Gastrin-releasing Peptide Levels Research Articles

Novel neuroendocrine role of γ-aminobutyric acid and gastrin-releasing peptide in the host response to influenza infection

Gastrin-releasing peptide (GRP), an evolutionarily conserved neuropeptide, significantly contributes to influenza-induced lethality and inflammation in rodent models. Because GRP is produced by pulmonary neuroendocrine cells (PNECs) in response to γ-aminobutyric acid (GABA), we hypothesized that influenza infection promotes GABA release from PNECs that activate GABAB receptors on PNECs to secrete GRP. Oxidative stress was increased in the lungs of influenza A/PR/8/34 (PR8)-infected mice, as well as serum glutamate decarboxylase 1, the enzyme that converts L-glutamic acid into GABA. The therapeutic administration of saclofen, a GABAB receptor antagonist, protected PR8-infected mice, reduced lung proinflammatory gene expression of C-C chemokine receptor type 2 (Ccr2), cluster of differentiation 68 (Cd68), and Toll like receptor 4 (Tlr4) and decreased the levels of GRP and high-mobility group box 1 (HMGB1) in sera. Conversely, baclofen, a GABAB receptor agonist, significantly increased the lethality and inflammatory responses. The GRP antagonist, NSC77427, as well as the GABAB antagonist, saclofen, blunted the PR8-induced monocyte infiltration into the lung. Together, these data provide the first report of neuroregulatory control of influenza-induced disease.

Gastrin-releasing peptide regulates fear learning under stressed conditions via activation of the amygdalostriatal transition area.

The amygdala, a critical brain region responsible for emotional behavior, is crucially involved in the regulation of the effects of stress on emotional behavior. In the mammalian forebrain, gastrin-releasing peptide (GRP), a 27-amino-acid mammalian neuropeptide, which is a homolog of the 14-amino-acid amidated amphibian peptide bombesin, is highly expressed in the amygdala. The levels of GRP are markedly increased in the amygdala after acute stress; therefore, it is known as a stress-activated modulator. To determine the role of GRP in emotional behavior under stress, we conducted some behavioral and biochemical experiments with GRP-knockout (KO) mice. GRP-KO mice exhibited a longer freezing response than wild-type (WT) littermates in both contextual and auditory fear (also known as threat) conditioning tests only when they were subjected to acute restraint stress 20 min before the conditioning. To identify the critical neural circuits associated with the regulation of emotional memory by GRP, we conducted Arc/Arg3.1-reporter mapping in the amygdala with an Arc-Venus reporter transgenic mouse line. In the amygdalostriatal transition area (AST) and the lateral side of the basal nuclei, fear conditioning after restraint stress increased neuronal activity significantly in WT mice, and GRP KO was found to negate this potentiation only in the AST. These results indicate that the GRP-activated neurons in the AST are likely to suppress excessive fear expression through the regulation of downstream circuits related to fear learning following acute stress.

Urine gastrin‐releasing peptide in the first week correlates with bronchopulmonary dysplasia and post‐prematurity respiratory disease

Bronchopulmonary dysplasia (BPD) is associated with post-prematurity respiratory disease (PRD) in survivors of extreme preterm birth. Identifying early biomarkers that correlate with later development of BPD and PRD may provide insights for intervention. In a preterm baboon model, elevated gastrin-releasing peptide (GRP) is associated with BPD, and GRP inhibition mitigates BPD occurrence. We performed a prospective cohort study to investigate whether urine GRP levels obtained in the first postnatal week were associated with BPD, PRD, and other urinary biomarkers of oxidative stress. Extremely low gestational age infants (23-28 completed weeks) were enrolled in a US multicenter observational study, The Prematurity and Respiratory Outcomes Program (http://clinicaltrials.gov/ct2/show/NCT01435187). We used multivariable logistic regression to examine the association between urine GRP in the first postnatal week and multiple respiratory outcomes: BPD, defined as supplemental oxygen use at 36 + 0 weeks postmenstrual age, and post-PRD, defined by positive quarterly surveys for increased medical utilization over the first year (PRD score). A total of 109 of 257 (42%) infants had BPD, and 120 of 217 (55%) had PRD. On adjusted analysis, GRP level more than 80 was associated with BPD (adjusted odds ratio [aOR], 1.83; 95% confidence interval [CI], 1.03-3.25) and positive PRD score (aOR, 2.46; 95% CI, 1.35-4.48). Urine GRP levels correlated with duration of NICU ventilatory and oxygen support and with biomarkers of oxidative stress: allantoin and 8-hydroxydeoxyguanosine. Urine GRP in the first postnatal week was associated with concurrent urine biomarkers of oxidative stress and with later diagnoses of BPD and PRD.

