Gastric blood flow, mast cell degranulation and micromorphology of gastric mucosa following experimental haemorrhagic shock in dogs

Hydrogen sulfide (H2S) is an endogenously produced molecule with anti-inflammatory and cytoprotective properties. We aimed to investigate for the first time if a novel, esterase-sensitive H2S-prodrug, BW-HS-101 with the ability to release H2S in a controllable manner, prevents gastric mucosa against acetylsalicylic acid-induced gastropathy on microscopic and molecular levels. Wistar rats were pretreated intragastrically with vehicle, BW-HS-101 (0.5–50 μmol/kg) or its analogue without the ability to release H2S, BW-iHS-101 prior to ASA administration (125 mg/kg, intragastrically). BW-HS-101 was administered alone or in combination with nitroarginine (L-NNA, 20 mg/kg, intraperitoneally) or zinc protoporphyrin IX (10 mg/kg, intraperitoneally). Gastroprotective effects of BW-HS-101 were additionally evaluated against necrotic damage induced by intragastrical administration of 75% ethanol. Gastric mucosal damage was assessed microscopically, and gastric blood flow was determined by laser flowmetry. Gastric mucosal DNA oxidation and PGE2 concentration were assessed by ELISA. Serum and/or gastric protein concentrations of IL-1α, IL-1β, IL-2, IL-4, IL-6, IL-10, IL-13, VEGF, GM-CSF, IFN-γ, TNF-α, and EGF were determined by a microbeads/fluorescent-based multiplex assay. Changes in gastric mucosal iNOS, HMOX-1, SOCS3, IL1-R1, IL1-R2, TNF-R2, COX-1, and COX-2 mRNA were assessed by real-time PCR. BW-HS-101 or BW-iHS-101 applied at a dose of 50 μmol/kg protected gastric mucosa against ASA-induced gastric damage and prevented a decrease in the gastric blood flow level. H2S prodrug decreased DNA oxidation, systemic and gastric mucosal inflammation with accompanied upregulation of SOCS3, and EGF and HMOX-1 expression. Pharmacological inhibition of nitric oxide (NO) synthase but not carbon monoxide (CO)/heme oxygenase (HMOX) activity by L-NNA or ZnPP, respectively, reversed the gastroprotective effect of BW-HS-101. BW-HS-101 also protected against ethanol-induced gastric injury formation. We conclude that BW-HS-101, due to its ability to release H2S in a controllable manner, prevents gastric mucosa against drugs-induced gastropathy, inflammation and DNA oxidation, and upregulate gastric microcirculation. Gastroprotective effects of this H2S prodrug involves endogenous NO but not CO activity and could be mediated by cytoprotective and anti-inflammatory SOCS3 and EGF pathways.

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Role of cardiac mast cells in complement C5a-induced myocardial ischemia

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1993.264.5.h1346 ◽

1993 ◽

Vol 264 (5) ◽

pp. H1346-H1354 ◽

Cited By ~ 10

Author(s):

B. R. Ito ◽

R. L. Engler ◽

U. del Balzo

Keyword(s):

Blood Flow ◽

Mast Cell ◽

Myocardial Ischemia ◽

Coronary Blood Flow ◽

Cell Activation ◽

Mast Cell Degranulation ◽

Mast Cell Activation ◽

Coronary Vein ◽

Arterial Blood ◽

Complement C5a

Activated complement component C5a causes myocardial ischemia mediated by thromboxane (Tx) A2 and leukotrienes C4/D4. Blood cells are not involved in either the mediator release or the myocardial effects of C5a, suggesting that a C5a-sensitive, cardiac resident inflammatory cell is responsible. The goals of this study were to determine whether 1) cardiac mast cell activation accompanies the C5a response, 2) inhibition of mast cell degranulation inhibits the response, and 3) histamine release plays a role in the C5a-induced myocardial ischemia. The left anterior descending coronary artery (LAD) of open-chest pigs (n = 13) was perfused with arterial blood at constant pressure (95 mmHg). Coronary blood flow (CBF) was measured (in-line flowmeter) and regional function [percent segment shortening (%SS)] determined with sonomicrometry. A coronary vein was cannulated for measurement of plasma TxB2 and histamine (a marker of mast cell degranulation). Intracoronary C5a (500 ng) decreased coronary blood flow (45% of preinfusion levels) and LAD %SS (65% of preinfusion) and was accompanied by increases in coronary venous TxB2 (delta 63.3 ng/ml) and histamine (delta 200 nM). Mast cell inhibition with lodoxamide (2 mg/kg iv, n = 8) attenuated the C5a-induced fall in CBF (14 vs. 53% decrease, P < 0.01) and %SS (10 vs. 38% decrease, P < 0.01) and also reduced the C5a-induced increase in both coronary venous histamine (delta 26 vs. 278 nM, P < 0.05) and TxB2 (delta 0.34 vs. 63.3 ng/ml, P < 0.01). However, histamine H1 (pyrilamine) and H2 (ranitidine) receptor blockade had no effect on the C5a-induced fall in CBF or LAD %SS.(ABSTRACT TRUNCATED AT 250 WORDS)

