Immune cell infiltration and growth-associated protein 43 expression correlate with pain in chronic pancreatitis

Sebastiano, Pierluigi di; Fink, Thorsten; Weihe, Eberhard; Frieß, Helmut; Innocenti, Paolo; Beger, H G; Büchler, M W

doi:10.1016/s0016-5085(97)70047-7

Cited by 152 publications

(83 citation statements)

References 4 publications

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“…NK-1R mRNA was expressed mainly in nerves and ganglia, and there was a strong relationship to the pain syndrome in these patients. These observations in chronic pancreatitis support the existence of neuroimmune interactions that seem to exist also in pancreatic cancer and might influence cancer cell behavior (Büchler et al, 1992;DiSebastiano et al, 1997;Roggo et al, 2002).…”

Section: Friess Et Almentioning

confidence: 54%

Neurokinin-1 Receptor Expression and Its Potential Effects on Tumor Growth in Human Pancreatic Cancer

Frieß

Zhu

Liard

et al. 2003

Laboratory Investigation

108

111

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SUMMARY:The neurokinin-1 receptor (NK-1R) and its ligand substance P (SP) are involved in the pathogenesis of certain neural tumors. Because nerves are significantly altered in pancreatic cancer, evidence for alteration of this pathway in human pancreatic cancer was sought. Expression of NK-1R was analyzed by real-time quantitative RT-PCR, in situ hybridization, immunohistochemistry, and Western blot analysis in normal human pancreatic and pancreatic cancer tissue samples and in pancreatic cancer cell lines. Furthermore, the influence of SP analogs and of the NK-1R antagonist MEN 11467 on pancreatic cancer cell growth was analyzed by sulforhodamine B (SRB) assay. By real-time quantitative RT-PCR, NK-1R mRNA was increased 36.7-fold (p Ͻ 0.001) in human pancreatic cancer samples compared with normal controls. Enhanced NK-1R expression levels were not related to tumor grade but were associated with advanced tumor stage and poorer prognosis. By in situ hybridization and immunohistochemistry, NK-1R mRNA and immunoreactivity were only occasionally weakly present in acinar and ductal cells in the normal pancreas. In contrast, moderate to strong NK-1R mRNA signals and immunoreactivity were present in most cancer cells. By Western blot analysis, NK-1R was increased 26-fold (p Ͻ 0.01) in pancreatic cancer samples in comparison to normal controls. NK-1R mRNA was detected in five pancreatic cancer cell lines by real-time quantitative RT-PCR, with the highest levels in CAPAN-1 cells and the lowest in ASPC-1 cells. SP analogs stimulated pancreatic cancer cell growth, depending on the NK-1R expression level, and this effect could be blocked by a selective NK-1R antagonist. These findings illustrate that the NK-1R pathway is activated in human pancreatic cancer and has the potential to contribute to cancer cell growth, thus suggesting the existence of a neuro-cancer cell interaction in vivo. (Lab Invest 2003, 83:731-742).

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Section: Friess Et Almentioning

confidence: 54%

Neurokinin-1 Receptor Expression and Its Potential Effects on Tumor Growth in Human Pancreatic Cancer

Frieß

Zhu

Liard

et al. 2003

Laboratory Investigation

108

111

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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: 84%

“…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.…”

mentioning

confidence: 99%

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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“…The pain of pancreatitis is multifactorial (Di Sebastiano et al, 1997;Di Sebastiano et al, 2004;Keith et al, 1985;). Even when there is increased ductal pressure, it is not necessarily the cause of the pain (Manes et al, 1994), and pain in patients who have CP exists in the absence of increased ductal pressure.…”

Section: Patient Selection and Pain Syndromementioning

confidence: 99%

Total Pancreatectomy and Islet Autotransplantation for Chronic Pancreatitis

E.R.¹,

Bellin²,

Juan³

et al. 2012

Chronic Pancreatitis

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Immune cell infiltration and growth-associated protein 43 expression correlate with pain in chronic pancreatitis

Cited by 152 publications

References 4 publications

Neurokinin-1 Receptor Expression and Its Potential Effects on Tumor Growth in Human Pancreatic Cancer

Neurokinin-1 Receptor Expression and Its Potential Effects on Tumor Growth in Human Pancreatic Cancer

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

Total Pancreatectomy and Islet Autotransplantation for Chronic Pancreatitis

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