scholarly journals Mast Cells Mediate Inflammatory Injury and Aggravate Neurological Impairment in Experimental Subarachnoid Hemorrhage Through Microglial PAR-2 Pathway

2021 ◽  
Vol 15 ◽  
Author(s):  
Bing Qin ◽  
Yucong Peng ◽  
Chen Zhong ◽  
Yong Cai ◽  
Shengjun Zhou ◽  
...  
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Mast Cells ◽  
Neuronal Damage ◽  
Neurological Impairment ◽  
Blue Staining ◽  
Vehicle Group ◽  
Inflammatory Injury ◽  
Pathophysiological Process

Subarachnoid hemorrhage (SAH) is a devastating cerebrovascular disease with high mortality and disability. Aberrant neuroinflammation has been identified as a critical factor accounting for the poor prognosis of SAH patients. Mast cells (MCs), the sentinel cells of the immune system, play a critical in the early immune reactions and participate in multiple pathophysiological process. However, the exact role of MCs on the pathophysiological process after SAH has not been fully understood. The current study was conducted to determine the role of MCs and MC stabilization in the context of SAH. Mouse SAH model was established by endovascular perforation process. Mice received saline or cromolyn (MC stabilizer) or compound 48/80 (MCs degranulator). Post-SAH evaluation included neurobehavioral test, western blot, immunofluorescence, and toluidine blue staining. We demonstrated that SAH induced MCs activation/degranulation. Administration of MC stabilizer cromolyn conferred a better neurologic outcome and decreased brain edema when compared with SAH+vehicle group. Furthermore, cromolyn significantly inhibited neuroinflammatory response and alleviated neuronal damage after SAH. However, pharmacological activation of MCs with compound 48/80 dramatically aggravated SAH-induced brain injury and exacerbated neurologic outcomes. Notably, pharmacological inhibition of microglial PAR-2 significantly reversed MCs-induced inflammatory response and neurological impairment. Additionally, the effect of MCs-derived tryptase in mediating neuroinflammation was also abolished by the microglial PAR-2 blockage in vitro. Taken together, MCs yielded inflammatory injury through activating microglia-related neuroinflammation after SAH. These data shed light on the notion that MCs might be a novel and promising therapeutic target for SAH.

Endothelium-derived relaxing factor in regulation of basal cardiopulmonary and renal function

1991 ◽  
Vol 261 (2) ◽  
pp. R323-R328 ◽  
Author(s):  
M. A. Perrella ◽  
F. L. Hildebrand ◽  
K. B. Margulies ◽  
J. C. Burnett
Keyword(s):  
Renal Function ◽  
Competitive Inhibitor ◽  
Vehicle Group ◽  
Relaxing Factor ◽  
Anesthetized Dogs ◽  
Endothelium Derived Relaxing Factor ◽  
Renal Vascular ◽  
Renal Responses

The endothelium has emerged as an important modulator of vascular tone by producing both vasodilating and vasoconstricting substances. In vitro studies have demonstrated that endothelial cells produce endothelium-derived relaxing factor (EDRF), which promotes vasodilation via the stimulation of intracellular guanosine 3',5'-cyclic monophosphate (cGMP). However, the role of EDRF in the basal regulation of cardiopulmonary and renal function is not well defined. The present study was therefore designed to assess the function of EDRF by studying two groups of normal anesthetized dogs, of which one received a competitive inhibitor to EDRF generation, NG-monomethyl-L-arginine (L-NMMA; 50 micrograms.kg-1.min-1 iv), and the other received a vehicle. The L-NMMA infusion produced no significant increase in mean arterial pressure but marked increases in systemic, pulmonary, and renal vascular resistances compared with the vehicle group. Although renal blood flow decreased with L-NMMA, no changes were observed in glomerular filtration rate or sodium excretion. Associated with the cardiopulmonary and renal responses with L-NMMA was a modest increase in plasma endothelin (7.9 +/- 1.3 to 10.2 +/- 1.8 pg/ml, P less than 0.05), an endothelium-derived vasoconstrictor. No alteration was observed in plasma or urinary cGMP with EDRF inhibition. These cardiopulmonary and renal responses with L-NMMA may be attributed not only to EDRF inhibition but to an imbalance between endothelium-derived relaxing and contracting factors.

