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![Immunostaining for CCK-2 receptor in rat mesentery. Positive staining is evident in macrophages (A) and PMN leukocytes (B). No staining was observed in the absence of primary Ab (not depicted). Insets in A correspond to immunostaining for 2 different macrophage markers: A) monoclonal anti-macrophage granulocyte Ab [OX41], Abcam; B) mAb against an ED2-like antigen [HIS36], eBioscience).](profile/Sara-Calatayud/publication/6780487/figure/fig6/AS:601605388898322@1520445310414/Immunostaining-for-CCK-2-receptor-in-rat-mesentery-Positive-staining-is-evident-in.png)
Immunostaining for CCK-2 receptor in rat mesentery. Positive staining is evident in macrophages (A) and PMN leukocytes (B). No staining was observed in the absence of primary Ab (not depicted). Insets in A correspond to immunostaining for 2 different macrophage markers: A) monoclonal anti-macrophage granulocyte Ab [OX41], Abcam; B) mAb against an ED2-like antigen [HIS36], eBioscience).
Source publication
Gastric mucosal inflammation causes hypergastrinemia, and gastrin receptors have been detected in several leukocyte types. We have analyzed whether gastrin affects the leukocyte-endothelial cell interactions in vivo by monitoring leukocyte rolling, adhesion, and emigration in rat mesenteric venules using intravital microscopy. Mesenteric superfusio...
Context in source publication
Context 1
... mesenteric tissue, which were later identified in the hematoxylin and eosin staining as PMN leukocytes and macro- phages. The identity of macrophages was further con- firmed by comparing the morphology of non-PMN CCK-2 receptor positive cells with cells stained with two different macrophage membrane markers in parallel immunohistochemical studies (Fig. 9). Endothelial cells tested negative for the CCK-2 receptor ...
Citations
... Digestive adverse effects of alcohol include stomach erosions, ulceration, bleeding, and perforation, as well as an increased risk of complications from pre-existing ulcers. The GI tract is one of the numerous organ systems that mediate the effects of alcohol on the human body and its health (43). First, the GI tract is the location of alcohol absorption into the circulation, as well as, to a lesser extent, alcohol Alcohol may interact directly with the stomach mucosa (i.e., topical stimulation), or it may work through a more general mechanism altering hormone release and neuron function control in acid secretion, mucosal inflammation can be caused by alcohol. ...
... 41 Gastrin is a hormone produced by gastrin cells and has a critical role in regulating cell growth and acid secretion through binding to gastrin receptors. 42 Gastrin shown to exert proinflammatory effect in rats, 43 via stimulating the release histamine, which mediates acute inflammatory reactions. 42 Gastrin may also act on endothelial cells where it seems to modify the expression of adhesion molecules and increase chemokine secretion. ...
Backgrounds: A gastric ulcer is a lesion on the mucosal layer of the stomach. Many irritating stimuli, such as excess acid, smoking, alcohol, H. pylori infection, ischemia,
hypoxia, and nonsteroidal anti-inflammatory drugs precipitate gastric hemorrhagic lesions. Alcohol is one of the substances that target the stomach via impairing structure and function, albeit the precise mechanism of alcohol-induced gastric injury is unclear. Among the most accepted processes are gastric mucous membrane injury, reactive species production, and inflammatory reaction. Renin angiotensin system plays an important role in regulating numerous body pathophysiology; the existence of renin angiotensin system and their local activity in the gastrointestinal tract and their participation in inflammatory responses support the possibility of angiotensin receptor blockers in gastroprotection. However, the mechanism of stomach mucosa protection has received little attention. On the other hand, angiotensin-(1-7) has a strong vasodilatory effect and reduces the severity of gastric lesions caused by numerous ulcerogens. This study aimed to look into the potential gastroprotective effects of different dosages of azilsartan in rats with ethanol-induced gastric ulcers.
