlargement
OT  - Group III PH
OT  - Hyaluronan
OT  - Hyaluronan synthases
OT  - Lung fibrosis
OT  - Macrophages
OT  - Pulmonary hypertension
COIS- Competing interestsThe authors declare no competing or financial interests.
EDAT- 2019/05/01 06:00
MHDA- 2019/05/01 06:00
CRDT- 2019/05/01 06:00
PHST- 2018/12/27 00:00 [received]
PHST- 2019/04/10 00:00 [accepted]
PHST- 2019/05/01 06:00 [pubmed]
PHST- 2019/05/01 06:00 [medline]
PHST- 2019/05/01 06:00 [entrez]
AID - dmm.038711 [pii]
AID - 10.1242/dmm.038711 [doi]
PST - epublish
SO  - Dis Model Mech. 2019 May 15;12(5). pii: dmm.038711. doi: 10.1242/dmm.038711.