Acinar injury and early cytokine response in human acute biliary pancreatitis

Jakkampudi, Aparna; Jangala, Ramaiah; Reddy, Ratnakar; Sasikala, Mitnala; Rao, Guduru Venkat; Rebala, Pradeep; Reddy, D. Nageshwar; Talukdar, Rupjyoti

doi:10.1038/s41598-017-15479-2

Cited by 35 publications

(16 citation statements)

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“…Recent studies have revealed that the initiating events of SAP, including zymogen activation and cell death, occur in pancreatic acinar cells (PACs) [ 3 ]. Furthermore, the earliest immune response in acute pancreatitis was shown to originate within the PACs that activate circulating immune cells to induce a systemic inflammatory response [ 4 ].…”

Section: Introductionmentioning

confidence: 99%

TSG-6 secreted by human adipose tissue-derived mesenchymal stem cells ameliorates severe acute pancreatitis via ER stress downregulation in mice

Song

Ryu

et al. 2018

Stem Cell Res Ther

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BackgroundThrough recent studies, the onset of acute pancreatitis in pancreatic acinar cells (PACs) and the regulatory role of PACs in severe acute pancreatitis (SAP) have been revealed. During the early stages of pancreatitis, the endoplasmic reticulum (ER) in PACs undergoes significant changes, including swelling and vacuolization. In response to an increase in the extracellular stress in ER, PACs lose their functions, leading to cell apoptosis and inflammation response. The beneficial effects of human adipose tissue-derived mesenchymal stem cells (hAT-MSCs) on SAP have been well documented in previous studies. However, the underlying mechanism of their action remains controversial.MethodsIn this study, the therapeutic effects of intraperitoneally administered hAT-MSCs in a caerulein (50 μg/kg)- and lipopolysaccharide (LPS) (10 mg/kg)-co-induced SAP mouse model were evaluated. Inflammatory response and ER stress were measured in pancreatic tissue samples, and the beneficial effects were evaluated through quantitative reverse transcription polymerase chain reaction (qRT-PCR), western blot, and immunofluorescence analysis.ResultsInflammatory response and ER stress were ameliorated following hAT-MSC injection, and the beneficial effects were observed in the absence of significant engraftment of hAT-MSCs. hAT-MSCs transfected with siRNA-targeting tumour necrosis factor-α-induced gene/protein 6 (TSG-6) were unable to inhibit ER stress and inflammation. In addition, TSG-6 from hAT-MSCs significantly suppressed ER stress-induced apoptosis and nuclear factor kappa B (NF-κB) activity in SAP model mice.ConclusionsTSG-6 secreted by hAT-MSCs protects PACs in SAP model mice via the inhibition of ER stress, as well as inflammatory responses. This study has revealed a new area for ER stress-targeted therapy in SAP patients.Graphical abstract Electronic supplementary materialThe online version of this article (10.1186/s13287-018-1009-8) contains supplementary material, which is available to authorized users.

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Section: Introductionmentioning

confidence: 99%

TSG-6 secreted by human adipose tissue-derived mesenchymal stem cells ameliorates severe acute pancreatitis via ER stress downregulation in mice

Song

Ryu

et al. 2018

Stem Cell Res Ther

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“…Interestingly, it has been shown in experimental models of AP using L-arginine that there could be PSC activation and early fibrosis even after the first episode of AP [11]. In our recent studies using human pancreatic acini, we could show that PSC activation could occur even after bile acid-mediated injury [4]. However, clinical acute biliary pancreatitis does not progress to CP.…”

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confidence: 75%

“…This is the sentinel acute pancreatitis event (SAPE) hypothesis that defines pancreatitis as a disease spectrum [1]. Even though several clinical and bench studies have provided insights into the pathophysiology of the disease [2][3][4][5], there is still no modality to accurately predict the progression of RAP to CP. This gap in understanding has likely, at least in part, precluded development of any specific interventions that could prevent progression of RAP to CP or reverse the changes of CP.…”

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confidence: 99%

Progression of recurrent acute to chronic pancreatitis: More questions than answers!

