Histone Deacetylase Regulates Trypsin Activation, Inflammation, and Tissue Damage in Acute Pancreatitis in Mice

Hartman, Hannes; Wetterholm, Erik; Thorlacius, Henrik; Regnér, Sara

doi:10.1007/s10620-014-3474-y

Cited by 22 publications

(17 citation statements)

References 25 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We found that, differently to what was observed upon pan-HDAC inhibitor treatment (Hartman et al, 2015), MS-275 neither prevented the initial acinar damage nor the expression of chemokines necessary to recruit leukocytes. However, the inhibitor could diminish the recruitment of leukocyte populations, including macrophages and T cells sub-populations into the pancreas.…”

Section: Ms-275 and Pancreatic Inflammationcontrasting

confidence: 91%

“…Based on these observations, we hypothesize that HDAC activity may be a key factor in modulating not only leukocyte infiltration in the injured tissue but also gene expression changes in acinar cells affecting pancreatic regeneration. In support of this hypothesis, two recent studies showed that in vivo treatment with the pan-HDAC inhibitors sodium butyrate and trichostatin A (TSA), which target both class I and class II HDAC subfamilies, alleviated pancreatic damage, inflammation and fibrosis following L-arginine- (Kanika et al, 2015) or taurocholic acid-induced pancreatitis (Hartman et al, 2015) in rodents. However, in another study treatment with valproic acid had a detrimental effect on cerulein-induced pancreatitis, consequently delaying tissue recovery and reducing acinar cell proliferation (Eisses et al, 2015).…”

Section: Introductionmentioning

confidence: 94%

See 1 more Smart Citation

Class I histone deacetylase inhibition improves pancreatitis outcome by limiting leukocyte recruitment and acinar‐to‐ductal metaplasia

Bombardo

Saponara

Malagola

et al. 2017

British J Pharmacology

View full text Add to dashboard Cite

BACKGROUND AND PURPOSEPancreatitis is a common inflammation of the pancreas with rising incidence in many countries. Despite improvements in diagnostic techniques, the disease is associated with high risk of severe morbidity and mortality and there is an urgent need for new therapeutic interventions. In this study, we evaluated whether histone deacetylases (HDACs), key epigenetic regulators of gene transcription, are involved in the development of the disease. EXPERIMENTAL APPROACHWe analysed HDAC regulation during cerulein-induced acute, chronic and autoimmune pancreatitis using different transgenic mouse models. The functional relevance of class I HDACs was tested with the selective inhibitor MS-275 in vivo upon pancreatitis induction and in vitro in activated macrophages and primary acinar cell explants. KEY RESULTSHDAC expression and activity were up-regulated in a time-dependent manner following induction of pancreatitis, with the highest abundance observed for class I HDACs. Class I HDAC inhibition did not prevent the initial acinar cell damage. However, it effectively reduced the infiltration of inflammatory cells, including macrophages and T cells, in both acute and chronic phases of the disease, and directly disrupted macrophage activation. In addition, MS-275 treatment reduced DNA damage in acinar cells and limited acinar de-differentiation into acinar-to-ductal metaplasia in a cell-autonomous manner by impeding the EGF receptor signalling axis. CONCLUSIONS AND IMPLICATIONSThese results demonstrate that class I HDACs are critically involved in the development of acute and chronic forms of pancreatitis and suggest that blockade of class I HDAC isoforms is a promising target to improve the outcome of the disease. IntroductionAbnormal activity of histone deacetylases (HDACs), a family of enzymes involved in the epigenetic control of gene transcription, has been implicated in the aetiology and development of several malignancies. However, recent evidence indicates that HDACs are also involved in the development of inflammatory diseases, highlighting the potential of targeting the activity of HDACs as a therapeutic approach to improve the outcome of rheumatoid arthritis (Choo et al., 2010(Choo et al., , 2013, neuritis (Zhang et al., 2010;Zhang and Schluesener, 2013), cholitis (Felice et al., 2015) and autoimmunity (Hancock et al., 2012).HDACs control the acetylation status of histone and non-histone proteins, thus regulating the expression of target genes (reviewed in Delcuve et al., 2012). The complexity of acetylation-based epigenetic regulation is reflected by the size of the mammalian HDAC family, composed of 11 zinc-dependent enzymes divided into three subfamilies (classes I, II and IV) and seven NAD-dependent enzymes in a fourth (sirtuin) subfamily (class III), with non-redundant functions.The function of HDAC subfamilies in the pathophysiology of pancreatitis, a highly debilitating inflammatory disease with a potentially lethal outcome, has not been thoroughly investigated. During pancreatitis, the ...

