Protective Effects and Anti-Inflammatory Pathways of Exogenous Calcitonin Gene-Related Peptide in Severe Necrotizing Pancreatitis

Schneider, Lutz; Hartwig, Werner; Flemming, Thomas; Hackert, Thilo; Fortunato, Franco; Heck, Matthias; Gebhard, Martha-Maria; Nawroth, Peter P.; Bierhaus, Angelika; Büchler, Markus W.; Werner, Jens

doi:10.1159/000212099

Cited by 35 publications

(24 citation statements)

References 36 publications

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“…22 Moreover, CGRP reduced the leukocyte infiltration into the pancreatic tissue and increased the pancreatic blood flow, permitting removal of active digestive enzymes and mediators of inflammation, thereby attenuating the pancreatic damage in pancreatitis. 10, 23 The present study found that the CALCB splice region variants ( CALCB_ p.S30P and IR [1]) resulted in a decreased βCGRP. This revealed a new meningeal neurovascular mechanism by showing that trypsin stimulation of PAR-2 and βCGRP induces a marked vasodilatory response in the obliterative vasculitis and perineural inflammation in pancreatic lesions of patients with IgG4-related AIP.…”

Section: Discussionmentioning

confidence: 80%

“…9, 10 CGRP is a potent microvascular dilator neuropeptide, considered to play an essential role in neurogenic vasodilatation and maintaining functional integrity in peripheral tissues, and it was known to downregulate the immune response and influence the key processes in autoimmunity. 10, 11, 12, 13 CGRP exists in two distinct isoforms: (1) αCGRP, which is the product of alternative splicing of the calcitonin gene ( CT/CALCA ) in neurons. (2) calcitonin gene-related peptide beta ( CALCB ), which has been discovered to form βCGRP, expressed primarily in the enteric sensory system, gut, and inner organs.…”

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confidence: 99%

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CALCB splice region pathogenic variants leading to plasma cell neurotropic enrichment in type 1 autoimmune pancreatitis

Liu

Chen

et al. 2017

Cell Death Dis

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Recently, we have demonstrated that PRSS1 mutations cause ectopic trypsinogen activation and thereby result in type 1 autoimmune pancreatitis (AIP). However, the molecules involved in inducing obliterative vasculitis and perineural inflammation in the pancreas are not well-described. The present study applied whole-exome sequencing (WES) to determine the underlying etiology and revealed novel missense splice region variants, CALCB c.88T>C (p.Ser30Pro) and IR [1]-mutants, in 2 of the 3 families and 2 of 26 unrelated patients with type 1 AIP. In vitro, both of the mutants displayed decreased βCGRP, ERK1/2 phosphorylation, and co-localized with endoplasmic reticulum and Golgi apparatus. The novel pathogenic variant identified in this case should contribute to our understanding of the expanding spectrum of AIP.

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Section: Discussionmentioning

confidence: 80%

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confidence: 99%

CALCB splice region pathogenic variants leading to plasma cell neurotropic enrichment in type 1 autoimmune pancreatitis

Liu

Chen

et al. 2017

Cell Death Dis

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“…Earlier studies showed that CGRP inhibits infiltration by macrophages and other inflammatory cells, as well as the expression of inflammatory mediators [34,35].…”

Section: Discussionmentioning

confidence: 98%

Endogenous CGRP protects against neointimal hyperplasia following wire-induced vascular injury

