Benzodiazepines inhibit neutrophil chemotaxis and superoxide production in a stimulus dependent manner; PK-11195 antagonizes these effects

1991 ◽  
Vol 22 (3) ◽  
pp. 185-194 ◽  
Author(s):  
Molly Finnerty ◽  
Thaddeus J. Marczynski ◽  
Harold J. Amirault ◽  
Minka Urbancic ◽  
Burton R. Andersen
Keyword(s):  
Superoxide Production ◽  
Dependent Manner ◽  
Neutrophil Chemotaxis

scholarly journals GPER modulates tone and coronary vascular reactivity in male and female rats

2017 ◽  
Vol 59 (2) ◽  
pp. 171-180 ◽  
Author(s):  
Angelina Rafaela Debortoli ◽  
Wender do Nascimento Rouver ◽  
Nathalie Tristão Banhos Delgado ◽  
Vinicius Mengal ◽  
Erick Roberto Gonçalves Claudio ◽  
...  
Keyword(s):  
Protein Expression ◽  
Vascular Reactivity ◽  
Coronary Circulation ◽  
Superoxide Production ◽  
Female Rats ◽  
Male Rats ◽  
Coronary Perfusion ◽  
Dependent Manner ◽  
Coronary Tone

Compared with age-matched men, premenopausal women are largely protected from coronary artery disease, a difference that is lost after menopause. The effects of oestrogens are mediated by the activation of nuclear receptors (ERα and ERβ) and by the G protein-coupled oestrogen receptor (GPER). This study aims to evaluate the potential role of GPER in coronary circulation in female and male rats. The baseline coronary perfusion pressure (CPP) and the concentration–response curve with a GPER agonist (G-1) were evaluated in isolated hearts before and after the blockade of GPER. GPER, superoxide dismutase (SOD-2), catalase and gp91phox protein expression were assessed by Western blotting. Superoxide production was evaluated ‘in situ’ via dihydroethidium fluorescence (DHE). GPER blockade significantly increased the CPP in both groups, demonstrating the modulation of coronary tone by GPER. G-1 causes relaxation of the coronary bed in a concentration-dependent manner and was significantly higher in female rats. No differences were detected in GPER, SOD-2 and catalase protein expression. However, gp91phox expression and DHE fluorescence were higher in male rats, indicating elevated superoxide production. Therefore, GPER plays an important role in modulating coronary tone and reactivity in female and male rats. The observed differences in vascular reactivity may be related to the higher superoxide production in male rats. These findings help to elucidate the role of GPER-modulating coronary circulation, providing new information to develop a potential therapeutic target for the treatment of coronary heart disease.

scholarly journals Rac2 Regulates Neutrophil Chemotaxis, Superoxide Production, and Myeloid Colony Formation through Multiple Distinct Effector Pathways

2005 ◽  
Vol 174 (8) ◽  
pp. 4613-4620 ◽  
Author(s):  
Dirk Carstanjen ◽  
Akira Yamauchi ◽  
Annemart Koornneef ◽  
Heesuk Zang ◽  
Marie-Dominique Filippi ◽  
...  
Keyword(s):  
Colony Formation ◽  
Superoxide Production ◽  
Neutrophil Chemotaxis ◽  
Effector Pathways

Impaired in vitro polymorphonuclear function secondary to the chemotherapeutic effects of vincristine, adriamycin, cyclophosphamide, and actinomycin D.

1986 ◽  
Vol 4 (5) ◽  
pp. 798-804 ◽  
Author(s):  
M S Cairo ◽  
C Mallett ◽  
C VandeVen ◽  
P Kempert ◽  
G A Bennetts ◽  
...  
Keyword(s):  
Actinomycin D ◽  
Chemotherapeutic Agents ◽  
Superoxide Production ◽  
In Vivo Studies ◽  
Dependent Manner ◽  
High Concentration ◽  
Bacterial Killing ◽  
Significant Depression ◽  
Vitro Effect