scholarly journals Garcinoic Acid Improves Cardiac Function and Enhances Angiogenesis Following Myocardial Infarction

2021 ◽  
Author(s):  
Hongyao Hu ◽  
Wei Li ◽  
Yanzhao Wei ◽  
Hui Zhao ◽  
Zhenzhong Wu ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Cardiac Function ◽  
Ventricular Remodeling ◽  
Vehicle Group ◽  
Potential Mechanism ◽  
Garcinia Kola ◽  
Angiogenic Proteins

Abstract Cardiac ischemia impairs angiogenesis in response to hypoxia, resulting in ventricular remodeling. Garcinoic acid (GA), the extraction from the plant garcinia kola, is validated to attenuate inflammatory response. However, the role of GA in heart failure (HF) and neovascularization after myocardial infarction (MI) is incompletely understood. The present study is striving to explore the role of GA and the potential mechanism of which in cardiac function after MI. SD rats were randomized into sham group, MI+vehicle group, and MI+GA group in vivo. Human umbilical endothelial cells (HUVECs) were cultured in vehicle or GA, and then additionally exposed to 2% hypoxia environment in vitro. MI rats displayed a dramatically reduced myocardial injury, cardiac function and vessel density in the peri-infarcted areas. GA delivery markedly improved cardiac performance and promoted angiogenesis. In addition, GA significantly enhanced tube formation in HUVECs under hypoxia condition. Furthermore, the expressions of pro-angiogenic factors HIF-1α, VEGF-A and bFGF, and pro-angiogenic proteins phospho-VEGFR2Tyr1175 and VEGFR2, as well as phosphorylation levels of Akt and eNOS were increased by GA treatment. In conclusion, GA preserved cardiac function after MI probably via promoting neovascularization. And the potential mechanism may be partially through upregulating the expressions of HIF-1α, VEGF-A, bFGF, phospho-VEGFR2Tyr1175 and VEGFR2 and activating the phosphorylations of Akt and eNOS.

scholarly journals Mast Cells in Cardiovascular Disease: From Bench to Bedside

2019 ◽  
Vol 20 (14) ◽  
pp. 3395 ◽  
Author(s):  
Hermans ◽  
Lennep ◽  
van Daele ◽  
Bot
Keyword(s):  
Cardiovascular Disease ◽  
Mast Cells ◽  
Animal Studies ◽  
Intraplaque Hemorrhage ◽  
Hematological Disease ◽  
Plaque Instability ◽  
Clonal Proliferation ◽  
Progression Of Atherosclerosis

Mast cells are pluripotent leukocytes that reside in the mucosa and connective tissue. Recent studies show an increased prevalence of cardiovascular disease among patients with mastocytosis, which is a hematological disease that is characterized by the accumulation of mast cells due to clonal proliferation. This association suggests an important role for mast cells in cardiovascular disease. Indeed, the evidence establishing the contribution of mast cells to the development and progression of atherosclerosis is continually increasing. Mast cells may contribute to plaque formation by stimulating the formation of foam cells and causing a pro-inflammatory micro-environment. In addition, these cells are able to promote plaque instability by neo-vessel formation and also by inducing intraplaque hemorrhage. Furthermore, mast cells appear to stimulate the formation of fibrosis after a cardiac infarction. In this review, the available data on the role of mast cells in cardiovascular disease are summarized, containing both in vitro research and animal studies, followed by a discussion of human data on the association between cardiovascular morbidity and diseases in which mast cells are important: Kounis syndrome, mastocytosis and allergy.

scholarly journals HIF-1α contributes to Ang II-induced inflammatory cytokine production in podocytes

2019 ◽  
Vol 20 (1) ◽  
Author(s):  
Hao Huang ◽  
Yanqin Fan ◽  
Zhao Gao ◽  
Wei Wang ◽  
Ning Shao ◽  
...  
Keyword(s):  
Hypoxia Inducible Factor ◽  
Renin Angiotensin System ◽  
Inflammatory Factors ◽  
Ang Ii ◽  
Angiotensin System ◽  
Inflammatory Injury ◽  
Tnf Α