Methodology: Forty-eight male adult Wistar rats were used and allocated randomly
into six groups: negative control treated with distilled water, positive control treated
with ethanol, lansoprazole treated group, and azilsartan (1mg, 5mg, and 10mg/kg)
treated group. The treatment protocol was for 15 days and all the groups except for the negative control group received 1ml of ethanol on the last day 1hr before scarification. Gastric content was collected for measuring the volume, free acidity, and pH. The stomach was used for measuring the gastric lesion area and ulcer index. Blood samples were collected for measuring serum hydroxyproline, gastrin, C-reactive protein, tumor necrosis factor-alpha, malondialdehyde, and total antioxidant capacity. Gastric tissues were sent for histopathological examinations.
Results: Ethanol administration significantly increased gastric lesions, gastric ulcer
index, and gastric acidity. Ethanol also decreased serum levels of hydroxyproline and total antioxidant capacity and increased serum gastrin, C-reactive protein, tumor necrosis factor-alpha, and malondialdehyde. Azilsartan 10mg/kg decreased the gastric lesion by 43.6%, increased gastric pH, and significantly decreased malondialdehydelevel. Both 5mg/kg and 10mg/kg azilsartan have successfully restored the level of hydroxyproline, gastrin, and tumor necrosis factor-alpha. The histopathological finding showed pronounced gastroprotection by azilsartan in a dose-dependent manner.
Conclusion: The study revealed that azilsartan possesses a gastroprotective effect.
This favorable action is likely mediated via boosting blood flow to the stomach, antioxidant capacity, and anti-inflammatory activity along with restoring hydroxyproline and gastrin levels. These findings suggest that azilsartan is a promising candidate for testing in a clinical setting.
... 41 Gastrin is a hormone produced by gastrin cells and has a critical role in regulating cell growth and acid secretion through binding to gastrin receptors. 42 Gastrin shown to exert proinflammatory effect in rats, 43 via stimulating the release histamine, which mediates acute inflammatory reactions. 42 Gastrin may also act on endothelial cells where it seems to modify the expression of adhesion molecules and increase chemokine secretion. ...
Objective
The present study was designed to evaluate the possible gastroprotective effects of different doses of azilsartan in ethanol-induced gastric ulcers in rats.
Methodology
Forty-eight male adult Wistar rats were used and allocated randomly into four groups: negative control treated with distilled water, positive control treated with ethanol, lansoprazole treated group, and azilsartan (1mg, 5mg, and 10mg/kg) treated group. The treatment protocol was for 15 days, and all the groups except for the negative control group received 1mL of ethanol on the last day 1hr before scarification. Gastric content was collected for measuring the volume, free acidity, and pH. The stomach was used for measuring the gastric lesion area and ulcer index. Blood samples were collected for measuring serum hydroxyproline, gastrin, CRP, TNF-α, MDA, and TAOC. Gastric tissues were sent for histopathological examinations.
Results
Ethanol administration significantly increased gastric lesion, gastric ulcer index, and gastric acidity. Ethanol also decreased serum levels of hydroxyproline and TAOC and increased serum gastrin, CRP, TNF-α, and MDA. Azilsartan 10mg/kg was able to decrease the lesion by 43.6% and increase gastric pH and significantly decreased MDA level. Both 5mg/kg and 10mg/kg azilsartan have successfully restored the level of hydroxyproline, gastrin, and TNF-α. The histopathological finding showed gastroprotection by azilsartan in a dose-dependent manner.
Conclusion
The study revealed that azilsartan possesses a gastroprotective effect. The proposed mechanisms could be increased blood flow to the stomach, antioxidant capacity, and anti-inflammatory activity along with restoring hydroxyproline and gastrin levels. These findings suggest azilsartan as a promising candidate to be tested in a clinical setting.
... [13,14] Third, abnormally elevated hormones (e.g., pancreatic polypeptide, glucagon, cholecystokinin, and gastrin) in the gastrointestinal tract can inhibit gastric emptying. [15][16][17] Fourth, gastrointestinal motility can be affected by altering endogenous nitric oxide levels. [18,19] In our current study, an H. pylori eradication regimen was performed in 53 patients with DGP, 47 with simple diabetes, 30 with NDG, and 59 normal subjects. ...
Background
Whether Helicobacter pylori infection is associated with diabetic gastroparesis (DGP) is unclear. This study aimed to investigate the potential correlation between H. pylori infection and DGP.
