Analysis of nerves in chronic pancreatitis

Bockman, Dale E.; Büchler, M.; Malfertheiner, Peter; Beger, H. G.

doi:10.1016/0016-5085(88)90687-7

Cited by 398 publications

(197 citation statements)

References 8 publications

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“…35,36,58 Previous studies have determined that the 'inflammatory' and the 'neuropathic' component of pain in CP may not be independent but instead closely linked: The 'neuro-immune crosstalk' through pancreatic neuritis, and changes in intrapancreatic neural plasticity were all associated with the severity of pain experienced by CP patients. 8,10,33,58 In addition, recent studies support the idea that the peripheral immune system and spinal microglia are crucial in the generation of neuropathic pain. 35,37,58 The contribution of fractalkine to general neuropathic pain was shown earlier: In several experimental models of neuropathic pain, it was shown that endogenous fractalkine is released by DRG and is accompanied by the upregulation of CX3CR1 in the spinal microglia and neuropathic pain behavior.…”

Section: Discussionmentioning

confidence: 82%

“…Here, one should note that damage to the perineurium of intrapancreatic nerves is a frequently observed phenomenon in CP. 8 One can imagine that once this barrier function is lost, neural fractalkine would exit the intraneural space and enhance mononuclear cell infiltration by acting as a chemoattractant ('inside-out effect'). On the other hand, inflammatory mediators released by mononuclear cells, such as TNF-a or IL-1, can gain access to the axons through the damaged perineural barrier ('outside-in effect') and induce neuropathic pain.…”

Section: Discussionmentioning

confidence: 99%

“…At the sites of inflammation, mononuclear cells can easily infiltrate the damaged perineurium and cause the characteristic pancreatic neuritis, which is strongly associated with abdominal pain in CP. [8][9][10] However, the precise pathophysiology of the neuro-immune crosstalk, and of pain initiation and maintenance in CP remains unclear.…”

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confidence: 99%

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Neural fractalkine expression is closely linked to pain and pancreatic neuritis in human chronic pancreatitis

Ceyhan

Deucker

Demir

et al. 2009

Laboratory Investigation

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The chemokine fractalkine induces migration of inflammatory cells into inflamed tissues, thereby aggravating inflammatory tissue damage and fibrosis. Furthermore, fractalkine increases neuropathic pain through glial activation, which can be diminished by blocking of its receptor, CX3CR1, through neutralizing antibodies. As chronic pancreatitis (CP) is characterized by tissue infiltration of inflammatory cells, fibrosis, pancreatic neuritis and severe pain, the roles of fractalkine and CX3CR1 were investigated in CP (n ¼ 61) and normal pancreas (NP, n ¼ 21) by QRT-PCR, western blot and immunohistochemistry analyses. Their expression correlated with the severity of pancreatic neuritis, fibrosis, intrapancreatic nerve fiber density and hypertrophy, pain, CP duration and with the amount of inflammatory cell infiltrate immuno-positive for CD45 and CD68. To investigate the influence of fractalkine on pancreatic fibrogenesis, human pancreatic stellate cells (hPSCs) were isolated from patients with CP, incubated with fractalkine and then Collagen-1 and a-smooth muscle actin (a-SMA) expressions were measured. CX3CR1, but not fractalkine, mRNA was overexpressed in CP. In contrast, the protein levels of both CX3CR1 and fractalkine were upregulated. Neuro-immunoreactivity for fractalkine and CX3CR1 was strongest in patients suffering from severe pain and pancreatic neuritis. Long-term suffering from CP was noticeably related to increased neural immunoreactivity of fractalkine. Furthermore, fractalkine and CX3CR1 mRNA overexpressions were associated with enhanced lymphocyte and macrophage infiltration. Advanced fibrosis was associated with increased fractalkine expression, whereas in vitro fractalkine had no significant impact on collagen-1 and a-SMA expressions in hPSCs. Therefore, pancreatic fractalkine expression appears to be linked to visceral pain and to the recruitment of inflammatory cells into the pancreatic tissue and nerve fibers, with subsequent pancreatic neuritis. However, pancreatic fibrogenesis is probably indirectly influenced by fractalkine. Taken together, these novel findings suggest that CX3CR1 represents a potential novel therapeutic target to reduce inflammation and modulate pain in CP.

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Section: Discussionmentioning

confidence: 82%

Section: Discussionmentioning

confidence: 99%

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Neural fractalkine expression is closely linked to pain and pancreatic neuritis in human chronic pancreatitis

Ceyhan

Deucker

Demir

et al. 2009

Laboratory Investigation

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“…In addition, these results are also in agreement with the growth inhibitory function of this gene. In both CP and pancreatic cancer, overgrowth of nerves has been observed (Bockman et al 1988(Bockman et al ,1994, suggesting that downregulation of PMP22 in some nerves in CP and cancer contributes to the nerve changes observed in these conditions.…”

Section: Discussionmentioning

confidence: 99%

Expression Analysis of PMP22/Gas3 in Premalignant and Malignant Pancreatic Lesions

Kleeff

Espósito

et al. 2005

J Histochem Cytochem.

