The role of FGF-2 in smoke-induced emphysema and the therapeutic potential of recombinant FGF-2 in patients with COPD

Abstract

Although the positive effects of recombinant fibroblast growth factor-2 (rFGF-2) in chronic obstructive pulmonary disease (COPD) have been implicated in previous studies, knowledge of its role in COPD remains limited. The mechanism of FGF2 in a COPD mouse model and the therapeutic potential of rFGF-2 were investigated in COPD. The mechanism and protective effects of rFGF-2 were evaluated in cigarette smoke-exposed or elastase-induced COPD animal models. Inflammation was assessed in alveolar cells and lung tissues from mice. FGF-2 was decreased in the lungs of cigarette smoke-exposed mice. Intranasal use of rFGF-2 significantly reduced macrophage-dominant inflammation and alveolar destruction in the lungs. In the elastase-induced emphysema model, rFGF-2 improved regeneration of the lungs. In humans, plasma FGF-2 was decreased significantly in COPD compared with normal subjects (10 subjects, P = 0.037). The safety and efficacy of inhaled rFGF-2 use was examined in COPD patients, along with changes in respiratory symptoms and pulmonary function. A 2-week treatment with inhaled rFGF-2 in COPD (n = 6) resulted in significantly improved respiratory symptoms compared with baseline levels (P < 0.05); however, the results were not significant compared with the placebo. The pulmonary function test results of COPD improved numerically compared with those in the placebo, but the difference was not statistically significant. No serious adverse events occurred during treatment with inhaled rFGF-2. The loss of FGF-2 production is an important mechanism in the development of COPD. Inhaling rFGF-2 may be a new therapeutic option for patients with COPD because rFGF-2 decreases inflammation in lungs exposed to cigarette smoke.

Rho-Kinase 1/2 Inhibition Prevents Transforming Growth Factor-β-Induced Effects on Pulmonary Remodeling and Repair

“…In addition, ROCK inhibition is presumably playing a major role in regulating secreted factors. We examined several key components of the WNT signaling and FGF signaling pathway, which are known to contribute to epithelial development and regeneration ( KathernMyrna et al, 2012 ; Ornitz and Itoh, 2015 ; Dean and Lloyd, 2017 ; Kim et al, 2018 ; Prince, 2018 ; Puschhof and Clevers, 2018 ; Villar et al, 2019 ). Increasing evidence demonstrated aberrant WNT signaling results in fibrotic lung diseases ( Baarsma and Königshoff, 2017 ; Cao et al, 2018 ; Martin-Medina et al, 2018 ).…”

“…Fibroblast growth factors (FGFs) are members of the heparin-binding growth factor family that are often involved in morphogenesis and wound repair and FGF signaling dysregulations is implicated in many disorders ( Ornitz and Itoh, 2015 ; Fehrenbach et al, 2017 ; Ohgiya et al, 2017 ; Plikus et al, 2017 ; Shiraishi et al, 2019 ; Weiner et al, 2019 ). FGF2 has attracted increasing attention in lung biology recently and is reported as an important factor in airway remodeling by increasing the deposition of proteoglycans resulting in bronchial hyperresponsiveness in asthmatic airways ( Kim et al, 2018 ). FGF10, a member of the FGF7-subfamily, is widely reported as a primary regulator for branching morphogenesis, cellular differentiation, and response to injury ( Prince, 2018 ; Weiner et al, 2019 ; Zepp and Morrisey, 2019 ).…”

“…*p < 0.05, **p < 0.01, ***p < 0.001. Ornitz and Itoh, 2015;Dean and Lloyd, 2017;Kim et al, 2018;Prince, 2018;Puschhof and Clevers, 2018;Villar et al, 2019). Increasing evidence demonstrated aberrant WNT signaling results in fibrotic lung diseases (Baarsma and Königshoff, 2017;Cao et al, 2018;Martin-Medina et al, 2018).…”

FGF/FGFR signaling in health and disease

“…501 In addition, inhaling recombinant FGF2 decreases lung inflammation in asthma and COPD. 502,503 Thus, targeting FGF2 is a potential method to alleviate certain inflammatory diseases such as neuroinflammation, asthma, and COPD.…”

Mesenchymal WNT-5A/5B Signaling Represses Lung Alveolar Epithelial Progenitors

“…Molecular signaling pathways that are essential regulators for alveolar progenitors to trigger respiratory epithelium repair include several secreted factors, such as Fibroblast Growth Factor (FGF)-10 signaling, the Notch pathway, Transforming Growth factor (TGF)-β signaling and WNT signaling [11,16,17,18,19,20,21,22]. These secreted factors and their pathways may yield potential drug targets.…”