Methods
In this study, 163 patients with type 2 diabetes mellitus and 175 nondiabetic patients who were treated in our department were divided into DGP, simple diabetes, non-DGP (NDG), and normal groups based on their conditions. The H. pylori infection rate in each group was calculated. H. pylori eradication therapy was performed for patients with H. pylori infection in each group. The eradication rates were compared between the groups, and the improvements in gastroparesis-associated symptoms were compared before and after treatment in patients with DGP.
Results
The H. pylori infection rate was 74.6% in the DGP group, which was significantly higher than that in the simple diabetes (51.1%, P < 0.01), NDG (57.7%, P < 0.05), and normal groups (48.0%, P < 0.01). With increased disease course, the incidence of DGP and the H. pylori infection rate gradually increased (P < 0.05). In the DGP group, the incidences of upper abdominal pain and distention, early satiety, and anorexia were 75.5%, 66.0%, and 67.9%, respectively, before eradication treatment; and 43.4%, 35.8%, and 39.6%, respectively, after eradication treatment, and the difference was statistically significant (P < 0.01). In patients with DGP with successful H. pylori eradication, the number of barium strips discharged after eradication was 5.9 ± 1.0, which was significantly larger than that before treatment (4.1 ± 0.7, P < 0.01). In addition, the number of barium strips discharged was significantly larger in patients with DGP with successful H. pylori eradication than those with failed H. pylori eradication (P < 0.01).
Conclusions
DGP development might be associated with H. pylori infection. H. pylori eradication can effectively improve dyspepsia-associated symptoms and delayed gastric emptying in patients with DGP.
... Furthermore, H. pylori infection raises basal and meal-stimulated serum gastrin concentrations and lowers iron stores, reducing in turn fasting glucose levels 18 . Infection also represents the main cause of nonautoimmune chronic gastritis, which increases gastrin secretion 19 . Hypergastrinemia usually leads to increased proliferation of gastric progenitor cells and a thickened mucosa. ...
Gastritis induced marked cellular changes which vary according to histological characters and causative mechanism. We aim to assess the therapeutic role of amoxicillin, black seed oil, curcuminoids either individually or combined on rat model of Helicobacter pylori (H. pylori) gastritis. H. pylori gastritis was induced in rats, followed by administration of Amoxicillin, black seed oil, curcuminoids or their combination for four weeks. Serum gastrin, pepsinogen activity, interleukin-6 (IL-6), and gastric mucosal myeloperoxidase (MPO) activity and prostaglandin E2 (PGE2) were measured. Histopathological examination of gastric mucosa and immunohistochemical reactions for inducible nitric oxide synthase (iNOS), nitrotyrosine (NTR) and DNA fragmentation were also evaluated. Administration of black seed oil and curcuminoids individually for four weeks significantly decreased serum gastrin, IL-6 as well as gastric mucosal MPO and PGE2 and increased total pepsinogen activity compared to un-treated rats. Their combination significantly decreased serum gastrin, IL-6, gastric mucosal MPO and PGE2 while total pepsinogen activity demonstrated further improvement. Histological results demonstrated marked improvement in agreements with biochemical markers. Amoxicillin-treated group demonstrated no significant changes regarding these biomarkers with moderate positive reaction for iNOS, NTR and DNA fragmentation. In conclusion, Black seed oil and/or curcuminoids either individually or combined improved H. pylori-associated inflammatory and oxidative injury. However, amoxicillin has failed to induce significant effect. © 2015, International Journal of Pharmaceutical and Clinical Research. All rights reserved.
... Although progastrin may bind with low affinity to gastrin CCK-2 receptors and this interaction may contribute to some extent to its biological activity [10], progastrin's growth-promoting effect appears to be mainly mediated by a non-conventional receptor recently identified as annexin II [9]. We have observed that gastrin exerts a pro-inflammatory activity through CCK-2 receptors [11][12][13], which are expressed in macrophages and endothelial cells, while annexin II is highly expressed on the surface of macrophages, where it serves as a pathogen recognition element and mediates macrophage activation [14]. ...
... This effect is in line with the previously described proinflammatory action of gastrin [11][12][13]. We observed that gastrin contributes to the inflammation induced by Helicobacter pylori in rats probably through CCK-2 receptor activation in macrophages while the stimulation of this receptor activates human endothelial cells to promote monocyte adhesion. ...