The present study investigated the in vitro effect of four different chemotherapeutic agents, namely, cyclophosphamide (CTX), vincristine (VCR), Adriamycin (Adria Laboratories, Columbus, Ohio) (ADR), and actinomycin D (ACT-D) on human polymorphonuclear leukocyte (PMN) function. Human PMNs suspended in phosphate-buffered saline (PBS) at 1 X 10(7) cells/mL were incubated with increasing concentrations of CTX (0, 10(-5), 10(-4), 10(-3) mol/L) or VCR (0, 10(-7), 10(-6), 10(-5), 10(-4) mol/L), ADR (0, 10(-6), 10(-5), 10(-4), 10(-3) mol/L), or ACT-D (0, 5 X 10(-8), 1 X 10(-7), 5 X 10(-7), and 10(-6) mol/L). The cells were then tested for bacterial killing against Staphylococcus aureus, chemotaxis activity stimulated by Escherichia coli endotoxin, N-formyl-methionyl-leucyl-phenylalanine (FMLP)-stimulated aggregation, and cytochalasin B (Cyto B)/FMLP-stimulated superoxide production and enzyme degranulation. High concentration of CTX, an alkylating agent, showed a significant depression of PMN superoxide production, (124 +/- 13 v 161 +/- 15 nmol/10(7) cells, 5 minutes, P less than or equal to .025). ADR, an intercalating agent and membrane inhibitor, showed a significant depression of PMN degranulation and lysozyme release at 10(-4) and 10(-3) mol/L (15.3% +/- 1.7% v 24% +/- 7%, P less than .01; and 15.0% +/- 2.5% v 24% +/- 7%, P less than or equal to .025). VCR, a microtubule inhibitor, showed a significant depression of PMN aggregation at 10(-6), 10(-5), and 10(-4) mol/L (P less than .05), lysozyme release at 10(-4) mol/L (P less than .004), and beta-glucuronidase release at 10(-4) mol/L (P less than .004). In addition, chemotaxis was inhibited by VCR in a dose-dependent manner at all concentrations (10(-7) mol/L, P less than .02; 10(-6) mol/L, P less than .007; 10(-5) mol/L, P less than .006, and 10(-4) mol/L, P less than .003). ACT-D showed no significant effect on the PMN functions tested. These studies conclude that chemotherapeutic agents have modulating in vitro effects on PMN function. Further in vivo studies are therefore needed to assess PMN abnormalities in patients receiving cancer chemotherapy to determine their role in infectious complications.

Influence of whey and purified whey proteins on neutrophil functions in sheep

1997 ◽  
Vol 64 (2) ◽  
pp. 281-288 ◽  
Author(s):  
CHUN W. WONG ◽  
AI H. LIU ◽  
GEOFFREY O. REGESTER ◽  
GEOFFREY L. FRANCIS ◽  
DENNIS L. WATSON
Keyword(s):  
Whey Protein ◽  
Inflammatory Responses ◽  
Whey Proteins ◽  
Milk Proteins ◽  
Superoxide Production ◽  
Whey Protein Concentrate ◽  
Dependent Manner ◽  
Protein Concentrate ◽  
Milk Whey

The effects of ruminant whey and its purified fractions on neutrophil chemotaxis and superoxide production in sheep were studied. Both colostral whey and milk whey were found to inhibit chemotaxis regardless of whether they were autologous or homologous, but the inhibitory effects were abolished by washing neutrophils with culture medium before their use in the chemotaxis assay. Colostral whey and milk whey also inhibited the chemotactic activity of zymosan-activated serum. Whey fractions of various degrees of purity such as lactoferrin, lacto-peroxidase, lactoferrin–lactoperoxidase, α-lactalbumin, bovine serum albumin and whey protein concentrate were then studied. While none of these proteins showed any effects on chemotaxis, lactoferrin–lactoperoxidase and whey protein concentrate were found to have an enhancing effect on superoxide production in a dose-dependent manner. Our results provide information on the modulatory role of ruminant milk proteins in inflammatory responses and warrant future investigation.

