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

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.

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NLRP3 Deficiency Alleviates Severe Acute Pancreatitis and Pancreatitis-Associated Lung Injury in a Mouse Model

BioMed Research International ◽

10.1155/2018/1294951 ◽

2018 ◽

Vol 2018 ◽

pp. 1-10 ◽

Cited By ~ 8

Author(s):

Qiang Fu ◽

Zhensheng Zhai ◽

Yuzhu Wang ◽

Lixia Xu ◽

Pengchong Jia ◽

...

Keyword(s):

Acute Pancreatitis ◽

Lung Injury ◽

Severe Acute Pancreatitis ◽

Nlrp3 Inflammasome ◽

Early Death ◽

Neutrophil Infiltration ◽

Multiple Organ ◽

Dependent Manner ◽

Dose Dependent ◽

Nlrp3 Expression

The rapid production and release of a large number of inflammatory cytokines can cause excessive local and systemic inflammation in severe acute pancreatitis (SAP) and multiple organ dysfunction syndrome (MODS), especially pancreatitis-associated acute lung injury (P-ALI), which is the main cause of early death in patients with SAP. The NLRP3 inflammasome plays an important role in the maturation of IL-1β and the inflammatory cascade. Here, we established a model of SAP using wild-type (NLRP3+/+) and NLRP3 knockout (NLRP3-/-) mice by intraperitoneal injections of caerulein (Cae) and lipopolysaccharide (LPS). Pathological injury to the pancreas and lungs, the inflammatory response, and neutrophil infiltration were significantly mitigated in NLRP3-/- mice. Furthermore, INF-39, an NLRP3 inflammasome inhibitor, could reduce the severity of SAP and P-ALI in a dose-dependent manner. Our results suggested that SAP and P-ALI were alleviated by NLRP3 deficiency in mice, and thus, reducing NLRP3 expression may mitigate SAP-associated inflammation and P-ALI.

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Effects of penehyclidine hydrochloride on severe acute pancreatitis-associated acute lung injury in rats

Biomedicine & Pharmacotherapy ◽

10.1016/j.biopha.2017.12.025 ◽

2018 ◽

Vol 97 ◽

pp. 1689-1693 ◽

Cited By ~ 6

Author(s):

Rongtao Zhu ◽

Yipu Zhao ◽

Xiaobo Li ◽

Tao Bai ◽

Shuai Wang ◽

...

Keyword(s):

Acute Pancreatitis ◽

Acute Lung Injury ◽

Lung Injury ◽

Severe Acute Pancreatitis ◽

Penehyclidine Hydrochloride

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Severe Acute Pancreatitis: Gut Barrier Failure, Systemic Inflammatory Response, Acute Lung Injury, and the Role of the Mesenteric Lymph

Surgical Infections ◽

10.1089/sur.2015.034 ◽

2015 ◽

Vol 16 (6) ◽

pp. 651-656 ◽

Cited By ~ 29

Author(s):

Per Landahl ◽

Daniel Ansari ◽

Roland Andersson

Keyword(s):

Acute Pancreatitis ◽

Acute Lung Injury ◽

Lung Injury ◽

Inflammatory Response ◽

Severe Acute Pancreatitis ◽

Systemic Inflammatory Response ◽

Mesenteric Lymph ◽

Barrier Failure ◽

Gut Barrier Failure

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A monoclonal anti-interleukin 8 antibody (WS-4) inhibits cytokine response and acute lung injury in experimental severe acute necrotising pancreatitis in rabbits

Gut ◽

10.1136/gut.43.2.232 ◽

1998 ◽

Vol 43 (2) ◽

pp. 232-239 ◽

Cited By ~ 75

Author(s):

M O Osman ◽

J U Kristensen ◽

N O Jacobsen ◽

S B Lausten ◽

B Deleuran ◽

...

Keyword(s):

Acute Pancreatitis ◽

Acute Lung Injury ◽

Lung Injury ◽

Severe Acute Pancreatitis ◽

Pancreatic Necrosis ◽

Interleukin 8 ◽

Systemic Complications ◽

Duct Ligation ◽

Tnf Α

Background—Interleukin 8 (IL-8) has recently been proposed to have an important role in mediating the development of the systemic sequelae associated with severe acute pancreatitis.Aims—To define the role of IL-8 in acute pancreatitis by neutralising its effects with a monoclonal anti-IL-8 antibody (WS-4), in a rabbit model of severe acute pancreatitis.Methods—Acute pancreatitis was induced by retrograde injection of 5% chenodeoxycholic acid into the pancreatic duct and duct ligation. Twenty rabbits were divided equally into two groups: acute pancreatitis controls received physiological saline and the treated group received WS-4, 30 minutes before induction of acute pancreatitis.Results—Pretreatment of animals with WS-4 resulted in significant down regulation of serum IL-8 and tumour necrosis factor α (TNF-α) from three to six hours after induction of acute pancreatitis (p=0.011 and 0.047 for IL-8 and 0.033 and 0.022 for TNF-α, respectively). In addition, a significant reduction in the CD11b and CD18 positive cells and the amount of interstitial neutrophil infiltration in the lungs from WS-4 treated animals was seen. In contrast, WS-4 did not alter the amount of pancreatic necrosis and the serum concentrations of amylase, lipase, calcium, and glucose.Conclusion—WS-4 cannot change the amount of pancreatic necrosis induced by injection of 5% bile acid, but does reduce the acute lung injury, presumably through inhibition of circulating IL-8 and TNF-α, and CD11b/CD18 in lung tissue. Therefore, a role of IL-8 in the progression of acute pancreatitis and the development of its systemic complications is suggested.

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Pathophysiological aspects of severe acute pancreatitis-associated lung injury

Srpski arhiv za celokupno lekarstvo ◽

10.2298/sarh0502076s ◽

2005 ◽

Vol 133 (1-2) ◽

pp. 76-81 ◽

Cited By ~ 13

Author(s):

Maja Surbatovic ◽

Krsta Jovanovic ◽

Sonja Radakovic ◽

Nikola Filipovic

Keyword(s):

Acute Pancreatitis ◽

Acute Lung Injury ◽

Mortality Rate ◽

Lung Injury ◽

Severe Acute Pancreatitis ◽

Distress Syndrome ◽

Severe Form ◽

Very High ◽

Intensive Medicine

Acute pancreatitis is an inflammatory process which occurs in severe form in 20% of all patients, out of whom 1596-25% will die. The incidence of severe acute pancreatitis-associated lung injury (APALI) varies from 15% to 55% and its severity varies from mild hypoxemia to acute respiratory distress syndrome (ARDS). Acute lung injury (ALI) and ARDS are the most significant manifestations of extra abdominal dysfunctions in severe acute pancreatitis with mortality rate as high as 60% in the first week of the onset of illness. Different pathophysiological mechanisms of severe acute pancreatitis-associated lung injury have been described. The role of enzymes, adhesion molecules, neutrophils, fibronectin and various inflammatory mediators has been emphasized. Mechanism of the acute lung injury associated with the acute pancreatitis is very complex and has not been clear yet. There is no specific therapeutic procedure and mortality rate is very high. Therefore, further studies are necessary to address this acute and growing problem in intensive medicine.

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