Gastrin-releasing peptide inhibits CA1 neurons via increasing inhibitory synaptic transmissions in hippocampal slices of rats.

Gastrin-releasing peptide plays an important role in regulating the advanced functions of the brain including emotional behavior, learning and memory. What's more, gastrin-releasing peptide levels are also associated with the central nervous system diseases. Our previous study proposed that intraperitoneal injection of gastrin-releasing peptide can improve spatial memory in chronic ischemic model rats. It is well known that the hippocampus is an important brain area related to spatial learning and memory, but the mechanisms of gastrin-releasing peptide on hippocampal neurons are still unclear. In this study, we examined the effects of gastrin-releasing peptide on excitability of hippocampal CA1 neurons and further explored the mechanisms of its effects on synaptic transmission. The results showed that gastrin-releasing peptide inhibited the excitability of CA1 neurons and increased the amplitude and frequency of inhibitory postsynaptic currents significantly. In summary, we demonstrate that gastrin-releasing peptide can inhibit the excitability of hippocampal CA1 area neurons in brain slices and clarify the synaptic transmission mechanism involved in this process, which provide a theoretical basis for gastrin-releasing peptide to improve animal cognitive function, and new ideas for the treatment of related central nervous system diseases.

Immediate Release of Gastrin-Releasing Peptide Mediates Delayed Radiation-Induced Pulmonary Fibrosis

Radiation-induced pulmonary fibrosis (RTPF) is a progressive, serious condition in many subjects treated for thoracic malignancies or after accidental nuclear exposure. No biomarker exists for identifying the irradiated subjects most susceptible to pulmonary fibrosis (PF). Previously, we determined that gastrin-releasing peptide (GRP) was elevated within days after birth in newborns exposed to hyperoxia who later developed chronic lung disease. The goal of the current study was to test whether radiation (RT) exposure triggers GRP release in mice and whether this contributes to RTPF invivo. We determined urine GRP levels and lung GRP immunostaining in mice 0 to 24 after post-thoracic RT (15 Gy). Urine GRP levels were significantly elevated between 24 hours post-RT; GRP-blocking monoclonal antibody 2A11, given minutes post-RT, abrogated urine GRP levels by 6 to 12 hours and also altered phosphoprotein signaling pathways at 24 hours post-RT. Strong extracellular GRP immunostaining was observed in lung at 6 hours post-RT. Mice given one dose of GRP monoclonal antibody 2A11 24 hours post-RT had significantly reduced myofibroblast accumulation and collagen deposition 15 weeks later, indicating protection against lung fibrosis. Therefore, elevation of urine GRP could be predictive of RTPF development. In addition, transient GRP blockade could mitigate PF in normal lung after therapeutic or accidental RT exposure.

Protective effects of gastrin-releasing peptide receptor antagonist RC-3095 in an animal model of hepatic ischemia/reperfusion injury.

We aimed to evaluate effects of RC-3095 on mice with hepatic ischemia followed by reperfusion (I/R) injury and further explore the possible underlying mechanism. Mice were subjected to partial hepatic ischemia for 60min followed by different durations of reperfusion. Levels of gastrin-releasing peptide (GRP) and GRP receptor (GRPR) in the blood and liver were detected by enzyme-linked immunosorbent assay (ELISA) or western blotting (WB) after 3, 6, 12, or 24h of reperfusion. RC-3095 or normal saline (control) was given i.p. at the time of reperfusion. Expressions of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, and IL-10 in blood and liver samples were examined with ELISA. Neutrophil influx into the liver was assessed by flow cytometry and myeloperoxidase assay. Hematoxylin-eosin staining of the liver and terminal deoxynucleotidyl transferase mediated dUTP-biotin nick end labeling assay were used to determine hepatic injury and hepatocellular necrosis. Activation of nuclear factor (NF)-κB and p38/extracellular regulated protein kinase (ERK) mitogen activated protein kinase (MAPK) was investigated with WB. The expression of GRP was upregulated within 3h after reperfusion and remained elevated for up to 24h in the liver, whereas GRPR was also upregulated after 3 or 6h of reperfusion, but returned to baseline levels within 24h. RC-3095 significantly reduced the inflammatory hepatic injury, liver neutrophil accumulation, and hepatocellular apoptosis, probably by inhibiting activation of NF-κB or p38/ERK MAPK. These findings supported that GRP-GRPR played an important role in hepatic I/R injury, and RC-3095 ameliorated liver damage by suppressing the inflammatory response and hepatocellular necrosis.