scholarly journals Radil controls neutrophil adhesion and motility through β2-integrin activation

2012 ◽  
Vol 23 (24) ◽  
pp. 4751-4765 ◽  
Author(s):  
Lunhua Liu ◽  
Wulin Aerbajinai ◽  
Syed M. Ahmed ◽  
Griffin P. Rodgers ◽  
Stephane Angers ◽  
...  
Keyword(s):  
Cell Adhesion ◽  
Inflammatory Responses ◽  
Neutrophil Adhesion ◽  
Dependent Manner ◽  
Neutrophil Chemotaxis ◽  
Integrin Activation ◽  
Chemotactic Migration ◽  
Long Tail ◽  
Β2 Integrin ◽  
Inhibitory Antibodies

Integrin activation is required to facilitate multiple adhesion-dependent functions of neutrophils, such as chemotaxis, which is critical for inflammatory responses to injury and pathogens. However, little is known about the mechanisms that mediate integrin activation in neutrophils. We show that Radil, a novel Rap1 effector, regulates β1- and β2-integrin activation and controls neutrophil chemotaxis. On activation and chemotactic migration of neutrophils, Radil quickly translocates from the cytoplasm to the plasma membrane in a Rap1a-GTP–dependent manner. Cells overexpressing Radil show a substantial increase in cell adhesion, as well as in integrin/focal adhesion kinase (FAK) activation, and exhibit an elongated morphology, with severe tail retraction defects. This phenotype is effectively rescued by treatment with either β2-integrin inhibitory antibodies or FAK inhibitors. Conversely, knockdown of Radil causes severe inhibition of cell adhesion, β2-integrin activation, and chemotaxis. Furthermore, we found that inhibition of Rap activity by RapGAP coexpression inhibits Radil-mediated integrin and FAK activation, decreases cell adhesion, and abrogates the long-tail phenotype of Radil cells. Overall, these studies establish that Radil regulates neutrophil adhesion and motility by linking Rap1 to β2-integrin activation.

scholarly journals GBF1 bears a novel phosphatidylinositol-phosphate binding module, BP3K, to link PI3Kγ activity with Arf1 activation involved in GPCR-mediated neutrophil chemotaxis and superoxide production

2012 ◽  
Vol 23 (13) ◽  
pp. 2457-2467 ◽  
Author(s):  
Yuichi Mazaki ◽  
Yasuharu Nishimura ◽  
Hisataka Sabe
Keyword(s):  
Phosphatidyl Inositol ◽  
Leading Edge ◽  
G Protein Coupled Receptors ◽  
Superoxide Production ◽  
Neutrophil Chemotaxis ◽  
Phosphate Binding ◽  
Gtpase Activating Protein ◽  
Phosphatidylinositol Phosphate ◽  
Arf Gtpases ◽  
G Protein Coupled

Most chemoattractants for neutrophils bind to the Gαifamily of heterotrimeric G protein–coupled receptors (GPCRs) and release Gβγ subunits to activate chemotaxis and superoxide production. GIT2, a GTPase-activating protein for Arf1, forms a complex with Gβγ and is integral for directional sensing and suppression of superoxide production. Here we show that GBF1, a guanine nucleotide exchanging factor for Arf-GTPases, is primarily responsible for Arf1 activation upon GPCR stimulation and is important for neutrophil chemotaxis and superoxide production. We find that GBF1 bears a novel module, namely binding to products of phosphatidyl inositol 3-kinase (PI3K), which binds to products of PI3Kγ. Through this binding, GBF1 is translocated from the Golgi to the leading edge upon GPCR stimulation to activate Arf1 and recruit p22phox and GIT2 to the leading edge. Moreover, GBF1-mediated Arf1 activation is necessary to unify cell polarity during chemotaxis. Our results identify a novel mechanism that links PI3Kγ activity with chemotaxis and superoxide production in GPCR signaling.

