Role of Neurogenic Inflammation in Pancreatitis and Pancreatic Pain

Vera–Portocarrero, Louis P.; Westlund, Karin N.

doi:10.1159/000087654

Cited by 39 publications

(28 citation statements)

References 129 publications

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“…But, could there be a more direct and fundamental interaction between these two cell types? It is well documented that sensory neurons have efferent function through the wide range of small molecules they release in the periphery such as glutamate, ATP, CGRP, and SP (27,(67)(68)(69). Moreover, sensory, sympathetic, and parasympathetic neurons express receptors for these molecules that when stimulated, release additional substances that modulate pancreatic cellular function.…”

Section: Discussionmentioning

confidence: 99%

Ablation of sensory neurons in a genetic model of pancreatic ductal adenocarcinoma slows initiation and progression of cancer

Saloman

Albers

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

266

243

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Pancreatic ductal adenocarcinoma (PDAC) is characterized by an exuberant inflammatory desmoplastic response. The PDAC microenvironment is complex, containing both pro-and antitumorigenic elements, and remains to be fully characterized. Here, we show that sensory neurons, an under-studied cohort of the pancreas tumor stroma, play a significant role in the initiation and progression of the early stages of PDAC. Using a well-established autochthonous model of PDAC (PKC), we show that inflammation and neuronal damage in the peripheral and central nervous system (CNS) occurs as early as the pancreatic intraepithelial neoplasia (PanIN) 2 stage. Also at the PanIN2 stage, pancreas acinar-derived cells frequently invade along sensory neurons into the spinal cord and migrate caudally to the lower thoracic and upper lumbar regions. Sensory neuron ablation by neonatal capsaicin injection prevented perineural invasion (PNI), astrocyte activation, and neuronal damage, suggesting that sensory neurons convey inflammatory signals from Kras-induced pancreatic neoplasia to the CNS. Neuron ablation in PKC mice also significantly delayed PanIN formation and ultimately prolonged survival compared with vehicle-treated controls (median survival, 7.8 vs. 4.5 mo; P = 0.001). These data establish a reciprocal signaling loop between the pancreas and nervous system, including the CNS, that supports inflammation associated with oncogenic Kras-induced neoplasia. Thus, pancreatic sensory neurons comprise an important stromal cell population that supports the initiation and progression of PDAC and may represent a potential target for prevention in high-risk populations.sensory neuron | pancreatic ductal adenocarcinoma | tumorigenesis | inflammation | PanIN P ancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers with a median survival of ∼6 mo from diagnosis (National Cancer Institute). A number of unique features distinguish PDAC from other carcinomas, but the most striking is the exuberant desmoplastic infiltrate within tumors. This compartment exhibits an array of cell types, including activated myofibroblasts and myeloid-derived cells. Indeed, this inflammatory infiltrate is present at the inception of neoplasia and accumulates at a near exponential rate during progression to carcinoma and tumor formation. It provides a complex balance of pro-and antitumorigenic signals to neoplastic cells (and also to each other) that is a focus of intense investigation. The pancreas tumor microenvironment has been studied previously, but new tools [genetically engineered mouse models (GEMs) that faithfully recapitulate the salient features of human PDAC] now allow for a careful dissection of the stroma. Using these models, we showed that generalized inflammation is required for the development of precancerous pancreatic intraepithelial neoplasias (1) and that Hedgehog-dependent stromal elements, including activated myofibroblasts, serve to constrain tumor growth and spread (2). Other cellular components of the pancreatic inflammatory str...

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Section: Discussionmentioning

confidence: 99%

Ablation of sensory neurons in a genetic model of pancreatic ductal adenocarcinoma slows initiation and progression of cancer

Saloman

Albers

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

266

243

View full text Add to dashboard Cite

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“…However, another feature of clinical relevance in acute pancreatitis is abdominal pain (Vera-Portocarrero and Westlund, 2005;Frossard et al, 2008). Studying abdominal pain in CBDO-induced pancreatitis can be a difficult task because this model of induction involves a laparotomy.…”

Section: Discussionmentioning

confidence: 99%

Beneficial effects of the ethanol extract of Caesalpinia pyramidalis on the inflammatory response and abdominal hyperalgesia in rats with acute pancreatitis

Santana

Santos

et al. 2012

Journal of Ethnopharmacology

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“…The pain in patients with CP is often burning and intermittent or shooting, features also seen in stimulus-independent neuropathic pain 16 17. In patients with CP the allodynia due to touch and movements seen in neuropathic pain from somatic structures may be reflected during postprandial pain.…”

Section: Neuropathic Pain Mechanisms and Clinical Featuresmentioning

confidence: 99%

“…A detailed description of this topic is far beyond the scope of this review. (For comprehensive reviews, the reader is referred to Fasanella et al 4 and Vera-Portocarrero and Westlund 17fig 3.…”

Section: Biochemical and Histopathological Findingsmentioning

confidence: 99%