Association of serum gastrin-releasing peptide levels with disease activity and pruritus in patients with chronic spontaneous urticaria

Objective To evaluate the correlation of serum gastrin-releasing peptide (GRP) levels with disease activity and pruritus in patients with chronic spontaneous urticaria. Methods Totally, 61 patients with chronic spontaneous urticaria were enrolled from the Department of Dermatology of Frist Hospital of Shanxi Medical University between June 2016 and December 2016, and 59 health checkup examinees served as controls. Peripheral blood samples were collected from these patients and healthy controls. The urticaria activity score over 7 days (UAS7) and visual analogue scale (VAS) score was used to evaluate the disease activity and degree of pruritus respectively. Enzyme-linked immunosorbent assay (ELISA) was performed to detect the serum GRP levels in the patients and healthy controls. The correlations of serum GRP levels with disease activity and degree of pruritus were analyzed. Statistical analysis was carried out by Mann-Whitney U test or Kruskal-Wallis test and Spearman′s correlation analysis for evaluation of correlations of GRP levels with UAS7 and VAS scores using SPSS22.0 software. Results The serum GRP level was significantly higher in the patients with chronic spontaneous urticaria than in the healthy controls (M[P25 - P75]: 11.2[7.31 - 22.23] ng/L vs. 7.74[7.064 ± 9.71] ng/L, Z = 4.44, P < 0.001) . Among the patients with chronic spontaneous urticaria, the serum GRP level was positively correlated with the UAS7 score (r = 0.36, P = 0.004) and the VAS score (r = 0.34, P = 0.007) . Conclusion The GRP level in the peripheral blood was elevated in the patients with chronic spontaneous urticaria, and positively correlated with the disease activity and degree of pruritus. Key words: Urticaria; Gastrin-releasing peptide; Pruritus

GABA promotes gastrin-releasing peptide secretion in NE/NE-like cells: Contribution to prostate cancer progression

In prostate cancer (PCa), neuroendocrine cells (NE) have been associated with the progression of the disease due to the secretion of neuropeptides that are capable of diffusing and influence surrounding cells. The GABAergic system is enriched in NE-like cells, and contributes to PCa progression. Additionally, γ-aminobutyric acid (GABA) stimulates the secretion of gastrin-releasing peptide (GRP) in peripheral organs. For the first time, in this study we show the role of GABA and GABAB receptor 1 (GABBR1) expression in GRP secretion in NE-like prostate cancer cells. We demonstrated an increase in GRP levels in NE-like cell medium treated with GABAB receptor agonist. Moreover, the blocking of this receptor inhibited GABA-induced GRP secretion. The invasive potential of PC3 cells was enhanced by either GRP or conditioned medium of NE-like cells treated with GABA. Additionally, we confirmed a positive correlation between GABA and GRP levels in the serum of PCa patients with NE markers. Finally, using public available data sets, we found a negative correlation between GABBR1 and androgen receptor (AR) expression, as well as a strong positive correlation between GABBR1 and enolase 2. These results suggest that GABA via GABBR1 induces GRP secretion in NE like cells involved in PCa progression.

