Impact of antifibrotic therapy on disease progression, all-cause mortality, and risk of acute exacerbation in non-IPF fibrosing interstitial lung diseases: evidence from a meta-analysis of randomized controlled trials and prospective controlled studies.

BACKGROUND: Nintedanib and pirfenidone are preferred pharmacological therapies for patients with idiopathic pulmonary fibrosis (IPF). However, evidence favoring antifibrotic therapy in patients with non-IPF fibrosing interstitial lung diseases (ILD) is limited. OBJECTIVE: To investigate the effects of antifibrotic therapy on disease progression, all-cause mortality, and acute exacerbation (AE) risk in patients with non-IPF fibrosing ILDs. DESIGN: Meta-analysis. DATA SOURCES AND METHODS: Electronic databases were searched for articles published before 28 February 2023. Studies that evaluated the efficacy of antifibrotic agents in patients with fibrosing ILDs were selected. The primary outcome was the disease progression risk, and the secondary outcomes included all-cause mortality and AE risk. The GRADE criteria were used for the certainty of evidence assessment. RESULTS: Nine studies with 1990 participants were included. Antifibrotic therapy reduced the rate of patients with disease progression (five trials with 1741 subjects; relative risk (RR), 0.56; 95% CI, 0.42-0.75; p < 0.0001; I2 = 0; high-certainty evidence). Antifibrotic therapy did not significantly decrease all-cause mortality (nine trials with 1990 subjects; RR, 0.76; 95% CI, 0.55-1.03; p = 0.08; I2 = 0; low-certainty evidence). However, in patients with progressive fibrosing ILDs (PF-ILD), antifibrotic therapy decreased all-cause mortality (four trials with 1100 subjects; RR, 0.69; 95% CI, 0.48-0.98; p = 0.04; I2 = 0; low-certainty evidence). CONCLUSION: Our study supports the use of antifibrotic agents in patients with PF-ILDs, which could slow disease progression and decrease all-cause mortality. TRIAL REGISTRATION: This study protocol was registered with PROSPERO (registration number: CRD42023411272).

Exploring the Mechanism Whereby Sinensetin Delays the Progression of Pulmonary Fibrosis Based on Network Pharmacology and Pulmonary Fibrosis Models.

The incidence of pulmonary fibrosis (PF), a progressively fatal disease, has increased in recent years. However, there are no effective medicines available. Previous results have shown that sinensetin probably has some curative effects on PF. Therefore, this paper aims to predict the targets of sinensetin using a network pharmacology method and to confirm its effects and functional targets in PF using a mouse PF model. First, network pharmacology analysis showed that sinensetin has 105 functional targets, and 1,698 gene targets closely relate to PF. The intersection of the functional targets and gene targets produced 52 targets for the treatment of PF with sinensetin. The PPIs (protein-protein interactions) led to several potential key target genes, including MAPK1, EGFR, SRC, and PTGS2. The results of GO and KEGG analyses suggested the crucial function of apoptosis in PF and its involvement in the PI3K signaling pathway. Subsequently, we tested the molecular docking of sinensetin with the PI3K protein using the AutoDock4 software. The results showed that sinensetin could fit well into several binding sites of the PI3K protein. Furthermore, we constructed a PF mouse model through one-off intratracheal instillation of bleomycin and then intragastrically administered different concentrations of sinensetin to the model mice. Twenty-eight days later, the mice were sacrificed, and the lung tissues, serum, and bronchoalveolar lavage fluid (BALF) were collected. The in vivo tests showed that the body weight of model mice increased slightly compared with that of PF mice after intragastric sinensetin. HE and Masson staining suggested a certain extent of reduction in the pathology of lung tissues. The expression of collagens I and III, as well as hydroxyproline in the lung tissues, was reduced to a certain extent. IL-6 levels in the serum and BALF decreased markedly. The expression of vimentin and α-SMA in pulmonary tissues decreased. Cell apoptosis, as well as P-PI3K and P-AKT levels, in lung tissues also reduced. In summary, network pharmacology and in vivo test results suggest sinensetin causes an effective delay in the progression of pulmonary fibrosis, and the functional mechanism is likely related to PI3K-AKT signaling.