Emodin Alleviates Severe Acute Pancreatitis-Associated Acute Lung Injury by Inhibiting the Cold-Inducible RNA-Binding Protein (CIRP)-Mediated Activation of the NLRP3/IL-1β/CXCL1 Signaling

Abstract

Objective: Severe acute pancreatitis (SAP) can lead to acute lung injury (ALI). This study investigated the therapeutic effect of emodin and its molecular mechanisms in a rat model of SAP-ALI.Methods: Forty male Sprague-Dawley rats were randomly divided into the groups: Control (CON), SAP (SAP), emodin (EMO), and C23 (C23). The latter three groups of rats were induced for SAP-ALI by retrograde injection of 5% sodium taurocholate into the biliary-pancreatic duct and were treated with vehicle, emodin or C23, respectively. One day post induction, their pancreatic and lung injury was assessed by histology and arterial blood gas analysis. In vitro, rat alveolar macrophages (NR8383 cells) were treated with recombinant rat CIRP in the presence or absence of TAK242 (a TLR4 inhibitor), C23 or emodin. The CIRP-mediated activation of the NLRP3/IL-1β/CXCL1 signaling in rat lungs and NR8383 cells was determined. Similarly, the role of IL-1β in the CIRP-induced CXCL1 expression was investigated.Results: Emodin treatment significantly reduced inflammation and tissue damages in the pancreatic and lung tissues in rats with SAP-ALI, accompanied by decreasing serum amylase, CIRP and IL-1β levels and improving lung function. Furthermore, emodin significantly mitigated the SAP-up-regulated CIRP expression in the pancreatic islets and lung tissues, and attenuated the SAP-activated NF-κB signaling, NLRP3 inflammasome formation and CXCL1 expression in lung resident macrophages as well as neutrophil infiltration in the lungs of rats. In addition, treatment with CIRP significantly activated the NF-κB signaling and NLRP3 inflammasome formation and induced IL-1β and CXCL1 expression and pyroptosis in NR8383 cells, which were abrogated by TAK242 and significantly mitigated by C23 or emodin. Moreover, CIRP only induced very lower levels of CXCL1 expression in IL-1β-silencing NR8383 cells and treatment with IL-1β induced CXCL1 expression in NR8383 cells in a dose and time-dependent manner.Conclusion: Emodin may inhibit the CIRP-activated NLRP3/IL-1β/CXCL1signaling to decrease neutrophil infiltration and ameliorate the SAP-ALI in rats.

Clozapine Induces an Acute Proinflammatory Response That Is Attenuated by Inhibition of Inflammasome Signaling: Implications for Idiosyncratic Drug-Induced Agranulocytosis

“…5E and 5F ). Because CXCL1 was found to be generated in an inflammasome-dependent mechanism in THP-1 cells ( Figure 2D ) and by other groups ( Tomalka et al , 2011 ; Xu et al , 2021 ), these data suggest that inflammasome activation is necessary for downstream amplification of the innate immune response to clozapine in vivo , as well. However, upon repeating this study using a different lot of anakinra, anakinra alone caused neutrophilia.…”

Treatment of Severe Acute Pancreatitis and Related Lung Injury by Targeting Gasdermin D-Mediated Pyroptosis

“…Plasma-derived exosomes from SAP mice were capable of triggering NLRP3-dependent pyroptosis in AMs ( Wu et al, 2020 ). Emodin might inhibit the cold-inducible RNA-binding protein (CIRP)-mediated activation of the NLRP3/IL-1β/CXCL1 signaling in rats, which then ameliorated the SAP-associated ALI ( Xu et al, 2021 ). Our study confirmed the crucial role of GSDMD-mediated pyroptosis in SAP-associated ALI.…”

“…Pyroptosis or gasdermins are involved in several diseases, including viral or bacterial infections, autoinflammatory genetic diseases, complex diseases exacerbated by inflammation, and cancer; inhibiting pyroptosis or gasdermins is a promising strategy to intervene in these diseases ( Liu et al, 2021 ). However, only very few studies focused on the role of pyroptosis in SAP-associated ALI ( Wu et al, 2020 ; Gao et al, 2021 ; Xu et al, 2021 ). It is unclear whether the targeted therapy of pyroptosis will be effective.…”

Advances in the study of emodin: an update on pharmacological properties and mechanistic basis

“…Xu et al . further determined that emodin (40 mg/kg) markedly mitigated SAP-upregulated cold-inducible RNA-binding protein expression and NLRP3 inflammasome formation to attenuate progressive pulmonary neutrophil infiltration in SAP-ALI rats, via deactivating NLRP3/IL-1β/CXCL1 signal [ 49 ]. Pyroptosis has recently been well-characterized as inflammasome-related programmed cell death and gasdermin D is defined as an executioner for pyroptosis downstream of inflammasome activation.…”