Macrophage infiltration is a negative prognostic factor for most cancers but gastrointestinal tumors seem to be an exception. The effect of macrophages on cancer progression depends on their phenotype, which may vary between M1 (pro-inflammatory, defensive) to M2 (tolerogenic, pro-tumoral). Gastrointestinal cancers often become an ectopic source of gastrins and macrophages present receptors for these peptides. The aim of the present study is to analyze whether gastrins can affect the pattern of macrophage infiltration in colorectal tumors. We have evaluated the relationship between gastrin expression and the pattern of macrophage infiltration in samples from colorectal cancer and the influence of these peptides on the phenotype of macrophages differentiated from human peripheral monocytes in vitro. The total number of macrophages (CD68+ cells) was similar in tumoral and normal surrounding tissue, but the number of M2 macrophages (CD206+ cells) was significantly higher in the tumor. However, the number of these tumor-associated M2 macrophages correlated negatively with the immunoreactivity for gastrin peptides in tumor epithelial cells. Macrophages differentiated from human peripheral monocytes in the presence of progastrin showed lower levels of M2-markers (CD206, IL10) with normal amounts of M1-markers (CD86, IL12). Progastrin induced similar effects in mature macrophages treated with IL4 to obtain a M2-phenotype or with LPS plus IFNγ to generate M1-macrophages. Macrophages differentiated in the presence of progastrin presented a reduced expression of Wnt ligands and decreased the number and increased cell death of co-cultured colorectal cancer epithelial cells. Our results suggest that progastrin inhibits the acquisition of a M2-phenotype in human macrophages. This effect exerted on tumor associated macrophages may modulate cancer progression and should be taken into account when analyzing the therapeutic value of gastrin immunoneutralization.
... 14 Gastrin is linked to inflammation via the CCK-2 receptor expressed on specific cell types such as cancer cells, enterochromaffin cells, parietal cells, macrophages, and neutrophils. 45 Binding of gastrin to the CCK2 receptors on AGS cells (a human stomach cancer cell line) overexpressing CCK-2 upregulates the expression of serpinB2 through a proteosome β subunit, PSMB1. 43 These data suggest a link between CCK-2 and increased serpinB2 expression to the effects of gastrin on maintenance of epithelial integrity, but this observation remains to be investigated in vivo. ...
Host defense is an orchestrated response involving changes in the expression of receptors and release of mediators from both immune and structural cells. There is a growing recognition of the important role of proteolytic pathways for the protective immune response to enteric pathogens. Enteric nematode infection induces a type 2 immune response with polarization of macrophages toward the alternatively activated phenotype (M2). The Th2 cytokines, IL-4, and IL-13, induce a STAT6-dependent upregulation of the expression of the protease inhibitor, serpinB2, which protects macrophages from apoptosis. M2 are critical to worm clearance and a novel role for serpinB2 is its regulation of the chemokine, CCL2, which is necessary for monocyte macrophage influx into small intestine during infection. There is a growing list of factors including immune (LPS, Th2 cytokines) as well as hormonal (gastrin, 5-HT) that are linked to increased expression of serpinB2. Thus, serpinB2 represents an immune regulated factor that has multiple roles in the intestinal mucosa.
... louis, MO, Usa) or the same volume of saline, 30 min before the intraperitoneal S. aureus inoculation (0.5-1 × 10 10 CFU/animal) (time "zero" hour). these doses of proglumide were chosen based on previous studies [17,24]. at 4 and 24 h, rats were deeply anesthetized (ketamine and xylazine at 55 and 10 mg/kg, respectively, i.p.) for sample collection. ...