Abstract Background Studies have indicated that changed expression of hypoxia-inducible factor-1α (HIF-1α) in epithelial cells from the kidney could affect the renal function in chronic kidney disease (CKD). As Angiotensin II (Ang II) is a critical active effector in the renin-angiotensin system (RAS) and was proved to be closely related to the inflammatory injury. Meanwhile, researchers found that Ang II could alter the expression of HIF-1α in the kidney. However, whether HIF-1α is involved in mediating Ang II-induced inflammatory injury in podocytes is not clear. Methods Ang II perfusion animal model were established to assess the potential role of HIF-1α in renal injury in vivo. Ang II stimulated podocytes to observe the corresponding between HIF-1α and inflammatory factors in vitro. Results The expression of inflammatory cytokines such as MCP-1 and TNF-α was increased in the glomeruli from rats treated with Ang II infusion compared with control rats. Increased HIF-1α expression in the glomeruli was also observed in Ang II-infused rats. In vitro, Ang II upregulated the expression of HIF-1α in podocytes. Furthermore, knockdown of HIF-1α by siRNA decreased the expression of MCP-1 and TNF-α. Moreover, HIF-1α siRNA significantly diminished the Ang II-induced overexpression of HIF-1α. Conclusion Collectively, our results suggest that HIF-1α participates in the inflammatory response process caused by Ang II and that downregulation of HIF-1α may be able to partially protect or reverse inflammatory injury in podocytes.

scholarly journals Novel role of mortalin in attenuating HIV-1 Tat-mediated astrogliosis

2020 ◽  
Vol 17 (1) ◽  
Author(s):  
Priyanka ◽  
Renu Wadhwa ◽  
Rituparna Chaudhuri ◽  
Tapas Chandra Nag ◽  
Pankaj Seth
Keyword(s):  
Western Blotting ◽  
Neuronal Death ◽  
Neuronal Damage ◽  
Fetal Brain ◽  
Luciferase Assay ◽  
Expression Vectors ◽  
Neurocognitive Dysfunction ◽  
Hiv 1

Abstract Background In human immunodeficiency virus-1 (HIV-1) infection, activation of astrocytes induces imbalance in physiological functions due to perturbed astrocytic functions that unleashes toxicity on neurons. This leads to inflammatory response finally culminating into neurocognitive dysfunction. In neuroAIDS, HIV-1 protein, transactivator of transcription (Tat) is detected in the cerebrospinal fluid of infected patients. Mortalin, a multifunctional protein, has anti-inflammatory role following its activation in various stress conditions. Recent studies demonstrate downregulation of mortalin in neurodegenerative diseases. Here, we explored the mechanisms of mortalin in modulating HIV-1 Tat-mediated neuroinflammation. Methods Expression of mortalin in autopsy section in normal and diseased individuals were examined using immunohistochemistry. To decipher the role of mortalin in HIV-1 Tat-induced activation, human fetal brain-derived astrocytes were transiently transfected with Tat and mortalin using expression vectors. HIV-1 Tat-mediated damage was analyzed using RT-PCR and western blotting. Modulatory role of mortalin was examined by coexpressing it with Tat, followed by examination of mitochondrial morphodynamics using biochemical assay and confocal and electron microscopy. Extracellular ATP release was monitored using luciferase assay. Neuroinflammation in astrocytes was examined using flow cytometry, dye based study, immunocytochemistry, immunoprecipitation, and western blotting. Indirect neuronal damage was also analyzed. Results HIV-1 Tat downregulates the expression of mortalin in astrocytes, and this is corroborated with autopsy sections of HIV-1 patients. We found that overexpression of mortalin with Tat reduced inflammation and also rescued astrocytic-mediated neuronal death. Using bioinformatics, we discovered that binding of mortalin with Tat leads to Tat degradation and rescues the cell from neuroinflammation. Blocking of proteosomal pathway rescued the Tat degradation and revealed the ubiquitination of Tat. Conclusion Overall, our data demonstrated the protective role of mortalin in combating HIV-1 Tat-mediated damage. We also showed that mortalin could degrade Tat through direct binding with HIV-1 Tat. Overexpression of mortalin in the presence of Tat could significantly reduce cytotoxic effects of Tat in astrocytes. Indirect neuronal death was also found to be rescued. Our in vitro findings were validated as we found attenuated expression of mortalin in the autopsy sections of HIV-1 patients.