Tumor necrosis factor induces matrix metalloproteinases in cardiomyocytes and cardiofibroblasts differentially via superoxide production in a PI3Kγ-dependent manner

2010 ◽  
Vol 298 (3) ◽  
pp. C679-C692 ◽  
Author(s):  
Ahmed E. Awad ◽  
Vijay Kandalam ◽  
Subhadeep Chakrabarti ◽  
Xiuhua Wang ◽  
Josef M. Penninger ◽  
...  
Keyword(s):  
Tumor Necrosis Factor ◽  
Matrix Metalloproteinases ◽  
Tumor Necrosis ◽  
Primary Cultures ◽  
Oxidase Inhibitor ◽  
Cardiac Cells ◽  
Superoxide Production ◽  
Dependent Manner ◽  
Necrosis Factor

Tumor necrosis factor (TNF) is an inflammatory cytokine that is upregulated in a number of cardiomyopathies. Adverse cardiac remodeling and dilation result from degradation of the extracellular matrix by matrix metalloproteinases (MMPs). We investigated whether TNF can directly trigger expression and activation of MMPs in cardiac cells. We compared MMP expression profile and activities between primary cultures of mouse neonatal cardiomyocytes and cardiofibroblasts and in cellular and extracellular compartments. In response to recombinant TNF (rTNF, 20 ng/ml), cardiomyocytes exhibited faster and more pronounced superoxide production compared with cardiofibroblasts, concomitant with increased expression of several MMPs. MMP9 levels increased more rapidly and about twofold more in cardiomyocytes than in cardiofibroblasts. TNF did not induce MMP2 expression. Expression of collagenases (MMP8, MMP12, MMP13, and MMP14) increased significantly, while total collagenase activity increased to a greater degree in conditioned medium of cardiomyocytes than in cardiofibroblasts. rTNF-mediated MMP expression and activation were dependent on superoxide production and were blocked by apocynin, an NADPH oxidase inhibitor. We identified phosphatidylinositol 3-kinase (PI3K)γ as a key factor in TNF-mediated events since TNF-induced superoxide production, MMP expression, and activity were significantly suppressed in cardiomyocytes and cardiofibroblasts deficient in PI3Kγ. We further demonstrated that the TNF-superoxide-MMP axis of events is in fact activated in heart disease in vivo. Wild-type and TNF−/− mice subjected to cardiac pressure overload revealed that TNF deficiency resulted in reduced superoxide levels, collagenase activities, PI3K activity, and fibrosis leading to attenuated cardiac dilation and dysfunction. Our study demonstrates that TNF triggers expression and activation of MMPs faster and stronger in cardiomyocytes than in cardiofibroblasts in a superoxide-dependent manner and via activation of PI3Kγ, thereby contributing to adverse myocardial remodeling in disease.

scholarly journals Exosomes mediate LTB4 release during neutrophil chemotaxis

PLoS Biology ◽  
2021 ◽  
Vol 19 (7) ◽  
pp. e3001271
Author(s):  
Ritankar Majumdar ◽  
Aidin Tavakoli Tameh ◽  
Subhash B. Arya ◽  
Carole A. Parent
Keyword(s):  
Chemotactic Activity ◽  
Multivesicular Bodies ◽  
Dependent Manner ◽  
Neutrophil Chemotaxis ◽  
In Trans

Leukotriene B4 (LTB4) is secreted by chemotactic neutrophils, forming a secondary gradient that amplifies the reach of primary chemoattractants. This strategy increases the recruitment range for neutrophils and is important during inflammation. Here, we show that LTB4 and its synthesizing enzymes localize to intracellular multivesicular bodies, which, upon stimulation, release their content as exosomes. Purified exosomes can activate resting neutrophils and elicit chemotactic activity in an LTB4 receptor-dependent manner. Inhibition of exosome release leads to loss of directional motility with concomitant loss of LTB4 release. Our findings establish that the exosomal pool of LTB4 acts in an autocrine fashion to sensitize neutrophils towards the primary chemoattractant, and in a paracrine fashion to mediate the recruitment of neighboring neutrophils in trans. We envision that this mechanism is used by other signals to foster communication between cells in harsh extracellular environments.

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