Abstract
Objective To investigate the effects of Danggui Buxue Tang (DBT) on rats with pulmonary fibrosis (PF) and the underlying mechanism. Methods Sixty specific pathogen-free (SPF) male Sprague-Dawley (SD) rats were randomly divided into 4 groups: control, PF, prednisone treatment, and DBT treatment. Intratracheal instillation of bleomycin (BLM) was performed to establish a PF rat model. DBT was administered to PF rats concurrently for 2 weeks. Lung samples were then collected for HE and Masson staining after pulmonary function testing, and semiquantitative analysis for the degree of alveolitis and fibrosis was performed using the Szapiel and Ashcroft score systems. Myeloperoxidase (MPO) activity, hydroxyproline (HYP), hyaluronic acid (HA), and inflammatory cytokine content were measured. Western blotting was performed to detect fibrotic marker and TLR4/NLRP3 signaling pathway changes. Results Oral administration of DBT attenuated weight loss, survival rate, and pulmonary index. Lung histopathologic lesions were also reduced. DBT inhibited PF by decreasing the secretion of inflammatory cytokines and collagen deposition. Specifically, DBT reduced tumor necrosis factor-alpha (TNF-α), interleukin 1 beta (IL-1β), IL-6, HYP, alpha-smooth muscle actin (α-SMA), collagen I, and collagen III levels. Corollary experiments identified a potential mechanism involving suppression of TLR4/MyD88/NF-κB signaling pathway activation and the NLRP3/ASC/caspase-1 axis, the downstream regulatory pathway. Conclusion DBT exhibited a potent effect on BLM-induced PF rats by inhibiting the TLR4/NLRP3 signaling pathway. Thus, DBT alleviates pulmonary inflammation to inhibit fibrotic pathology and should be considered as a candidate for the clinical treatment of PF.
Highlights
Pulmonary fibrosis (PF) is a fatal and incurable lung disease that is characterized by deposition of extracellular matrix (ECM) [1, 2]. e median survival time of PF is 2–5 years, and the main cause of death is impaired pulmonary function and respiratory failure induced by ECM with irreversible scarring [3, 4]
Recent studies have confirmed that the excessive release of inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α), interleukin 1 beta (IL-1β), and IL-6, are involved in the pathogenesis of PF [8]
We have demonstrated that Danggui Buxue Tang (DBT) could ameliorate BLM-induced PF rats by inhibiting pulmonary inflammation and collagen deposition [17], oxidative damage [18], and angiogenesis [19]
Summary
Pulmonary fibrosis (PF) is a fatal and incurable lung disease that is characterized by deposition of extracellular matrix (ECM) [1, 2]. e median survival time of PF is 2–5 years, and the main cause of death is impaired pulmonary function and respiratory failure induced by ECM with irreversible scarring [3, 4]. E median survival time of PF is 2–5 years, and the main cause of death is impaired pulmonary function and respiratory failure induced by ECM with irreversible scarring [3, 4]. E pathogenesis underlying PF has not been established. Environmental agents, and infections are thought to induce and contribute to the pulmonary inflammation leading to PF [7]. Recent studies have confirmed that the excessive release of inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α), interleukin 1 beta (IL-1β), and IL-6, are involved in the pathogenesis of PF [8]. Toll-like receptor 4 (TLR4) is an important mediator of inflammation and has been reported to activate both proinflammatory and profibrotic pathways in PF [9, 10]. In TLR4 knockout mice, PF has been shown to be significantly attenuated by inhibiting fibroblast activation
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