Relationships among plasma granzyme B level, pruritus and dermatitis in patients with atopic dermatitis

BackgroundAtopic dermatitis (AD) is a multifactorial inflammatory skin disease characterized by skin barrier dysfunction, allergic inflammation and intractable pruritus resistant to conventional antipruritic treatments, including H1-antihistamines. Granzymes (Gzms) are a family of serine proteases expressed by cytotoxic T lymphocytes and natural killer cells that have been shown to modulate inflammation. However, the relationship between Gzms and pathology in AD remains unclear. ObjectiveThis study assessed the correlation between plasma GzmB levels and severity of pruritus and dermatitis, in AD patients. MethodsPlasma was collected from 46 patients with AD, 24 patients with psoriasis, and 30 healthy controls. AD severity was assessed with the scoring atopic dermatitis (SCORAD) index, psoriasis severity with the psoriasis area and severity index (PASI), and degree of pruritus by visual analogue scale (VAS) score. GzmA, GzmB and gastrin releasing peptide (GRP) levels were measured by enzyme-linked immunosorbent assays. ResultsPlasma GzmB concentrations were significantly higher in patients with AD and psoriasis than in healthy controls. Correlation analyses showed that plasma GzmB concentrations positively correlated with SCORAD and serum levels of severity markers such as thymus and activation-regulated chemokine, and lactate dehydrogenase in AD patients. Moreover, plasma levels of GRP, an itch-related peptide, were higher in patients with AD, positively correlating with VAS score and plasma GzmB level. In addition, plasma GzmB concentration was significantly lower in the treatment group than the untreated group with AD. Meanwhile, there were no correlations among GzmB levels, VAS score and PASI score in patients with psoriasis. In contrast to the results of plasma GzmB, plasma GzmA levels were unchanged among AD, psoriasis and healthy groups, and showed no correlations with VAS score and SCORAD index in patients with AD. ConclusionPlasma GzmB levels may reflect the degree of pruritus and dermatitis in patients with AD.

Early Radiation‐Induced Secretion of Gastrin‐Releasing Peptide (GRP) Mediates Late Pulmonary Fibrosis

Pulmonary fibrosis (PF), a devastating disease affecting &gt;105 Americans, can have environmental, autoimmune, or idiopathic causes. In lung, pulmonary neuroendocrine cells secrete GRP in response to oxidant exposures. Previously, we showed early GRP elevation precedes PF in hyperoxic baboons. Also, GRP blockade given to mice twice weekly abrogates radiation (RT)‐induced pulmonary fibrosis at 20 wks. We have now tested the hypothesis that early GRP secretion mediates PF by using a C57L/J mouse model of RT‐induced PF, with prolonged, irreversible kinetics like human PF. 1‐24h post‐RT mice were injected IP with PBS, 2A11 (GRP‐blocking mAb), or 77427 (GRP‐blocking small molecule). Sham controls were not irradiated. Urine was collected every 6h for 24h pre‐ and post‐RT. Lung tissue sections 10‐15 weeks post‐RT were stained for collagen (Masson's trichrome), elastin (Hall's method), and α‐smooth muscle actin immunostaining (SMA, myofibroblast marker). Quantitative image analysis was performed on alveolar photomicrographs by blinded observers. Mice had tenfold‐elevated urine GRP levels 0‐6h post‐RT, which declined to 2‐fold elevated at 18‐24h, abrogated by GRP blockade 1h post‐RT. Multiplex analysis of lungs at 24h showed only IL‐10 elevation, prevented by GRP blockade 1h post‐RT. One dose of GRP blockade 24h post‐RT abolished parameters of PF 15‐wks later: increased interstitial collagen, elastin, and myofibroblasts. In conclusion, urine GRP is elevated before 24h post‐RT, prevented by GRP blockade, which also blocks pathological hallmarks of PF months later. GRP is a novel biomarker for PF and GRP blockade might prevent PF and its sequelae.

Phthalocyanine–Peptide Conjugates: Receptor-Targeting Bifunctional Agents for Imaging and Photodynamic Therapy

The synthesis of a series of new zinc phthalocyanine-peptide conjugates targeting the gastrin-releasing peptide (GRP) and integrin receptors is reported. Two alternative synthetic methods based on Sonogashira cross-coupling of an iodinated zinc phthalocyanine with acetylenic bombesin or arginine-glycine-aspartic acid (RGD) derivatives, either in solution or on solid phase, are presented. The water-soluble conjugates were screened for their photodynamic efficacy against several cancer cell lines expressing different levels of GRP and integrin receptors, and their intracellular localization was evaluated via confocal fluorescence microscopy. Variations in photocytotoxicity between the conjugates correlate to differences in hydrophobicity as well as receptor-mediated cell uptake. In the case of the phthalocyanine-bombesin conjugate, competition experiments confirm the involvement of the GRP receptor in both the phototherapeutic activity as well as intracellular localization. These findings warrant further in vivo studies to evaluate the potential of this conjugate as photosensitizer for photodynamic therapy (PDT) of cancers overexpressing the GRP receptor.