Staphylococcus aureus is a Gram-positive bacteria described as an important causative agent of sepsis. The contact between host leukocytes and bacteria activates the innate immune response. Nitric oxide, tumor necrosis factor (TNF)-α and interleukin (IL)-1β play a key role in increasing microbicidal activity and controlling cell influx into infectious focus. Contrarily, IL-10 acts as an anti-inflammatory cytokine and bacterial killing suppressor. Immunoregulatory properties have also been attributed to hormones, including cholecystokinin (CCK). CCK protects cardiovascular function and inhibits the inflammatory response induced by lipopolysaccharide, product derived from Gram-negative bacteria. Nevertheless, the role of CCK during Gram-positive infection remains a literature gap. Our aims were to investigate whether CCK protects rats against bacterial dissemination during sepsis induced by S. aureus. We determined whether CCK modulates local and systemic inflammatory response, as well as the cell migration into the infectious focus and the bactericidal capacity of leukocytes. Our results revealed that proglumide (nonselective CCK receptor antagonist) pretreated rats showed higher bacterial counts in blood and peritoneal lavage fluid (PLF) and reduced TNF-α and IL-10 levels in PLF. Moreover, the dissemination of S. aureus may be related to the failure of neutrophil and macrophage migration into the peritoneal cavity. Also, CCK improved the phagocytic and bactericidal ability of these inflammatory cells. Noteworthy is that the adoptive transfer of CCK-treated neutrophils and macrophages in septic rats improved immune defense, reducing bacterial number in blood and PLF. All together, our study clearly demonstrates an important protective role of CCK against sepsis induced by S. aureus.
... Leucocyte-endothelial cell interactions were evaluated in fasted male Sprague-Dawley rats (200-250 g) following a standard experimental technique. 25,26 In brief, rats were anaesthetized with sodium pentobarbital [65 mg/kg, intraperitoneally (ip)] and, following a midline abdominal incision, a segment of the mid-jejunum was exteriorized and placed on an optically clear viewing pedestal at 378C for tissue transillumination. The exposed mesentery was visualized using an orthostatic microscope (Nikon Optiphot-2, SMZ1, Nikon, Badhoevedor, The Netherlands) equipped with a ×20 objective lens (Nikon SLDW) and ×10 eyepieces, during which time it was continuously superfused with bicarbonate buffer saline (pH 7.4, 378C, 2 mL/min). ...
... The preparation was subsequently observed under a clear field microscope (×63), and the infiltrated leucocytes were counted (number per 2.5×10 24 cm 2 ) and classified morphologically as PMN leucocytes, macrophages and lymphocytes by an observer who was unaware of the treatment in question. 26 Animals were injected (2.5 mL, ip) with saline, vehicles (methanol or azide water) or one of the following antiretroviral drug solutions: efavirenz (10-25 mM, equivalent to 40 -100 mg/kg), nevirapine (10 -50 mM; 35 -165 mg/kg) or lopinavir (10 -25 mM; 80-200 mg/kg). Images (5 min period) were recorded 4 h later in order to allow enough time for the process of leucocyte emigration to initiate and were then evaluated by an observer who was blind to the treatment. ...
The potential cardiovascular (CV) toxicity associated with combined antiretroviral therapy (cART) has been attributed mainly to the nucleoside reverse transcriptase inhibitors abacavir and didanosine. However, the other two components of cART-non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs)-may also be implicated, either directly or by influencing the action of the other drugs. This study evaluates the acute direct effects of the NNRTIs efavirenz and nevirapine and one of the most widely employed PIs, lopinavir, on leucocyte-endothelium interactions, a hallmark of CV disease.
Drugs were analysed in vitro in human cells (interactions of peripheral blood polymorphonuclear or mononuclear cells with human umbilical vein endothelial cells) using a flow chamber system, and in vivo in rat mesenteric vessels by means of intravital microscopy. The expression of adhesion molecules in leucocytes and endothelial cells was studied by flow cytometry, and the role of these molecules in white cell recruitment was evaluated by pre-treating human cells or rats with blocking antibodies.
Efavirenz and nevirapine, but not lopinavir, increased the rolling flux and adhesion of leucocytes in vitro and in vivo while inducing emigration in rat venules. Efavirenz, but not nevirapine, augmented the levels of CD11b, CD11c and CD18 in neutrophils and monocytes. The actions of efavirenz, but not of nevirapine, were reversed by antibodies against Mac-1 (CD11b/CD18), gp150,95 (CD11c/CD18) or ICAM-1 (CD54).
