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

doi:10.1016/S0016-5085(97)70047-7

Gastroenterology

Volume 112, Issue 5, May 1997, Pages 1648-1655

https://doi.org/10.1016/S0016-5085(97)70047-7 Get rights and content

Abstract

BACKGROUND & AIMS: Changes in innervation pattern and neuropeptide content have been shown in chronic pancreatitis (CP), including increased neuronal expression of growth-associated protein 43 (GAP-43). We used GAP-43 as an established marker of neuronal plasticity and correlated histological findings with pain scores of patients with CP. METHODS: In tissue samples from 29 patients with CP, the parenchyma- fibrosis ratio, degree of perineural immune cell infiltration, and neuronal GAP-43 immunoreactivity were determined by digitized morphometry and correlated with individual pain scores. RESULTS: In CP, GAP-43 was significantly increased in pancreatic nerve fibers and intrinsic neurons. GAP-43 expression correlated with individual pain scores. The infiltration of pancreatic nerves by immune cells was significantly correlated with the intensity of pain. Pain scores correlated neither with the degree of pancreatic fibrosis nor with the duration of the disease. CONCLUSIONS: The results suggest that infiltration of pancreatic nerves by immune cells and neuronal plasticity are pathogenic factors for the generation of pain, whereas the degree of pancreatic fibrosis has no major impact on pain in CP. (Gastroenterology 1997 May;112(5):1648-55)

References (0)

Cited by (164)