show abstract

Section: Ms-275 and Pancreatic Inflammationcontrasting

confidence: 91%

Section: Introductionmentioning

confidence: 94%

Class I histone deacetylase inhibition improves pancreatitis outcome by limiting leukocyte recruitment and acinar‐to‐ductal metaplasia

Bombardo

Saponara

Malagola

et al. 2017

British J Pharmacology

View full text Add to dashboard Cite

show abstract

“…This is very important as recently published data from Hartman et al showed that inhibition of HDAC decreased markers of pancreatitis and protected from tissue injury of the pancreas in C57Bl/6 mice subjected to taurocholic acid model of pancreatitis. 40 …”

Section: Discussionmentioning

confidence: 99%

Characterization of Mouse Models of Early Pancreatic Lesions Induced by Alcohol and Chronic Pancreatitis

Xu¹,

Chheda²,

Ouhaddi³

et al. 2015

Pancreas

View full text Add to dashboard Cite

Objective We describe the first mouse model of pancreatic intra-epithelial neoplasia (PanIN) lesions induced by alcohol in the presence and absence of chronic pancreatitis. Methods Pdx1-Cre; LSL-Kras (KC) mice were exposed to Lieber-DeCarli alcohol diet for 6 weeks with cerulein injections. PanIN lesions and markers of fibrosis, inflammation, histone de-acetylation, epithelial-to-mesenchymal transition (EMT), and cancer stemness were measured by immuno-histochemistry and Western. Results Exposure of KC mice to an alcohol diet significantly stimulated fibrosis and slightly, but not significantly, increased the level of PanIN lesions associated with an increase in tumor-promoting M2-macrophages. Importantly, the alcohol diet did not increase activation of stellate cells. Alcohol diet and cerulein injections resulted in synergistic and additive effects on PanIN lesion and M2-Macrophage phenotype induction, respectively. Cerulein-pancreatitis caused stellate cell activation, EMT, and cancer stemness in the pancreas. Pancreatitis caused histone deacetylation which was promoted by the alcohol diet. Pancreatitis increased EMT and cancer stemness markers which not further affected by the alcohol diet. Conclusion The results suggest that alcohol has independent effects on promotion of PDAC associated with fibrosis formed through a stellate cell-independent mechanism and that it further promotes early PDAC and M2 macrophage induction in the context of chronic pancreatitis.

show abstract

“…Of the 1976 cases of severe acute pancreatitis admitted to the 15 medical centers in China between 1990 and 2005, 25.2% were idiopathic [4]. 19.8% of the 337 patients with severe acute pancreatitis in Peking Union Medical College Hospital were idiopathic [4]. With the development of research and the progress of detection technology, the causes of some of idiopathic severe acute pancreatitis can be identified, such as small stone disease, Audi sphincter dysfunction and others [9].…”

Section: Idiopathicmentioning

confidence: 99%

Emodin in Severe Acute Pancreatitis Treatment

Liu¹,

Yuan²,

Guo³

et al. 2017

View full text Add to dashboard Cite

show abstract

Histone Deacetylase Regulates Trypsin Activation, Inflammation, and Tissue Damage in Acute Pancreatitis in Mice

Abstract: Our findings show that HDAC regulates trypsin activation, inflammation, and tissue damage in AP. Thus, targeting HDAC could serve as novel therapeutic approach in the management of severe AP.

Cited by 22 publications

References 25 publications

Class I histone deacetylase inhibition improves pancreatitis outcome by limiting leukocyte recruitment and acinar‐to‐ductal metaplasia

Class I histone deacetylase inhibition improves pancreatitis outcome by limiting leukocyte recruitment and acinar‐to‐ductal metaplasia

Characterization of Mouse Models of Early Pancreatic Lesions Induced by Alcohol and Chronic Pancreatitis

Emodin in Severe Acute Pancreatitis Treatment

Contact Info

Product

Resources

About