Yang

Sakurai

Kamiyoshi

et al. 2013

Journal of Molecular and Cellular Cardiology

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Neointimal hyperplasia is the primary lesion underlying atherosclerosis and restenosis after percutaneous coronary intervention. Calcitonin gene-related peptide (CGRP) is produced by alternative splicing of the primary transcript of the calcitonin/CGRP gene.Originally identified as a strongly vasodilatory neuropeptide, CGRP is now known to be a pleiotropic peptide widely distributed in various organs and tissues. Our aim was to investigate the possibility that CGRP acts as an endogenous vasoprotective molecule.We compared the effect of CGRP deficiency on neointima formation after wire-induced vascular injury in wild-type and CGRP knockout (CGRP-/-) mice. We found that neointima formation after vascular injury was markedly enhanced in CGRP-/-mice, which also showed a higher degree of oxidative stress, as indicated by reduced expression of nitric oxide synthase, increased expression of p47phox, and elevated levels of 4HNE, as well as greater infiltration of macrophages. In addition, CGRP-deficiency led to increased vascular smooth muscle cell (VSMC) proliferation within the neointima. By contrast, bone marrow-derived cells had little or no effect on neointima formation in CGRP-/-mice. In vitro analysis showed CGRP-treatment suppressed VSMC proliferation, migration, and ERK1/2 activity. These results clearly demonstrate that endogenous CGRP suppresses the oxidative stress and VSMC proliferation induced by vascular injury. As a vasoprotective molecule, CGRP could be an important therapeutic target in cardiovascular disease.

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“…Although we cannot explain this contradiction, the inability of TRPV4 agonists to cause neurogenic inflammation in the pancreas may relate to the doses of agonists that were used or the rapid degradation of released neuropeptides by pancreatic proteases, especially in the inflamed states when these proteases are prematurely activated. It is also possible that TRPV4 agonists release neuropeptides such as CGRP that can protect against pancreatic inflammation (37).…”

Section: Discussionmentioning

confidence: 99%

Transient receptor potential ion channels V4 and A1 contribute to pancreatitis pain in mice

Ceppa¹,

Cattaruzza²,

Lyo³

et al. 2010

American Journal of Physiology-Gastrointestinal and Liver Physi

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The mechanisms of pancreatic pain, a cardinal symptom of pancreatitis, are unknown. Proinflammatory agents that activate transient receptor potential (TRP) channels in nociceptive neurons can cause neurogenic inflammation and pain. We report a major role for TRPV4, which detects osmotic pressure and arachidonic acid metabolites, and TRPA1, which responds to 4-hydroxynonenal and cyclopentenone prostaglandins, in pancreatic inflammation and pain in mice. Immunoreactive TRPV4 and TRPA1 were detected in pancreatic nerve fibers and in dorsal root ganglia neurons innervating the pancreas, which were identified by retrograde tracing. Agonists of TRPV4 and TRPA1 increased intracellular Ca(2+) concentration ([Ca(2+)](i)) in these neurons in culture, and neurons also responded to the TRPV1 agonist capsaicin and are thus nociceptors. Intraductal injection of TRPV4 and TRPA1 agonists increased c-Fos expression in spinal neurons, indicative of nociceptor activation, and intraductal TRPA1 agonists also caused pancreatic inflammation. The effects of TRPV4 and TRPA1 agonists on [Ca(2+)](i), pain and inflammation were markedly diminished or abolished in trpv4 and trpa1 knockout mice. The secretagogue cerulein induced pancreatitis, c-Fos expression in spinal neurons, and pain behavior in wild-type mice. Deletion of trpv4 or trpa1 suppressed c-Fos expression and pain behavior, and deletion of trpa1 attenuated pancreatitis. Thus TRPV4 and TRPA1 contribute to pancreatic pain, and TRPA1 also mediates pancreatic inflammation. Our results provide new information about the contributions of TRPV4 and TRPA1 to inflammatory pain and suggest that channel antagonists are an effective therapy for pancreatitis, when multiple proinflammatory agents are generated that can activate and sensitize these channels.

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Protective Effects and Anti-Inflammatory Pathways of Exogenous Calcitonin Gene-Related Peptide in Severe Necrotizing Pancreatitis

Cited by 35 publications

References 36 publications

CALCB splice region pathogenic variants leading to plasma cell neurotropic enrichment in type 1 autoimmune pancreatitis

CALCB splice region pathogenic variants leading to plasma cell neurotropic enrichment in type 1 autoimmune pancreatitis

Endogenous CGRP protects against neointimal hyperplasia following wire-induced vascular injury

Transient receptor potential ion channels V4 and A1 contribute to pancreatitis pain in mice

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