Talukdar

2018

Indian J Gastroenterol

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Acute pancreatitis (AP) continues to pose a substantial challenge to clinicians and researchers. It has been proposed that an index episode of AP could progress to recurrent AP (RAP) and may finally culminate into chronic pancreatitis (CP). This is the sentinel acute pancreatitis event (SAPE) hypothesis that defines pancreatitis as a disease spectrum [1]. Even though several clinical and bench studies have provided insights into the pathophysiology of the disease [2][3][4][5], there is still no modality to accurately predict the progression of RAP to CP. This gap in understanding has likely, at least in part, precluded development of any specific interventions that could prevent progression of RAP to CP or reverse the changes of CP.In the current issue, Kalaria and colleagues have reported their observations on the progression of RAP to CP in a tertiary care private hospital in western India [6]. They observed the development of features of CP during a median period of 32 months in five out of 72 patients who had a single episode of AP. 27.8% had RAP of which 13 (48.1%) developed features of chronicity after a median of 47 months from the index or sentinel episode. Chronicity was observed with a higher frequency among patients with alcoholic and idiopathic subtypes. In a meta-analysis by Sankaran et al. in 2015 [7], the crude prevalence of RAP based on 11 studies (n = 8017) was estimated to be 22% (95% CI 18% to 26%). However, on analysis of the prospective studies only (nine studies, n = 1869), the pooled prevalence of RAP turned out to be 20% (95% CI 15% to 25%). Five studies (n = 6826) in this metaanalysis reported the subsequent diagnosis of CP after RAP, which was reported to be 36% (95% CI 20% to 53%). On the other hand, 10% of patients who had a single episode of AP subsequently developed CP. Unpublished data from an ongoing study from our institute also reveals that 10% of patients with a single episode of AP and 28% with RAP eventually developed CP.Since only a proportion of RAP progresses to CP, it becomes speculative as to what determines the progression of RAP to CP. A recent study from the Dutch group involving 669 patients who survived the first episode of AP defined independent risk factors for the development of CP after an index and recurrent AP [8]. RAP conferred an odds of 2.90 (95% CI 2.07 to 4.05) per episode for progression to CP. Among patients who had RAP as a risk factor, the other independent risk factors for progression to CP were alcohol as the etiology (OR 4.85 [95% CI 2.04 to 11.52]) and development of necrotizing pancreatitis (OR 8.78 [95% CI 4.09 to 18.86]). On the other hand, among patients who did not have RAP, the independent risk factors were alcohol (OR 4.22 [95% CI 1.83 to 9.73]; p = 0.001) and idiopathic etiology (OR 3.98 [95% CI 1.64 to 9.65]; p = 0.002), current smoker (OR 2.90 [95% CI 1.42 to 5.93]; p = 0.004), and necrotizing pancreatitis (OR 6.65 [95% CI 3.40 to 13.01]; p < 0.001).It is now clearly established that the pathological hallmark of CP is progressive fibros...

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“…Another study reported a similar effect of pro-inflammatory interferon-β and anti-inflammatory cytokine IL-10 in macrophages after LPS treatment in vitro 49 . Considering that pro-inflammatory cytokines are crucially associated with the pathogenesis of acute pancreatic injury 50 , 51 , the impaired homeostasis between pro- and anti-inflammatory mediators in acinar cells might predispose LPS-challenged autophagy-deficient Atg7 Δpan mice to developing more severe pancreatic injury than normal mice.…”

Section: Discussionmentioning

confidence: 99%

Impaired autophagy increases susceptibility to endotoxin-induced chronic pancreatitis

Xia

Zhou

et al. 2020

Cell Death Dis

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Chronic pancreatitis (CP) is associated with elevated plasma levels of bacterial lipopolysaccharide (LPS) and we have demonstrated reduced acinar cell autophagy in human CP tissue. Therefore, we investigated the role of autophagy in experimental endotoxin-induced pancreatic injury and aimed to identify LPS in human CP tissue. Pancreatic Atg7-deficient mice were injected with a single sub-lethal dose of LPS. Expression of autophagy, apoptosis, necroptosis, and inflammatory markers was determined 3 and 24 h later utilizing immunoblotting and immunofluorescence. The presence of LPS in pancreatic tissue from mice and from patients and healthy controls was determined using immunohistochemistry, immunoblots, and chromogenic assay. Mice lacking pancreatic autophagy exhibited local signs of inflammation and were particularly sensitive to the toxic effect of LPS injection as compared to control mice. In response to LPS, Atg7Δpan mice exhibited enhanced vacuolization of pancreatic acinar cells, increase in TLR4 expression coupled to enhanced expression of NF-κΒ, JNK, and pro-inflammatory cytokines by acinar cells and enhanced infiltration by myeloid cells (but not Atg7F/F controls). Cell death was enhanced in Atg7Δpan pancreata, but only necroptosis and trypsin activation was further amplified following LPS injection along with elevated pancreatic LPS. The presence of LPS was identified in the pancreata from all 14 CP patients examined but was absent in the pancreata from all 10 normal controls. Altogether, these results support a potential role for metabolic endotoxemia in the pathogenesis of CP. Moreover, the evidence also supports the notion that autophagy plays a major cytoprotective and anti-inflammatory role in the pancreas, and blunting metabolic endotoxemia-induced CP.

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Acinar injury and early cytokine response in human acute biliary pancreatitis

Cited by 35 publications

References 37 publications

TSG-6 secreted by human adipose tissue-derived mesenchymal stem cells ameliorates severe acute pancreatitis via ER stress downregulation in mice

TSG-6 secreted by human adipose tissue-derived mesenchymal stem cells ameliorates severe acute pancreatitis via ER stress downregulation in mice

Progression of recurrent acute to chronic pancreatitis: More questions than answers!

Impaired autophagy increases susceptibility to endotoxin-induced chronic pancreatitis

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