The mucus present inside the human airway covers the surface of the respiratory epithelium. It protects the airway from toxic stimulation by performing a physiological defense against toxic substances and infection sources from microdust particles and pathogenic microorganisms(Na et al., 2016). On the other hand, acute or chronic inflammatory respiratory diseases occur, such as asthma, chronic obstructive pulmonary disease, cystic fibrosis, and pneumonia, which result in the excessive secretion of mucus. A change in the properties of mucus may worsen the course of the disease. Therefore, it is essential to control mucus oversecretion (Park et al., 2013).

MUC5AC is expressed mainly in airway epithelial cells or mucus secretion cells. MUC5AC increases secretion as symptoms in patients with bronchial disease worsen and is the cause of abnormal mucus or mucus cell proliferation (Song et al., 2003). Also, it has been reported that the expression of MUC5AC is regulated by TNF-α, which is known as a major cytokine causing asthma and COPD. TNF-α is a well-known stimulant for secretion and gene expression of airway mucin (Sikder et al., 2014). Therefore, a pharmacological approach to regulate the production of mucin itself, or regulate its secretion, a major component that gives viscosity to mucus, is critical in treating respiratory diseases (Liu et al., 2012). Among several natural products that exhibit anti-inflammatory, antioxidant, and anticancer efficacy, it is crucial to explore natural materials that may control the production and over secretion of airway mucins observed in respiratory inflammatory diseases (Leach and Page, 2015).

Many traditional herbal medicines are now used for treatment for respiratory inflammatory diseases prevention or therapy. According to traditional oriental medicine, Paeoniae Radix rubra (PRR), the dried root of Paeonia lactiflora Pall., has been used to regulate various inflammatory diseases (Tan et al., 2020). PRR is used frequently to enhance blood circulation (Jin et al., 2012), dissipate stasis (Xie et al., 2017), and protect the liver (Wang et al., 2012). In addition, PRR is used as an ingredient in prescriptions of many herbal medicines, such as Yihuo Huatan Formula, COPD treatment (Zhang et al., 2019), Yangqing Kangxian formula, IPF (Idiopathic pulmonary fibrosis) treatment, and Xiao-Qing-Long (XQL) decoction, Asthma treatment (Yang et al., 2020). Paeoniflorin (PF), one of the chemical components of PRR, has been reported to have various pharmacological activities, such as antioxidant, anti-inflammatory, and neuroprotective effects on various types of cells (Tan et al., 2020). Many studies have reported that PF has effective anti-inflammatory and immunosuppressive activities. The active mechanisms are associated with regulation of B, T cells, and DCs, enhancement of Akt, PKA, PPARγ, IL-4, IL-10, and TGF-β, inhibition of JNK, ERK, iNOS, COX-2, IL-1β, IL-6, IL-17, and IFN-γ, and modulation of the signaling pathways, such as GPCRs, NF-κB, MAPK and PI3K/Akt (Zhou et al., 2020). Similarly, a study suggested that PF possesses a neuroprotective activity by reducing the production of NO, TNF-α, and IL-1β from the primary microglial cells for neuroprotection (Nam et al., 2013). On the other hand, while the focus was on pharmacokinetic studies using a single ingredient, studies related to respiratory inflammatory disease modulating ERK pathway in PRR are rare.

Considering these properties, this study examined whether PRRE and PF affect modulating cytokines production and gene expression of air way mucin induced by TNF-α in NCI–H292 (H292) cells, a human airway epithelial cell line.