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

2021 ◽  
Vol 9 ◽  
Author(s):  
Jinxiang Wu ◽  
Jintao Zhang ◽  
Jiping Zhao ◽  
Shihong Chen ◽  
Tao Zhou ◽  
...  
Keyword(s):  
Acute Pancreatitis ◽  
Lung Injury ◽  
Mouse Models ◽  
Severe Acute Pancreatitis ◽  
Proinflammatory Cytokines ◽  
Potential Application ◽  
Receptor Protein ◽  
Wild Type ◽  
Functional Relevance

The functional relevance and effects of the pyroptosis executioner gasdermin D (GSDMD) on severe acute pancreatitis (SAP)-associated lung injury are unclear. We established caerulein-induced mouse models of SAP-associated lung injury, which showed that GSDMD-mediated pyroptosis was activated in both pancreatic and lung tissues. Compared with Gsdmd wild-type SAP mouse models, Gsdmd knockout (Gsdmd–/–) ameliorated SAP-induced pancreas and related lung injury. Additionally, we investigated the effects of disulfiram on the treatment of SAP. Disulfiram is a Food and Drug Administration (FDA)-approved anti-alcoholism drug, which is reported as an effective pyroptosis inhibitor by either directly covalently modifying GSDMD or indirectly inhibiting the cleavage of GSDMD via inactivating Nod-like receptor protein 3 inflammasome. We demonstrated that disulfiram inhibited the cleavage of GSDMD, alleviated caerulein-induced SAP and related lung injury, and decreased the expression levels of proinflammatory cytokines (IL-1β and IL-18). Collectively, these findings disclosed the role of GSDMD-mediated pyroptosis in SAP and the potential application of disulfiram in the treatment of SAP.

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

Gut ◽  
1998 ◽  
Vol 43 (2) ◽  
pp. 232-239 ◽  
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.

scholarly journals Pathophysiological aspects of severe acute pancreatitis-associated lung injury

2005 ◽  
Vol 133 (1-2) ◽  
pp. 76-81 ◽  
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.

scholarly journals CTRP3 ameliorates cerulein-induced severe acute pancreatitis in mice via SIRT1/NF-κB/p53 axis

2020 ◽  
Vol 40 (10) ◽  
Author(s):  
Chunyang Lv ◽  
Yuan He ◽  
Mingli Wei ◽  
Guiyun Xu ◽  
Chuang Chen ◽  
...  
Keyword(s):  
Acute Pancreatitis ◽  
Mouse Models ◽  
Severe Acute Pancreatitis ◽  
Intraperitoneal Injection ◽  
Protective Effects ◽  
P53 Signaling ◽  
Abdominal Disease ◽  
Life Threatening ◽  
Dependent Protein

Abstract Severe acute pancreatitis (SAP) is a common and life-threatening clinical acute abdominal disease. C1q/tumor necrosis factor-related protein 3 (CTRP3), a novel paralog of adiponectin, has been identified as a crucial regulator in multiple types of inflammatory disorders. However, the biological role of CTRP3 in SAP remains poorly understood. The present study aimed to characterize the role of CTRP3 in SAP and illuminate the potential mechanisms involved. In the current study, SAP mouse models were induced by seven hourly intraperitoneal injection of cerulein (50 μg/kg) and an immediate intraperitoneal injection of lipopolysaccharide (10 mg/kg) after the last cerulein administration. Histological examination and serological analysis demonstrated that SAP mouse models were successfully established. Herein, we found that CTRP3 expression was significantly decreased in the pancreatic tissues of SAP mice compared with normal control mice. Furthermore, we explored the effects of CTRP3 rescue in SAP mice and discovered that CTRP3 overexpression attenuated pathological lesions, inhibited inflammatory mediator release and repressed acinar cell apoptosis. Notably, mechanistic studies revealed that CTRP3 overexpression suppressed NF-κB p65 phosphorylation and p53 acetylation to alleviate cerulein-induced SAP in mouse models through activation of silent information regulator 1 (SIRT1), a nicotinamide adenine dinucleotide-dependent protein deacetylase. Collectively, our data indicate that CTRP3 may exert its protective effects in SAP mice via regulation of SIRT1-mediated NF-κB and p53 signaling pathways, implying a promising therapeutic strategy against SAP.

Regulation of HSP60 and the role of MK2 in a new model of severe experimental pancreatitis

2009 ◽  
Vol 297 (5) ◽  
pp. G981-G989 ◽  
Author(s):  
Yong-Yu Li ◽  
Stephanie Ochs ◽  
Zhi-Rong Gao ◽  
Antje Malo ◽  
Chang-Jie Chen ◽  
...  
Keyword(s):  
Acute Pancreatitis ◽  
Severe Acute Pancreatitis ◽  
Inflammatory Responses ◽  
Pancreatic Enzyme ◽  
Homozygous Deletion ◽  
Experimental Pancreatitis ◽  
Wild Type ◽  
New Model ◽  
Response Expression

The objective of this study was to investigate the role of MAPKAP kinase 2 (MK2) and heat shock protein (HSP) HSP60 in the pathogenesis of a new model of severe acute pancreatitis (AP). MK2 plays a significant role in the regulation of cytokines. It has been shown that induction and expression of several HSPs can protect against experimental pancreatitis. Interplay between both systems seems of high interest. Mice with a homozygous deletion of the MK2 gene were used. Severe AP was induced by combined intraperitoneal injections of cerulein with lipopolysaccharide (LPS). Severity of AP was assessed by biochemical markers and histology. The serum IL-6 and lung myeloperoxidase (MPO) levels were determined for assessing the extent of systemic inflammatory response. Expression of HSP25, HSP60, HSP70, and HSP90 was analyzed by Western blotting. Repeated injections of cerulein alone or cerulein plus LPS (Cer+LPS) resulted in local inflammatory responses in the pancreas and corresponding systemic inflammatory changes with pronounced severity in the Cer+LPS group. Compared with the C57Bl wild-type mice, the MK2−/− mice presented with significant milder pancreatitis and attenuated responses of serum amylase and trypsinogen activity. Furthermore, serum IL-6 was decreased as well as lung MPO activity. Injection of LPS alone displayed neither pancreatic inflammatory responses nor alterations of pancreatic enzyme activities but evidently elevated serum IL-6 levels and increased lung MPO activity. In contrast hereto, in the MK2−/− mice, these changes were much milder. Increased expression of HSP25 and HSP60 occurred after induction of AP. Especially, HSP60 was robustly elevated after Cer+LPS treatment, in both MK2−/− and wild-type mice. Thus the homozygous deletion of the MK2 gene ameliorates the severity of acute pancreatitis and accompanying systemic inflammatory reactions in a new model of severe acute pancreatitis. Our data support the hypothesis that MK2 participates in the multifactorial regulation of early inflammatory responses in AP, independently of the regulation of stress proteins like HSP25 and HSP60 and most likely due to its effect on cytokine regulation.

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

2018 ◽  
Vol 2018 ◽  
pp. 1-10 ◽  
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.

scholarly journals Role of Macrophage Inflammatory Peptide-2 in Cerulein-Induced Acute Pancreatitis and Pancreatitis-Associated Lung Injury

2003 ◽  
Vol 83 (4) ◽  
pp. 471-478 ◽  
Author(s):  
Catherine M Pastor ◽  
Laura Rubbia-Brandt ◽  
Antoine Hadengue ◽  
Martha Jordan ◽  
Philippe Morel ◽  
...  
Keyword(s):  
Acute Pancreatitis ◽  
Lung Injury
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