scholarly journals Impaired FcϵRI stability, signaling, and effector functions in murine mast cells lacking glycosylphosphatidylinositol-anchored proteins

Blood ◽  
2011 ◽  
Vol 118 (16) ◽  
pp. 4377-4383 ◽  
Author(s):  
Wouter L. W. Hazenbos ◽  
Ping Wu ◽  
Jeffrey Eastham-Anderson ◽  
Taroh Kinoshita ◽  
Eric J. Brown
Keyword(s):  
Mast Cells ◽  
Targeted Disruption ◽  
Potential Therapeutic Target ◽  
Effector Functions ◽  
Ige Mediated ◽  
Interchain Interactions ◽  
Β Chain ◽  
Stimulation Of

Abstract A key event and potential therapeutic target in allergic and asthmatic diseases is signaling by the IgE receptor FcϵRI, which depends on its interactions with Src family kinases (SFK). Here we tested the hypothesis that glycosylphosphatidylinositiol-anchored proteins (GPI-AP) are involved in FcϵRI signaling, based on previous observations that GPI-AP colocalize with and mediate activation of SFK. We generated mice with a hematopoietic cell-specific GPI-AP deficiency by targeted disruption of the GPI biosynthesis gene PigA. In these mice, IgE-mediated passive cutaneous anaphylaxis was largely abolished. PigA-deficient mast cells cultured from these mice showed impaired degranulation in response to stimulation with IgE and antigen in vitro, despite normal IgE binding and antigen-induced FcϵRI aggregation. On stimulation of these cells with IgE and antigen, coprecipitation of the FcϵRI α-chain with the γ-chain and β-chain was markedly reduced. As a result, IgE/antigen–induced FcϵRI-Lyn association and γ-chain tyrosine phosphorylation were both impaired in PigA-deficient cells. These data provide genetic evidence for an unanticipated key role of GPI-AP in FcϵRI interchain interactions and early FcϵRI signaling events, necessary for antigen-induced mast cell degranulation.

scholarly journals Interleukin-6 (IL-6) Activates the NOTCH1 Signaling Pathway Through E-Proteins in Endometriotic Lesions

2020 ◽  
Vol 105 (5) ◽  
pp. 1316-1326
Author(s):  
Yong Song ◽  
Ren-Wei Su ◽  
Niraj R Joshi ◽  
Tae Hoon Kim ◽  
Bruce A Lessey ◽  
...  
Keyword(s):  
Mouse Model ◽  
Vehicle Group ◽  
E Proteins ◽  
Eutopic Endometrium ◽  
Baboon Model ◽  
Notch1 Signaling Pathway ◽  
Interfering Rna

Abstract Context NOTCH signaling is activated in endometriotic lesions, but the exact mechanisms remains unclear. IL-6, which is increased in the peritoneal fluid of women with endometriosis, induces NOTCH1 through E-proteins including E2A and HEB in cancer. Objective To study the role of E-proteins in inducing NOTCH1 expression under the regulation of IL-6 in endometriosis. Setting and Design The expression of E-proteins and NOTCH1 was first investigated in endometrium of women with endometriosis and the baboon model of endometriosis. Regulation of E-proteins and NOTCH1 expression was examined after IL-6 stimulation and siRNA mediated inhibition of E2A or/and HEB in human endometriotic epithelial cells (12Z) in vitro, and subsequently following IL-6 treatment in the mouse model of endometriosis in vivo. Results E2A, HEB, and NOTCH1 were significantly upregulated in glandular epithelium (GE) of ectopic endometrium compared to eutopic endometrium in both women and the baboon model. IL-6 treatment upregulated the expression of NOTCH1 together with E2A and HEB in 12Z cells. Small interfering RNA inhibition of E2A and HEB or HEB alone decreased NOTCH1 expression. Binding efficiency of both E2A and HEB was significantly higher at the binding sites on the human NOTCH1 promoter after IL-6 treatment. Finally, IL-6 treatment resulted in a significantly increased number of endometriotic lesions along with increased expression of E2A, HEB, and NOTCH1 in GE of the lesions compared with the vehicle group in an endometriosis mouse model. Conclusions IL-6 induced NOTCH1 expression is mediated by E-proteins in the ectopic GE cells, which may promote endometriotic lesion development.