The effect of fasting and refeeding on mRNA expression of PepT1 and gastrointestinal hormones regulating digestion and food intake in zebrafish (Danio rerio)

In vertebrates, a significant part of ingested protein is absorbed as di- and tripeptides through a brush border membrane proton/oligopeptide transporter protein called PepT1. The aim of the present study was to determine the effect of short-term food deprivation and refeeding in adult zebrafish (Danio rerio) on gastrointestinal mRNA expression of PepT1 as well as on the satiety hormones cholecystokinin (CCK), gastrin-releasing peptide (GRP) and ghrelin (GHR) in order to elucidate a potential mechanism driving compensatory growth. Sixty adult zebrafish were stocked in a 40-L aquarium and fed daily a commercial flake diet to satiation for 10 days where the digestive tracts (DT) of sampled fish (n = 5) were dissected out. Samplings were repeated following 1, 2 and 5 days of food deprivation and after 1, 2 and 5 days of refeeding. The RNA was extracted from all sampled DTs and analyzed by quantitative real-time PCR for the mRNA expression of PepT1, rRNA 18S, CCK, GRP and GHR. PepT1 mRNA expression increased with successive refeedings reaching a level approximately 8 times higher than pre-fast levels. CCK, GRP and GHR mRNA levels also decreased during fasting, but increased only to pre-fasting levels with refeeding. Overall, the results suggest that PepT1 may be a contributing mechanism to compensatory growth that could influence CCK secretion and GRP and GHR activity.

Gastrin-Releasing Peptide Receptor Antagonism Induces Protection from Lethal Sepsis: Involvement of Toll-like Receptor 4 Signaling

In sepsis, toll-like receptor (TLR)-4 modulates the migration of neutrophils to infectious foci, favoring bacteremia and mortality. In experimental sepsis, organ dysfunction and cytokines released by activated macrophages can be reduced by gastrin-releasing peptide (GRP) receptor (GRPR) antagonist RC-3095. Here we report a link between GRPR and TLR-4 in experimental models and in sepsis patients. RAW 264.7 culture cells were exposed to lipopolysaccharide (LPS) or tumor necrosis factor (TNF)-α and RC-3095 (10 ng/mL). Male Wistar rats were subjected to cecal ligation and puncture (CLP), and RC-3095 was administered (3 mg/kg, subcutaneously); after 6 h, we removed the blood, bronchoalveolar lavage, peritoneal lavage and lung. Human patients with a clinical diagnosis of sepsis received a continuous infusion with RC-3095 (3 mg/kg, intravenous) over a period of 12 h, and plasma was collected before and after RC-3095 administration and, in a different set of patients with systemic inflammatory response syndrome (SIRS) or sepsis, GRP plasma levels were determined. RC-3095 inhibited TLR-4, extracellular-signal-related kinase (ERK)-1/2, Jun NH(2)-terminal kinase (JNK) and Akt and decreased activation of activator protein 1 (AP-1), nuclear factor (NF)-κB and interleukin (IL)-6 in macrophages stimulated by LPS. It also decreased IL-6 release from macrophages stimulated by TNF-α. RC-3095 treatment in CLP rats decreased lung TLR-4, reduced the migration of cells to the lung and reduced systemic cytokines and bacterial dissemination. Patients with sepsis and systemic inflammatory response syndrome have elevated plasma levels of GRP, which associates with clinical outcome in the sepsis patients. These findings highlight the role of GRPR signaling in sepsis outcome and the beneficial action of GRPR antagonists in controlling the inflammatory response in sepsis through a mechanism involving at least inhibition of TLR-4 signaling.

