Daphnetin ameliorates acute lung injury in mice with severe acute pancreatitis by inhibiting the JAK2\u2013STAT3 pathway

Shujun Yang,Qiaofang Wang,Yaodong Song,Xiaojia Duan,Yanna Liu,Changju Zhu,Xiuqian Bi,Zhongwei Wu,Yan Zhang,Yuanzhang Geng,Sanyang Chen

doi:10.1038/s41598-021-91008-6

Shujun Yang, Qiaofang Wang + Show 9 more

Open Access

https://doi.org/10.1038/s41598-021-91008-6

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Abstract

Severe acute pancreatitis (SAP) is often associated with pulmonary inflammation leading to acute lung injury. Daphnetin, a natural coumarin derivative, has been reported to exert anti-inflammatory effects. Here, we explored the effect and possible mechanism of daphnetin in a mouse model of SAP-associated lung injury induced by an intraperitoneal injection of l-arginine. The severity of pancreatic and lung injury is determined by histology and its score. Immunostaining of inflammatory and apoptotic cells was used to demonstrate lung tissue inflammation and apoptosis; ELISA analysis of serum and tissue cytokine levels; and western blotting and immunohistochemical staining for the activated Janus kinase 2 (JAK2)–signal transducer and activator of transcription protein 3 (STAT3) signalling pathway in lung tissues. Daphnetin pretreatment significantly reduced SAP-induced pancreatic and lung tissue damage, reduced interleukin-6 and tumour necrosis factor-α concentrations in both serum and lung tissues, reduced serum amylase and myeloperoxidase activities, and reduced macrophage (CD11b) and neutrophil (Ly6G) infiltration and cell apoptosis in the lung tissue. Moreover, SAP-induced phosphorylation of JAK2 and STAT3 in the lung tissue was also significantly diminished by the daphnetin pretreatment. These results indicated that daphnetin reduces SAP-associated lung tissue damage, likely by inhibiting the activation of JAK2–STAT3 signalling.

Highlights

Severe acute pancreatitis (SAP) is often associated with pulmonary inflammation leading to acute lung injury
Increases in serum and tissue concentrations of the cytokines tumour necrosis factor-α (TNF-α) and IL-6 indicate localized and/or systemic inflammatory responses. Consistent with this finding, TNF-α (Fig. 1H) and IL-6 (Fig. 1I) levels were markedly increased in the SAP group compared with the CON and daphnetin alone (DAP) groups, but the levels were significantly lower in the SAP + DAP group
While previous studies have shown that daphnetin exerts a range of anti-inflammatory effects on acute liver failure[26], experimental c olitis[27], and e ncephalomyelitis[28], little is known about the precise molecular mechanisms that mediate the beneficial effects of daphnetin

Summary

Introduction

Severe acute pancreatitis (SAP) is often associated with pulmonary inflammation leading to acute lung injury. SAP induces the production of pro-inflammatory mediators, including chemokines and cytokines such as interleukin-6 (IL-6) and tumour necrosis factor-α (TNF-α), and increases the tissue infiltration and activation of macrophages (CD11b) and neutrophils (Ly6G), leading to pancreatic tissue necrosis[5,6]. Daphnetin has been suggested to protect rats from acute pancreatitis induced by sodium taurocholate[19] and to exert an anti-inflammatory effect on an endotoxin-induced model of lung injury[20]. It alleviates acute liver failure by inhibiting NLRP3, MAPK and NF-κB20. These observations suggest that daphnetin may be useful for the treatment of PALI

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