Smoking-Related Clinical and Molecular Abnormalities in Idiopathic Pulmonary Fibrosis-Associated Pulmonary Hypertension.

Pulmonary hypertension (PH) is a frequent complication of interstitial lung diseases (ILD) that worsens morbidity and mortality. Cigarette smoking has a detrimental effect on transplant-free survival of patients with ILD, including patients with idiopathic pulmonary fibrosis (IPF). However, smoking-related molecular alterations in patients with ILD-PH are not well understood. We performed analysis of 226 patients with ILD with and without PH (59.3% smokers, 40.3% with IPF) from the University of California, Davis cohort. Supporting previous findings, smokers with ILD had significantly shorter transplant-free survival than ILD non-smokers. Using a multivariable Cox regression model, we identified cigarette smoking as a significant independent predictor of mortality of patients with ILD. Smokers with IPF-PH have significantly lower diffusing capacity of the lungs for carbon monoxide (DLCO) compared to non-smokers. Transcriptomic analysis of whole blood of IPF-PH patients identified 616 differentially expressed genes (DEGs) in smokers compared to non-smokers with most deregulated fat cell differentiation and protein ubiquitination pathways. Three DEGs belonging to these pathways (BBS1, BARD1, and SMURF1) showed moderate negative correlation with mean pulmonary arterial pressure (mPAP) in patients with IPF-PH. These data show that, in patients with IPF-PH, smoking is associated with reduced DLCO, and suggest that BBS1, BARD1, and SMURF1 could be considered as potential biomarkers of PH severity in smokers with IPF-PH.