Abstract
ABSTRACTCombined 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.
Highlights
Chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF) embody the third leading cause of death in the US
The adenosinergic response in combined pulmonary fibrosis and emphysema’ (CPFE) Using explanted lung tissue derived from upper or lower lung lobes from CPFE patients or from normal lungs that were discarded for transplantation, we evaluated mediators that are involved in the generation and degradation of adenosine, in addition to adenosine receptors
We have characterized an experimental model of CPFE using male 6 month old Ada−/− mice and demonstrated that they present with features of CPFE, namely fibrotic deposition, airspace enlargement and pulmonary hypertension (PH)
Summary
Chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF) embody the third leading cause of death in the US (https://www.cdc.gov/nchs/data/hus/2017/019. pdf ). COPD ( emphysema) and IPF are regarded as separate disease entities Hallmarks of both COPD and IPF were first described in autopsies of lungs in 1974 (Auerbach et al, 1974); it was not until 2005 that this condition was classified as a well-defined syndrome termed ‘combined pulmonary fibrosis and emphysema’ (CPFE) (Cottin et al, 2005). Confirmation of PH by right-heart catheterization data reduces 1-year survival rates to only 60% (Cottin et al, 2010) Despite this dismal prognosis, no therapy options exist for patients with CPFE outside of smoking cessation, oxygen therapy and lung transplantation (Jankowich and Rounds, 2012; Lin and Jiang, 2015). These agents are not recommended for PH in CPFE because of their vasodilation profile that results in ventilation/perfusion mismatch
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