Abstract
Pulmonary fibrosis (PF) is a chronic and progressive process of tissue repair. Azithromycin (AZM) may be beneficial for the treatment of PF because AZM has anti-inflammatory and immune regulatory roles and inhibits remodeling, but the mechanism is not entirely clear. In this study, we established a mouse PF model induced by bleomycin (BLM) and primary mouse lung fibroblasts stimulated by transforming growth factor (TGF)-β1 to explore the possible mechanisms of AZM in PF. Results showed that AZM reduces mortality and lung inflammation and attenuates BLM-induced PF in mice. AZM effectively reduced the expression of α-smooth muscle actin (SMA) and type I collagen. Meanwhile, expression of lysyl oxidase (LOX) and lysyl oxidase-like protein (LOXL)-2 in the lung tissue of mice after AZM treatment was significantly lower than in the BLM group. In addition, this study found that AZM significantly inhibits the TGF-β1/Smad and JNK/c-Jun signaling pathways in vivo, and expression of a-SMA, type I collagen, LOX and LOXL-2 in the lung tissue of mice treated with AZM was significantly lower than that in the BLM group. In vitro, AZM also effectively inhibited type I collagen, LOX, LOXL-2 and JNK-c-Jun signaling pathways in TGF-β1-stimulated primary mouse fibroblasts, and this effect was similar to that of a JNK-specific inhibitor (SP600125). In conclusion, AZM effectively attenuated BLM-induced PF in mice, which may play a role by partially inhibiting the JNK/c-Jun and TGF-β1/Smad signaling pathways and reducing production of LOX and LOXL2.
Highlights
Pulmonary fibrosis (PF) can occur in a variety of clinical conditions and is a chronic and progressive tissue repair response process that leads to irreversible scarring and remodeling of the lung (Noble et al, 2012)
Our study revealed that AZM effectively reduced expression levels of α-smooth muscle actin (SMA) and type I collagen in BLMinduced PF in mice (Figure 1)
The study found that AZM effectively inhibited the expression of type I collagen in mouse lung fibroblasts stimulated by transforming growth factor (TGF)-β1 (Figure 6), which is consistent with results previously reported by Wuyts et al (Wuyts et al, 2010)
Summary
Pulmonary fibrosis (PF) can occur in a variety of clinical conditions and is a chronic and progressive tissue repair response process that leads to irreversible scarring and remodeling of the lung (Noble et al, 2012). Many factors, including respiratory virus infection, connective tissue disease (CTD), environmental and occupational exposure, therapy (such as radiotherapy and immunotherapy), diabetes, gastroesophageal reflux and so on, can cause and maintain fibrosis (Noble et al, 2012; Sgalla et al, 2019). PF can occur in the absence of any known causes, known as idiopathic pulmonary fibrosis (IPF). In secondary PF, the prognosis of PF may be different with distinct etiologies. CTD combined with PF may lead to a significant increase in mortality (Cottin et al, 2018; Spagnolo et al, 2021)
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