Hemoglobin, NO, and 20-HETE interactions in mediating cerebral vasoconstriction following SAH

2006 ◽  
Vol 290 (1) ◽  
pp. R84-R89 ◽  
Author(s):  
Kazuhiko Takeuchi ◽  
Noriyuki Miyata ◽  
Marija Renic ◽  
David R. Harder ◽  
Richard J. Roman
Keyword(s):  
Nitric Oxide ◽  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Subarachnoid Hemorrhage ◽  
Methyl Ester ◽  
Cerebral Vasoconstriction ◽  
Vasoactive Factors ◽  
Vasoconstrictor Response

Recent studies have indicated that 20-hydroxyeicosatetraenoic acid (20-HETE) contributes to the fall in cerebral blood flow (CBF) after subarachnoid hemorrhage (SAH), but the factors that stimulate the production of 20-HETE are unknown. This study examines the role of vasoactive factors released by clotting blood vs. the scavenging of nitric oxide (NO) by hemoglobin (Hb) in the fall in CBF after SAH. Intracisternal (icv) injection of blood produced a greater and more prolonged (120 vs. 30 min) decrease in CBF than that produced by a 4% solution of Hb. Pretreating rats with Nω-nitro-l-arginine methyl ester (l-NAME; 10 mg/kg iv) to block the synthesis of NO had no effect on the fall in CBF produced by an icv injection of blood. l-NAME enhanced rather than attenuated the fall in CBF produced by an icv injection of Hb. Blockade of the synthesis of 20-HETE with TS-011 (0.1 mg/kg iv) prevented the sustained fall in CBF produced by an icv injection of blood and the transient vasoconstrictor response to Hb. Hb (0.1%) reduced the diameter of the basilar artery (BA) of rats in vitro by 10 ± 2%. This response was reversed by TS-011 (100 nM). Pretreatment of vessels with l-NAME (300 μM) reduced the diameter of BA and blocked the subsequent vasoconstrictor response to the addition of Hb to the bath. TS-011 returned the diameter of vessels exposed to l-NAME and Hb to that of control. These results suggest that the fall in CBF after SAH is largely due to the release of vasoactive factors by clotting blood rather than the scavenging of NO by Hb and that 20-HETE contributes the vasoconstrictor response of cerebral vessels to both Hb and blood.

scholarly journals Mast cells are responsible for the lack of anti-inflammatory effects of morphine in CBA mice

2004 ◽  
Vol 13 (5-6) ◽  
pp. 365-368 ◽  
Author(s):  
Elzbieta Stankiewicz ◽  
Ewa Wypasek ◽  
Barbara Plytycz
Keyword(s):  
Mast Cells ◽  
Histamine Release ◽  
Swiss Mice ◽  
Cba Mice ◽  
Peritoneal Mast Cells ◽  
Anti Inflammatory ◽  
Zymosan Peritonitis

BACKGROUND and aim: Morphine co-injection has anti-inflammatory effects on zymosan-induced peritonitis in several strains of mice except that of CBA. As peritoneal mast cells (pMCs) are much more numerous in CBA mice than in SWISS mice, the role of pMCs in morphine-modulated zymosan peritonitis is compared in CBA and SWISS males.Methods: pMCs were treatedin vitrowith morphine or C48/80 for comparison of histamine release.In vivoaccumulation of leukocytes and histamine in peritoneal exudate were recorded after intraperitoneal injection with morphine, zymosan, or zymosan plus morphine.Results and conclusion: Morphine induces histamine release by pMCs from CBA mice but not SWISS mice.In vivomorphine-induced peritonitis is stronger in CBA mice than SWISS mice. Corollary, morphine anti-inflammatory effects on zymosan peritonitis are reversed in CBA mice by its pro-inflammatory action through CBA pMCs.

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