NNRTIs, but not PIs, interfere with leucocyte-endothelial interactions. However, differences between efavirenz and nevirapine suggest a specific CV profile for each compound.
... In a separate set of experiments, to evaluate the direct role of the CCK (sulfated CCK-8 ammonium salt, Bachem, Torrance, Calif), it was administered intravenously at two different doses, 0.4 or 40 2g/kg, 10 min before LPS-induced endotoxemia. These doses of proglumide and CCK were chosen based on previous studies (19,21). ...
Cholecystokinin (CCK) was first described as a gastrointestinal hormone, but its receptors have been located in cardiac and vascular tissues, as well as in immune cells. Our aims were to investigate the role of CCK on lipopolysaccharide (LPS)-induced hypotension and its ability to modulate previously reported inflammatory mediators, therefore affecting cardiovascular function. To conduct these experiments, rats had their jugular vein cannulated for drug administration, and also, the femoral artery cannulated for mean arterial pressure (MAP) and heart rate records. Endotoxemia induced by LPS from Escherichia coli (1.5 mg/kg; i.v.) stimulated the release of CCK, a progressive drop in MAP, and increase in heart rate. Plasma tumor necrosis factor α (TNF-α), interleukin 10 (IL-10), nitrate, vasopressin, and lactate levels were elevated in the endotoxemic rats. The pretreatment with proglumide (nonselective CCK antagonist; 30 mg/kg; i.p.) aggravated the hypotension and also increased plasma TNF-α and lactate levels. On the other hand, CCK (0.4 μg/kg; i.v.) administered before LPS significantly restored MAP, reduced aortic and hepatic inducible nitric oxide synthase (iNOS) production, and elevated plasma vasopressin and IL-10 concentrations; it did not affect TNF-α. Physiological CCK concentration reduced nitrite and iNOS synthesis by peritoneal macrophages, possibly through a self-regulatory IL-10-dependent mechanism. Together, these data suggest a new role for the peptide CCK in modulating MAP, possibly controlling the inflammatory response, stimulating the anti-inflammatory cytokine, IL-10, and reducing vascular and macrophage iNOS-derived nitric oxide production. Based on these findings, CCK could be used as an adjuvant therapeutic agent to improve cardiovascular function.
... Gastrin is secreted from the G cells located in antrum and the duodenum directly into the gastrointestinal tract (GIT). Infection represents the main cause of non-autoimmune chronic gastritis, which increases gastric secretion; such correlation between gastrinemia and the severity of gastritis has been identified before [38]. PG, the precursor of pepsin, exists as two main types (I and II), produced by the chief and mucus cells in the gastric fundus [39]. ...
Gastritis, an inflammation of gastric mucosa, may be due to many pathological factors and infection, such as with Helicobacter pylori. The use of experimental models of gastritis is important to evaluate the biochemical changes and study chemotherapeutic intervention. In a previous study we demonstrated an acute gastritis model induced by iodoacetamide.
Our objective in this study was to evaluate a new gastritis model induced by H. pylori infection in experimental rats in terms of certain biomarkers in serum and mucosal tissues in addition to histopathological examination.
Gastritis was induced in 20 albino Wistar rats by H. pylori isolated from antral biopsy taken from a 49-year-old male patient endoscopically diagnosed as having H. pylori infection. Another ten rats were used as controls. Serum gastrin, pepsinogen I activity, interleukin-6 (IL-6) and gastric mucosal myeloperoxidase (MPO) activity and prostaglandin E(2) (PGE(2)) were measured. Immunostaining for inducible nitric oxide synthase (iNOS), nitrotyrosine and DNA fragmentation were used to further evaluate H. pylori-induced gastritis.
Serum gastrin, IL-6, mucosal MPO activity, and PGE(2) demonstrated significant increases joined with a decreased serum pepsinogen I activity (P < 0.001). Immunohistochemistry demonstrated positive reaction for iNOS, nitrotyrosine and DNA fragmentation.
Helicobacter pylori-induced gastritis models demonstrated massive oxidative stress and pronounced injury in mucosal tissue. Since our model in rats reflected the clinical picture of H. pylori infection, it can be considered as a consistent model to study chemotherapeutic intervention for this type of gastritis.