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Anti-inflammatory effects of angiotensin II AT1 receptor antagonism prevent stress-induced gastric injury

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00058.2003 ◽

2003 ◽

Vol 285 (2) ◽

pp. G414-G423 ◽

Cited By ~ 79

Author(s):

Claudia Bregonzio ◽

Ines Armando ◽

Hiromichi Ando ◽

Miroslava Jezova ◽

Gustavo Baiardi ◽

...

Keyword(s):

Blood Flow ◽

Angiotensin Ii ◽

Gastric Mucosa ◽

Restraint Stress ◽

Neutrophil Infiltration ◽

Gastric Blood Flow ◽

Gastric Injury ◽

Tnf Α ◽

Cold Restraint Stress ◽

Cold Restraint

Stress reduces gastric blood flow and produces acute gastric mucosal lesions. We studied the role of angiotensin II in gastric blood flow and gastric ulceration during stress. Spontaneously hypertensive rats were pretreated for 14 days with the AT1 receptor antagonist candesartan before cold-restraint stress. AT1 receptors were localized in the endothelium of arteries in the gastric mucosa and in all gastric layers. AT1 blockade increased gastric blood flow by 40–50%, prevented gastric ulcer formation by 70–80% after cold-restraint stress, reduced the increase in adrenomedullary epinephrine and tyrosine hydroxylase mRNA without preventing the stress-induced increase in adrenal corticosterone, decreased the stress-induced expression of TNF-α and that of the adhesion protein ICAM-1 in arterial endothelium, decreased the neutrophil infiltration in the gastric mucosa, and decreased the gastric content of PGE2. AT1 receptor blockers prevent stress-induced ulcerations by a combination of gastric blood flow protection, decreased sympathoadrenal activation, and anti-inflammatory effects (with reduction in TNF-α and ICAM-1 expression leading to reduced neutrophil infiltration) while maintaining the protective glucocorticoid effects and PGE2 release. Angiotensin II has a crucial role, through stimulation of AT1 receptors, in the production and progression of stress-induced gastric injury, and AT1 receptor antagonists could be of therapeutic benefit.

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Gastroprotective Mechanisms

10.5772/intechopen.101631 ◽

2021 ◽

Author(s):

Cirlane Alves Araujo de Lima ◽

Robson Silva de Lima ◽

Jesica Batista de Souza ◽

Ariel de Souza Graça ◽

Sara Maria Thomazzi ◽

...

Keyword(s):

Blood Flow ◽

Immune System ◽

Gastric Mucosa ◽

Common Type ◽

Gastric Epithelium ◽

Gastric Blood Flow ◽

Mucus Layer ◽

Repair Capacity ◽

Biological Responses ◽

The Status

Gastric ulcer (GU), a common type of peptic ulcer, results from an imbalance in the action of protective and aggressive agents. Gastroprotective mechanisms are mucus layer, gastric epithelium, gastric blood flow, gastric neurons, mucosal repair capacity, and immune system. Thus, the aim of this chapter was to provide an update on gastroprotective mechanisms. It was carried out through searches in PubMed covering the years 2016–2021 using several keywords. This survey resulted in 428 articles, of which 110 were cited in this chapter. It was reviewed the status of gastroprotective mechanisms and highlighted that mucins can act as a filter; gastric epithelial defenses are composed of the cell barrier, stem cells, and sensors on the mucosal surface; nitric oxide (NO) and hydrogen sulfide (H2S) act for gastric blood flow homeostasis (GBF); the main effector neurons in the gastric mucosa are cholinergic, nitrergic and VIPergic, and oxytocin can activate neurons; repair of the gastric mucosa requires complex biological responses; the immune system regulates the entry of antigens and pathogens. The main knowledge about gastroprotective mechanisms remains unchanged. However, we conclude that there has been progressing in this area.

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Luteolin ameliorates lipopolysaccharide-induced microcirculatory disturbance through inhibiting leukocyte adhesion in rat mesenteric venules

BMC Complementary Medicine and Therapies ◽

10.1186/s12906-020-03196-9 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Jie Su ◽

Han-Ting Xu ◽

Jing-Jing Yu ◽

Mei-Qiu Yan ◽

Ting Wang ◽

...

