FGF10 mediates protective anti-oxidative effects in particulate matter-induced lung injury through Nrf2 and NF-κB signaling

Abstract

Background: Particulate matter (PM), a well-known environmental pollutant, is an independent risk factor associated with the morbidity of various respiratory diseases. Oxidative stress is an important pathophysiological mechanism related to PM exposure, which mediates redox-sensitive inflammatory signaling, leading to lung injury. Fibroblast growth factor 10 (FGF10), a paracrine fibroblast growth factor that mediates mesenchymal to epithelial signaling, participates in epithelial repair during lung injury. However, whether FGF10-mediated repair in PM-induced lung injury is related to the regulation of oxidative stress remains to be elucidated. Methods:In vivo, the C57BL/6 mice were randomly divided, with intratracheal instillation of 5 mg/kg FGF10 1 h before 4 mg/kg PM for 2 consecutive days. In vitro, the BEAS-2B cells were pretreated with 10 ng/mL FGF10 before exposed to 200 µg/mL PM. Besides, the specific Nrf2 inhibitor ML385 was adopted in vitro. The harvested lung tissues were pathologic grading scored. The state of oxidative stress was assessed with dihydroethidium (DHE) staining, malondialdehyde (MDA) activity, hydrogen peroxide (H 2 O 2 ) assays and reactive oxygen species (ROS). The contents of IL-6 and IL-8 in bronchoalveolar lavage (BAL) as well as culture supernatant were quantified by ELISA. The protein levels of nuclear factor erythroid 2 related factor 2 (Nrf2) and nuclear factor-κB (NF-κB) signaling from lung tissue as well as cell lysate were determined by Western blot.Results: In this study, recombinant FGF10 administration relieved the degree of lung injury, which is characterized by bronchitis, in a mouse model of PM exposure. In addition, reduced ROS levels, which are indicative of restrained oxidative stress, were also observed. Moreover, two redox-sensitive signaling pathways, Nrf2 and NF-κB, were found to be differentially regulated by FGF10. Using a cellular model of PM exposure, we found that the anti-inflammatory effect of FGF10 on NF-κB signaling was mediated through the regulation of oxidative stress. The anti-oxidative effect relied on the stimulation of Nrf2 signaling. Blockade of Nrf2 signaling with ML385 significantly compromised the anti-inflammatory effect of FGF10.Conclusions: These results underscore that the protective anti-oxidative effects of FGF10 in lung injury are mediated by the stimulation of Nrf2 signaling and inhibition of the NF-κB pathway.

FGF18 alleviates sepsis-induced acute lung injury by inhibiting the NF-κB pathway

“…Tichelaar JW et al confirmed that FGF7 improved survival during ALI in adult mouse lungs after short-term expression [ 23 ]. Wang Q et al demonstrated that the anti-inflammatory effect of FGF10 on NF-κB signaling was mediated through the regulation of oxidative stress [ 24 ].…”

Particulate Matter-Induced Oxidative Stress – Recent Mechanistic Insights from In Vitro Studies

“…iii) Antioxidants based on endogenous molecules Fibroblast growth factor 10 (FGF10) is an endogenous paracrine signaling molecule that has a role in the maintenance of lung homeostasis, as well as epithelial regeneration and repair. Exogenous FGF10 has also demonstrated to protect against lung injury, and in vitro works on bronchial epithelial cells exposed to PM have confirmed that FGF10 triggered Nrf2 induction (Liu et al, 2022b), as well as NF-κB downregulation (Wang et al, 2022b), resulting in antioxidant and anti-inflammatory activities. The amino acid proline is yet another endogenous molecule that has recently been studied in the context of PM-induced oxidative stress, due to its inherent broad antioxidant profile.…”

“…The participation of the nuclear factor erythroid 2-related factor 2 (Nrf2) in the oxidative stress triggered by PM has been extensively reported in recent years (Badran et al, 2020;Bagam et al, 2021;Housseiny et al, 2020;Ito et al, 2020;Liu et al, 2022b;Saha et al, 2022;Shi et al, 2023;Shrestha et al, 2021;Son et al, 2020;Tian et al, 2021;Wang et al, 2022aWang et al, , 2022bWang et al, , 2022cXue et al, 2021b). This is not surprising given the key role of Nrf2 in the protection against oxidative stimuli (Saha et al, 2020), acting as a sensor to protect the cells against oxidative damage induced by PM-generated ROS.…”

“…i) Antioxidants based on synthetic drugs N-acetylcysteine (NAC), a pro-drug of the GSH precursor, L-cysteine, is by far the most often referred to antioxidant in recent literature (see Table S1). NAC is used medically to relieve mucus production and to fight acetaminophen overdose, and has been used preclinically to underpin the relationship between PM-induced ROS generation and inflammation (Wang et al, 2022b), autophagy regulation (Bagam et al, 2021a;Zhang et al, 2021), ER stress (Guan et al, 2021), cell senescence (Baskara et al, 2020), M2 polarization (Liu et al, 2022a), EMT promotion (Chen et al, 2020), ROSmediated epigenetic alterations (Gilmour et al, 2003;Wei et al, 2017), as well as apoptosis and pyroptosis (Ren et al, 2022). Therefore, NAC has been a key tool to study the oxidative stress-related effects induced by PM.…”