Tumor-associated macrophages in clear cell renal cell carcinoma express both gastrin-releasing peptide and its receptor: a possible modulatory role of immune effectors cells

PurposeRenal cell carcinomas (RCC) frequently express the gastrin-releasing peptide receptor (GRP-R). Gastrin-releasing peptide (GRP) stimulates tumor cell proliferation and neoangiogenesis. Tumor-associated macrophages (TAM) comprise an important cellular component of these tumors. We analyzed the GRP/GRP-R network in clear cell RCC (ccRCC) and non-clear cell RCC (non-ccRCC) with special regard to its expression by macrophages, tumor cells and microvessels.MethodsGastrin-releasing peptide and GRP-R expression in 17 ccRCC and 9 non-ccRCC were analyzed by RT-PCR, immunohistochemistry and double immunofluorescence staining.ResultsTumor-associated macrophages expressed GRP and GRP receptor in ccRCC. Tumor cells and microvessels showed low to intermediate GRP-R expression in nearly all cases. In 12 ccRCC tumor epithelia also expressed low levels of GRP. Microvascular GRP expression was found in nine cases of ccRCC. For non-RCC, the expression of GRP and GRP receptor expression pattern was similar.ConclusionsTumor-associated macrophages are the main source of GRP in RCC. GRP receptor on TAM, tumor epithelia and microvessels might be a molecular base of a GRP/GRP receptor network, potentially acting as a paracrine/autocrine modulator of TAM recruitment, tumor growth and neoangiogenesis.

Impact of repeated stressor exposure on the release of corticotropin-releasing hormone, arginine-vasopressin and bombesin-like peptides at the anterior pituitary

Repeated exposure to stressors was reported to increase the expression of arginine-vasopressin (AVP), especially in corticotropin-releasing hormone (CRH) neurons co-expressing AVP, within the hypothalamus. This may increase the potential for subsequent stressor-elicited enhancement of hypothalamic–pituitary–adrenal (HPA) functioning as these peptides synergistically stimulate pituitary ACTH secretion. Likewise, members of the bombesin (BB) family of peptides (including its mammalian analogues gastrin-releasing peptide (GRP) and neuromedin B (NMB)) stimulate the release of ACTH and may play a role in the mediation and/or modulation of the CRH stress response. In the present investigation, chronic stressor exposure (daily restraint over 14 days) was associated with increased co-expression of CRH and AVP at the median eminence. In addition, in vivo interstitial levels of anterior pituitary AVP, GRP and NMB (but not CRH) were elevated following chronic stressor exposure. Basal pituitary corticosterone levels, in contrast, were unaffected by chronic stressor exposure. Following consumption of a highly palatable snack, interstitial levels of CRH, GRP, NMB and corticosterone (but not AVP) were elevated at the pituitary; however, a cross-sensitization was not apparent among rats previously exposed to the stressor and then provided with the snack. As the CRH, AVP and BB-like peptide systems have been associated with altered anxiety and depressive symptoms, the sustained peptidergic alterations observed in the chronically stressed rats may have implications for the development of these stressor-related disorders.

Levels of gastrin-releasing peptide and substance P in synovial fluid and serum correlate with levels of cytokines in rheumatoid arthritis

Levels of gastrin-releasing peptide and substance P in synovial fluid and serum correlate with levels of cytokines in rheumatoid arthritis

Circulating levels of cholecystokinin and gastrin-releasing peptide in rainbow trout fed different diets

Cholecystokinin (CCK) and gastrin-releasing peptide (GRP) are gastrointestinal peptides thought to be important regulators of intake and digestion of food in vertebrates. In this study, pre- and postprandial plasma levels of CCK and GRP were measured in rainbow trout ( Oncorhynchus mykiss) by the establishment of homologous radioimmunoassays, and the hormonal levels assessed in relation to dietary lipid:protein ratio and food intake. Fish were acclimated to either a high protein/low lipid diet (HP/LL diet; 14.1% lipids) or a normal protein/high lipid diet (NP/HL diet; 31.4% lipids). On three consecutive sampling days, radio-dense lead-glass beads were included in the diets for assessment of feed intake. Fish were terminally sampled for blood and stomach contents prior to feeding at time 0, and at 0.3, 1, 2, 4, 6, and 24 h after feeding. There was a postprandial elevation of plasma CCK levels, which was most evident after 4 and 6 h. Fish fed the NP/HL diet had higher plasma CCK levels compared with those fed the HP/LL diet. Plasma CCK levels were not affected by the amount of food ingested. GRP levels in plasma were not influenced by sampling time, diet, or feed intake. The results indicate that the endocrine release of gastrointestinal CCK is increased during feeding and may be further influenced by the dietary lipid:protein ratio in rainbow trout. Plasma GRP levels, on the other hand, appear not to be influenced by feeding or diet composition.