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S U M M A R YPMP22 is a structural protein of Schwann cells, but it also influences cell proliferation. In the present study, quantitative RT-PCR (QRT-PCR) and immunohistochemistry were used to determine PMP22 mRNA levels and to localize PMP22 in the normal pancreas ( n ϭ 20), chronic pancreatitis (CP) ( n ϭ 22), pancreatic ductal adenocarcinoma (PDAC) ( n ϭ 31), intraductal papillary mucinous neoplasms (IPMN) ( n ϭ 9), mucinous cystic tumors (MCN) ( n ϭ 4), and in a panel of PanIN lesions ( n ϭ 29). PMP22 mRNA levels were significantly higher in CP (3-fold) and PDAC (2.5-fold), compared to normal pancreatic tissues. PMP22 expression was restricted to nerves in the normal pancreas, while in CP and PDAC PMP22 was also expressed in PanIN lesions and in a small percentage of pancreatic cancer cells. PMP22 was weak to absent in the tumor cells of IPMNs and MCNs. PMP22 mRNA was present at different levels in cultured pancreatic cancer cells and up-regulated by transforming growth factor (TGF)-␤ 1 in 2 of 8 of these cell lines. In conclusion, PMP22 expression is present in both CP and PDAC tissues. Its expression in PanIN lesions and some pancreatic cancer cells in vitro and in vivo suggests a role of PMP22 in the neoplastic transformation process from the normal pancreas to pre-malignant lesions to pancreatic cancer.

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“…In Western industrialized countries, chronic alcohol ingestion is the main etiologic factor in approximately 80% of patients with CP (Adler and Schmid, 1997). The typical histomorphologic changes present in CP include acinar cell degeneration and dedifferentiation of acinar cells into duct-like tubular complexes, pseudoductular hyperplasia, enlarged pancreatic ducts, replacement of the functional parenchyma by variable amounts of fibrosis, infiltration by inflammatory cells, and an increase in the size and number of pancreatic nerves, some of which exhibit morphologic changes suggestive of cell damage (Bockman et al, 1988;Korc and Schmiegel, 1994). Although recent studies indicate that various cytokines and growth factors and their receptors are involved in the pathophysiologic processes of CP, the exact biochemical and molecular mechanisms that underlie these changes are still not clear (Kornmann et al, 1998).…”

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confidence: 99%

Galectin-1 and Galectin-3 in Chronic Pancreatitis

Wang

Frieß

Zhu

et al. 2000

Laboratory Investigation

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SUMMARY:Galectin-1 and galectin-3 have important functions in cell-cell interactions, cell adhesion to extracellular matrix, the organization of extracellular matrix, and tissue remodeling. To assess their potential role in chronic pancreatitis (CP), we examined their expression by Northern blot analysis, in situ hybridization, immunohistochemistry, and Western blot analysis in normal and CP pancreatic tissues. Northern blot analysis revealed a 4.5-fold increase of galectin-1 mRNA (p Ͻ 0.01) and a 3.8-fold increase of galectin-3 mRNA (p Ͻ 0.01) in CP samples compared with normal controls. In situ hybridization analysis of normal pancreas indicated low abundance of galectin-1 mRNA in fibroblasts, whereas galectin-3 mRNA was moderately present in ductal cells. CP samples exhibited moderate to intense galectin-1 mRNA signals in fibroblasts, whereas galectin-3 mRNA signals were intense in the cells of ductular complexes and weak in the degenerating acinar cells. In addition, intense galectin-1 and galectin-3 mRNA signals were present in nerves of normal and CP samples. Immunohistochemistry showed a distribution pattern of galectin-1 and galectin-3 similar to that described for in situ hybridization. Relative quantification of galectin-1 and galectin-3 protein by immunoblotting revealed an increase of 3.2-fold and 3.0-fold, respectively, in CP compared with normal controls. There was a significant correlation between galectin-1 and fibrosis and between galectin-3 and fibrosis and the density of ductular complexes. Up-regulation of galectin-1 in fibroblasts and galectin-3 in ductular complexes suggests a role of these lectins in tissue remodeling in CP. Galectin-1 might participate in ECM changes, whereas galectin-3 seems to be involved in both ECM changes and ductular complex formation. (Lab Invest 2000, 80:1233-1241.

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Analysis of nerves in chronic pancreatitis

Cited by 398 publications

References 8 publications

Neural fractalkine expression is closely linked to pain and pancreatic neuritis in human chronic pancreatitis

Neural fractalkine expression is closely linked to pain and pancreatic neuritis in human chronic pancreatitis

Expression Analysis of PMP22/Gas3 in Premalignant and Malignant Pancreatic Lesions

Galectin-1 and Galectin-3 in Chronic Pancreatitis

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