No abstract

Idiopathic pulmonary fibrosis (IPF) is the most common idiopathic interstitial pulmonary disease with a median survival of 2–4 years after diagnosis. A significant number of IPF patients have risk factors, such as a history of smoking or concomitant emphysema, both of which can predispose the patient to lung cancer (LC) (mostly non-small cell lung cancer (NSCLC)). In fact, IPF itself increases the risk of LC development by 7% to 20%. In this regard, there are multiple common genetic, molecular, and cellular processes that connect lung fibrosis with LC, such as myofibroblast/mesenchymal transition, myofibroblast activation and uncontrolled proliferation, endoplasmic reticulum stress, alterations of growth factors expression, oxidative stress, and large genetic and epigenetic variations that can predispose the patient to develop IPF and LC. The current approved IPF therapies, pirfenidone and nintedanib, are also active in LC. In fact, nintedanib is approved as a second line treatment in NSCLC, and pirfenidone has shown anti-neoplastic effects in preclinical studies. In this review, we focus on the current knowledge on the mechanisms implicated in the development of LC in patients with IPF as well as in current IPF and LC-IPF candidate therapies based on novel molecular advances.

Background Idiopathic pulmonary fibrosis (IPF) is characterised by the aberrant epithelial to mesenchymal transition (EMT) and myofibroblast accumulation. Sphingosine-1-phosphate (S1P) and sphingosine kinase 1 (SPHK1) have been implicated in lung myofibroblast transition, but their role in EMT and their expression in patients with IPF is unknown. Methods and results S1P levels were measured in serum (n¼27) and bronchoalveolar lavage (BAL; n¼15) from patients with IPF and controls (n¼30 for serum and n¼15 for BAL studies). SPHK1 expression was measured in lung tissue from patients with IPF (n¼12) and controls (n¼15). Alveolar type II transformation into mesenchymal cells was studied in response to S1P (10À5 M). The median (IQR) of S1P serum levels was increased in patients with IPF (1.4 (0.4) mM) versus controls (1 (0.26) mM; p<0.0001). BAL S1P levels were increased in patients with IPF (1.12 (0.53) mM) versus controls (0.2 (0.5); p<0.0001) and correlated with diffusion capacity of the lung for carbon monoxide, forced expiratory volume in 1 s and forced vital capacity (Spearman's r¼À0.87, À0.72 and À0.68, respectively) in patients with IPF. SPHK1 was upregulated in lung tissue from patients with IPF and correlated with asmooth muscle actin, vimentin and collagen type I (Spearman's r¼0.82, 0.85 and 0.72, respectively). S1P induced EMT in alveolar type II cells by interacting with S1P 2 and S1P 3 , as well as by the activation of p-Smad3, RhoA-GTP, oxidative stress and transforming growth factor-b1 (TGF-b1) release. Furthermore, TGF-b1-induced EMT was partially conducted by the S1P/SPHK1 activation, suggesting crosstalk between TGF-b1 and the S1P/SPHK1 axis. Conclusions S1P is elevated in patients with IPF, correlates with the lung function and mediates EMT.