Morphological and immunohistochemical comparison of intrapancreatic nerves between chronic pancreatitis and type 1 autoimmune pancreatitis
2017, Pancreatology
Citation Excerpt :
The presence of GAP43 in intrinsic neurons and nerve fibers is associated with pain intensity. These observations indicate that neural structure alterations may significantly contribute to pain generation in patients with CP [8]. Our results are consistent with literature in demonstrating an increase in neural number and density, and their close correlation with the severity of pancreatic inflammation in CP.
The abdominal pain associated with chronic pancreatitis (CP) may be related to the increased number and size of intrapancreatic nerves. On the other hand, patients with type 1 autoimmune pancreatitis (AIP) rarely suffer from the pain syndrome, and there are no previous studies concerning the histopathological findings of intrapancreatic nerves in patients with type 1 AIP. The current study is aimed at investigating the differences in the histopathological and immunohistochemical findings of intrapancreatic nerves in patients with CP and type 1 AIP.
Neuroanatomical differences between CP and type 1 AIP were assessed by immunostaining with a pan-neuronal marker, protein gene product 9.5 (PGP9.5). The number (neural density) and area (neural hypertrophy) of PGP9.5-immunopositive nerves were quantitatively analyzed. Furthermore, the expression of nerve growth factor (NGF), and a high affinity receptor for NGF, tyrosine kinase receptor A (TrkA), was assessed by immunohistochemistry.
Both neural density and hypertrophy were significantly greater in pancreatic tissue samples from patients with CP than those with normal pancreas or type 1 AIP. NGF expression was stronger in type 1 AIP than in CP, whereas TrkA expression in type 1 AIP was poorer than in CP.
Although CP and type 1 AIP are both characterized by the presence of sustained pancreatic inflammation, they are different in terms of the density and hypertrophy of intrapancreatic nerve fibers. It is possible that this may be related to the difference in the activity of the NGF/TrkA-pathway between the two types of pancreatitis.
Mechanism, assessment and management of pain in chronic pancreatitis: Recommendations of a multidisciplinary study group
2016, Pancreatology
Pain in patients with chronic pancreatitis (CP) remains the primary clinical complaint and source of poor quality of life. However, clear guidance on evaluation and treatment is lacking.
Pancreatic Pain working groups reviewed information on pain mechanisms, clinical pain assessment and pain treatment in CP. Levels of evidence were assigned using the Oxford system, and consensus was based on GRADE. A consensus meeting was held during PancreasFest 2012 with substantial post-meeting discussion, debate, and manuscript refinement.
Twelve discussion questions and proposed guidance statements were presented. Conference participates concluded: Disease Mechanism: Pain etiology is multifactorial, but data are lacking to effectively link symptoms with pathologic feature and molecular subtypes. Assessment of Pain: Pain should be assessed at each clinical visit, but evidence to support an optimal approach to assessing pain character, frequency and severity is lacking. Management: There was general agreement on the roles for endoscopic and surgical therapies, but less agreement on optimal patient selection for medical, psychological, endoscopic, surgical and other therapies.
Progress is occurring in pain biology and treatment options, but pain in patients with CP remains a major problem that is inadequately understood, measured and managed. The growing body of information needs to be translated into more effective clinical care.
Ectopic uterine tissue as a chronic pain generator
2012, Neuroscience
While chronic pain is a main symptom in endometriosis, the underlying mechanisms and effective therapy remain elusive. We developed an animal model enabling the exploration of ectopic endometrium as a source of endometriosis pain. Rats were surgically implanted with autologous uterus in the gastrocnemius muscle. Within two weeks, visual inspection revealed the presence of a reddish-brown fluid-filled cystic structure at the implant site. Histology demonstrated cystic glandular structures with stromal invasion of the muscle. Immunohistochemical studies of these lesions revealed the presence of markers for nociceptor nerve fibers and neuronal sprouting. Fourteen days after surgery rats exhibited persistent mechanical hyperalgesia at the site of the ectopic endometrial lesion. Intralesional, but not contralateral, injection of progesterone was dose-dependently antihyperalgesic. Systemic administration of leuprolide also produced antihyperalgesia. In vivo electrophysiological recordings from sensory neurons innervating the lesion revealed a significant increase in their response to sustained mechanical stimulation. These results are consistent with clinical and pathological findings observed in patients with endometriosis, compatible with the ectopic endometrium as a source of pain. This model of endometriosis allows mechanistic exploration at the lesion site facilitating our understanding of endometriosis pain.
Enhanced expression of neuronal proteins in idiopathic frozen shoulder
2012, Journal of Shoulder and Elbow Surgery
Citation Excerpt :
Growing peripheral nerves often display sensitization and are associated with increased pain.24 A number of painful conditions are correlated with increased GAP43 expression, including chronic pancreatitis,9,11 peritoneal endometriosis,25 and chronic discogenic pain.15 Thus the increased presence of GAP43+ in growing nerves in the capsular tissue may explain why frozen shoulder can be so painful.
Our understanding of the pathogenesis of frozen shoulder and why it is so painful is undetermined. This study investigated the expression of neuronal proteins in the capsular tissue of frozen shoulder.
Shoulder capsular samples were collected from 8 patients with idiopathic adhesive capsulitis and 10 patients with a rotator cuff tear but no stiffness (controls). Samples were analyzed by immunohistochemistry using antibodies against protein gene product 9.5 (PGP9.5), a general nerve marker; growth associated protein 43 (GAP43), a nerve growth marker; nerve growth factor receptor p75; and CD34, an endothelial cell marker.
Samples from frozen shoulders showed subsynovial hypercellularity and fibroblastic proliferation, with increased expression of nerve growth factor receptor p75 and CD34 compared with controls. Nerves positive for PGP9.5 and GAP43 were more abundant in samples of frozen shoulder (2.8 ± 0.2 and 2.4 ± 0.4 per field; P < .01) compared with controls (1.6 ± 0.3 and 1.3 ± 0.3 per field; P < .05). Expression of neuronal proteins followed that of CD34.
Increased expression of nerve growth factor receptor and new nerve fibers were found in the shoulder capsular tissue of patients with frozen shoulder compared with those without a frozen shoulder. These data suggest that neoinnervation and neoangiogenesis in the shoulder capsule are important events in the pathogenesis of frozen shoulder and may help explain the often-severe pain of patients with frozen shoulder.
Management of chronic pancreatitis: Conservative, endoscopic, and surgical
2012, Blumgart's Surgery of the Liver, Biliary Tract and Pancreas
Immune cell infiltration in the pancreas of type 1, type 2 and type 3c diabetes
2023, Therapeutic Advances in Endocrinology and Metabolism

View all citing articles on Scopus

View full text