Keyword(s):

Hydrogen Peroxide ◽

Blood Flow ◽

Mast Cell ◽

Small Intestine ◽

Leukocyte Adhesion ◽

Mast Cell Degranulation ◽

Microcirculatory Disturbance ◽

Hydrogen Peroxide Production ◽

Intestinal Microcirculation ◽

Pro Inflammatory Cytokines

Abstract Background Microcirculatory disturbance is closely associated with multiple diseases such as ischemic and septic stroke. Luteolin (3,4,5,7-tetrahydroxyflavone) is a vascular protective flavonoid present in several dietary foods. However, how luteolin plays a role in microcirculatory disturbance is still unknown. The purpose of this study was to find out the influence of luteolin on the lipopolysaccharide (LPS)-induced microcirculatory disturbance, focusing on its effect on leukocyte adhesion and the underlying mechanism of this effect. Methods After injecting LPS into rats, we used an inverted intravital microscope to observe the velocity of red blood cells in venules, numbers of leukocytes adherent to and emigrated across the venular wall, hydrogen peroxide production in venular walls and mast cell degranulation. Intestinal microcirculation blood flow was measured by High-resolution Laser Doppler Perfusion Imaging. Histological changes of small intestine and mesenteric arteries were evaluated. Additionally, cell adhesion stimulated by LPS was tested on EA.hy926 and THP-1 cells. The production of pro-inflammatory cytokines, adhesion molecules and the activation of TLR4/Myd88/NF-κB signaling pathway were determined. Results The results showed luteolin significantly inhibited LPS-induced leukocyte adhesion, hydrogen peroxide production and mast cell degranulation, and increased intestinal microcirculation blood flow and ameliorated pathological changes in the mesenteric artery and the small intestine. Furthermore, luteolin inhibited the release of pro-inflammatory cytokines, the expression of TLR4, Myd88, ICAM-1, and VCAM-1, the phosphorylation of IκB-α and NF-κB/p65 in LPS stimulated EA.hy926. Conclusions Our findings revealed that it is likely that luteolin can ameliorate microcirculatory disturbance. The inhibitory effects of luteolin on the leukocyte adhesion stimulated by LPS, which participates in the development of microcirculatory disturbance, are mediated through the regulation of the TLR4/Myd88/NF-κB signaling pathway.

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Mast cell degranulation and de novo histamine formation contribute to sustained postexercise vasodilation in humans

Journal of Applied Physiology ◽

10.1152/japplphysiol.00633.2016 ◽

2017 ◽

Vol 122 (3) ◽

pp. 603-610 ◽

Cited By ~ 11

Author(s):

Steven A. Romero ◽

Jennifer L. McCord ◽

Matthew R. Ely ◽

Dylan C. Sieck ◽

Tahisha M. Buck ◽

...

Keyword(s):

Skeletal Muscle ◽

Blood Flow ◽

Mast Cell ◽

Aerobic Exercise ◽

Histidine Decarboxylase ◽

De Novo ◽

Vastus Lateralis ◽

Muscle Blood Flow ◽

Mast Cell Degranulation ◽

Local Blood Flow

In humans, acute aerobic exercise elicits a sustained postexercise vasodilation within previously active skeletal muscle. This response is dependent on activation of histamine H1and H2receptors, but the source of intramuscular histamine remains unclear. We tested the hypothesis that interstitial histamine in skeletal muscle would be increased with exercise and would be dependent on de novo formation via the inducible enzyme histidine decarboxylase and/or mast cell degranulation. Subjects performed 1 h of unilateral dynamic knee-extension exercise or sham (seated rest). We measured the interstitial histamine concentration and local blood flow (ethanol washout) via skeletal muscle microdialysis of the vastus lateralis. In some probes, we infused either α-fluoromethylhistidine hydrochloride (α-FMH), a potent inhibitor of histidine decarboxylase, or histamine H1/H2-receptor blockers. We also measured interstitial tryptase concentrations, a biomarker of mast cell degranulation. Compared with preexercise, histamine was increased after exercise by a change (Δ) of 4.2 ± 1.8 ng/ml ( P < 0.05), but not when α-FMH was administered (Δ−0.3 ± 1.3 ng/ml, P = 0.9). Likewise, local blood flow after exercise was reduced to preexercise levels by both α-FMH and H1/H2blockade. In addition, tryptase was elevated during exercise by Δ6.8 ± 1.1 ng/ml ( P < 0.05). Taken together, these data suggest that interstitial histamine in skeletal muscle increases with exercise and results from both de novo formation and mast cell degranulation. This suggests that exercise produces an anaphylactoid signal, which affects recovery, and may influence skeletal muscle blood flow during exercise.NEW & NOTEWORTHY Blood flow to previously active skeletal muscle remains elevated following an acute bout of aerobic exercise and is dependent on activation of histamine H1and H2receptors. The intramuscular source of histamine that drives this response to exercise has not been identified. Using intramuscular microdialysis in exercising humans, we show both mast cell degranulation and formation of histamine by histidine decarboxylase contributes to the histamine-mediated vasodilation that occurs following a bout of aerobic exercise.

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