Adenosine and hyaluronan promote lung fibrosis and pulmonary hypertension in combined pulmonary fibrosis and emphysema

Scott D. Collum, Jose G. Molina, Ankit Hanmandlu, Weizhen Bi, Mesias Pedroza, Tinne C.J. Mertens, Nancy Wareing, Wang Wei, Cory Wilson, Wenchao Sun, Jayakumar Rajadas, Paul L. Bollyky, Kemly M. Philip, Dewei Ren, Rajarajan Amirthalingam Thandavarayan, Brian A. Bruckner, Yang Xia, Michael R. Blackburn, Harry Karmouty-Quintana

Research output: Contribution to journalArticle

3 Scopus citations

Abstract

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.

Original languageEnglish (US)
Article numberdmm038711
JournalDMM Disease Models and Mechanisms
Volume12
Issue number5
DOIs
StatePublished - May 15 2019

Keywords

  • Adenosine
  • Airspace enlargement
  • Group III PH
  • Hyaluronan
  • Hyaluronan synthases
  • Lung fibrosis
  • Macrophages
  • Pulmonary hypertension

ASJC Scopus subject areas

  • Neuroscience (miscellaneous)
  • Medicine (miscellaneous)
  • Immunology and Microbiology (miscellaneous)
  • Biochemistry, Genetics and Molecular Biology(all)

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  • Cite this

    Collum, S. D., Molina, J. G., Hanmandlu, A., Bi, W., Pedroza, M., Mertens, T. C. J., Wareing, N., Wei, W., Wilson, C., Sun, W., Rajadas, J., Bollyky, P. L., Philip, K. M., Ren, D., Amirthalingam Thandavarayan, R., Bruckner, B. A., Xia, Y., Blackburn, M. R., & Karmouty-Quintana, H. (2019). Adenosine and hyaluronan promote lung fibrosis and pulmonary hypertension in combined pulmonary fibrosis and emphysema. DMM Disease Models and Mechanisms, 12(5), [dmm038711]. https://doi.org/10.1242/dmm.038711