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Randomized Controlled Trial
. 2018 Nov 14;50(11):1-10.
doi: 10.1038/s12276-018-0178-y.

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

You-Sun Kim  1 , Goohyeon Hong  2 , Doh Hyung Kim  2 , Young Min Kim  2 , Yoon-Keun Kim  3 , Yeon-Mok Oh  4 , Young-Koo Jee  5
Affiliations
Randomized Controlled Trial

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

You-Sun Kim et al. Exp Mol Med. .

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 VSports手机版. 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. .

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Conflict of interest statement

The authors declare that they have no conflict of interest.

Figures

Fig. 1
Fig. 1. Fibroblast growth factor-2 (FGF-2) levels in lung lysates decreased in response to short-term smoke exposure.
a–c FGF-2 levels were measured in 5 μg of lung lysate using an enzyme-linked immunosorbent assay. a Mice were exposed to cigarette smoke once, and lung tissues were obtained 3 and 24 h after exposure (n = 6 per group). b, c Mice were exposed to cigarette smoke for 4 days or 6 months, and lung tissues were collected 18 h after the last exposure (b n = 12 per group, c n = 5 per group). P-values were determined by the Mann–Whitney test
Fig. 2
Fig. 2. Characterization of short-term exposure to cigarette smoke.
a–d The mice were exposed to cigarette smoke for 4 days using an inhalation box. a Cellularity in bronchoalveolar lavage (BAL) fluid. P < 0.0001 using two-way analysis of variance. b Mean linear intercept (MLI) (n = 6 per group). c Caspase-3/7 and elastase activities were measured in 10 μg of lung lysate (n = 11 per group). P-values were determined by the Mann–Whitney test (b–d)
Fig. 3
Fig. 3. Protective effects of FGF-2 on early emphysema in response to short-term exposure to cigarette smoke.
a–c The mice were exposed to cigarette smoke for 4 days, and 0.1, 10, and 1000 pg of FGF-2 was administered intranasally within 1 h after smoke exposure. Mice were killed 18 h after the final smoke exposure. a Cellularity in BAL fluid. P-values were determined by two-way analysis of variance. b MLI (n = 6–12 per group). P-values were determined by the Mann–Whitney test. c Lung histology with hematoxylin and eosin (H&E) staining (scale bar = 1 mm)
Fig. 4
Fig. 4. Lung resident cell apoptosis in response to smoke was protected against by FGF-2 and dependent on caspase-3/7 signaling.
a, b The mice were exposed to cigarette smoke for 4 days, and 10 pg of FGF-2 was intranasally administered within 1 h after smoke exposure. Mice were killed 18 h after the final smoke exposure. a Caspase-3/7 activity using 10 μg of lung lysate (n = 9 per group). P-values were determined by the Mann–Whitney test. b Western blotting using antibodies against caspase-3 and β-actin
Fig. 5
Fig. 5. Regenerative effects of FGF-2 on the elastase-induced emphysema model.
The mice were intratracheally injected with 0.4 U of porcine elastase on day 0. Aliquots (10 pg) of FGF-2 and PD173074 were intranasally and intraperitoneally administered on days 7–13. The mice were killed on day 14. a MLI (n = 4–6 per group). P-values were determined by the Mann–Whitney test; *p < 0.05. b Lung histology with H&E staining (scale bar = 1 mm)
Fig. 6
Fig. 6. FGF-2 levels in plasma from patients with chronic obstructive pulmonary disease (COPD) and normal controls.
A 100-µL aliquot of plasma was used to measure FGF-2 (n = 10/group). P = 0.037 according to the Mann–Whitney test
Fig. 7
Fig. 7
Flowchart of the clinical pilot trial. V visit; Wk week
Fig. 8
Fig. 8
Change in pulmonary function tests (PFTs) [a change in forced expiratory flow in 1 s (Δ FEV1) and b change in forced vital capacity (Δ FVC)] during and after fibroblast growth factor (FGF)-2 treatment. PFTs, including FEV1 and FVC, tended to improve during the recombinant (r) FGF-2 treatment period but not significantly between the rFGF-2 group and the control group (p > 0.05)
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