Levels of gastrin-releasing peptide and substance P in synovial fluid and serum correlate with levels of cytokines in rheumatoid arthritis

It is well known that cytokines are highly involved in the disease process of rheumatoid arthritis (RA). Recently, targeting of neuropeptides has been suggested to have potential therapeutic effects in RA. The aim of this study was to investigate possible interrelations between five neuropeptides (bombesin/gastrin-releasing peptide (BN/GRP), substance P (SP), vasoactive intestinal peptide, calcitonin-gene-related peptide, and neuropeptide Y) and the three cytokines tumour necrosis factor (TNF)-α, IL-6, and monocyte chemoattractant protein-1 in synovial fluid of patients with RA. We also investigated possible interrelations between these neuropeptides and soluble TNF receptor 1 in serum from RA patients. Synovial fluid and sera were collected and assayed with ELISA or RIA. The most interesting findings were correlations between BN/GRP and SP and the cytokines. Thus, in synovial fluid, the concentrations of BN/GRP and SP grouped together with IL-6, and SP also grouped together with TNF-α and monocyte chemoattractant protein-1. BN/GRP and SP concentrations in synovial fluid also grouped together with the erythrocyte sedimentation rate. In the sera, BN/GRP concentrations and soluble TNF receptor 1 concentrations were correlated. These results are of interest because blocking of SP effects has long been discussed in relation to RA treatment and because BN/GRP is known to have trophic and growth-promoting effects and to play a role in inflammation and wound healing. Furthermore, the observations strengthen a suggestion that combination treatment with agents interfering with neuropeptides and cytokines would be efficacious in the treatment of RA. In conclusion, BN/GRP and SP are involved together with cytokines in the neuroimmunomodulation that occurs in the arthritic joint.

Age-dependent levels of plasma neuropeptides in normal children.

Several neuropeptides are secreted in high amounts in pediatric tumors such as neuroblastoma and have been used as markers of residual or recurrent disease. Plasma levels of neuropeptides might be expected to change during development, but have not been determined in normal children. We have obtained fresh plasma from cord blood of six full-term infants and from peripheral blood in 41 healthy children, ages 1 month to 21 years. Levels of six neuropeptides, vasoactive intestinal peptide (VIP), somatostatin, gastrin releasing peptide (GRP), substance P, pancreastatin and neuropeptide Y (NPY) were measured by radioimmunoassay along with insulin-like growth factor-1 (IGF-1) whose plasma levels are known to vary during development. A child with neuroblastoma was treated with the somatostatin analogue, octreotide, and the effect on plasma neuropeptides quantified. Octreotide doses of 2-3 microg/kg daily resulted in a 40-60% decrease in plasma levels of IGF-1, pancreastatin and GRP. These results are the first publication of plasma neuropeptide levels in normal children.

A New Cause of Zollinger-Ellison Syndrome: Non-Small Cell Lung Cancer

Numerous epidemiologic studies suggest a relationship between lung cancer and peptic ulcer disease. Furthermore, various lung cancers synthesize and release a number of peptides such as gastrin and gastrin-releasing peptide that could cause acid hypersecretion; however, Zollinger-Ellison syndrome (ZES), because of a lung tumor, has never been described. We report such a patient for the first time. A 60-year-old man with a non-small cell lung carcinoma (large cell type) presented with diarrhea, heartburn, abdominal pain, and duodenal ulcers. Evaluation showed ZES was present (fasting hypergastrinemia, hyperchlorhydria) and control of all symptoms by omeprazole. No abdominal or cardiac tumor, the other known locations of gastrinomas causing ZES, was found on detailed tumor imaging studies. Resection of the lung tumor resulted in a decrease in gastrin levels to normal values. Plasma radioimmunoassays showed elevated gastrin, chromogranin A and normal levels of gastrin-releasing peptide, and 9 other hormones. The tumor showed similar immunocytochemical results. The characteristics of this case are compared with 100 cases of sporadic abdominal gastrinomas, and the evidence reviewed suggests why ZES should be considered in patients with lung cancer with peptic symptoms.