Modulation of PGF2α- and hypoxia-induced contraction of rat intrapulmonary artery by p38 MAPK inhibition: a nitric oxide-dependent mechanism

2005 ◽  
Vol 289 (6) ◽  
pp. L1039-L1048 ◽  
Author(s):  
Greg A. Knock ◽  
Anushika S. De Silva ◽  
Vladimir A. Snetkov ◽  
Richard Siow ◽  
Gavin D. Thomas ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
P38 Mapk ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Smooth Muscle Contraction ◽  
Mitogen Activated Protein Kinase ◽  
No Donor ◽  
P38 Mapk Inhibitors ◽  
Prostaglandin F ◽  
Mapk Inhibitors ◽  
Sb 203580

The mechanisms through which p38 mitogen-activated protein kinase (p38 MAPK) is involved in smooth muscle contraction remain largely unresolved. We examined the role of p38 MAPK in prostaglandin F2α (PGF2α)-induced vasoconstriction and in hypoxic pulmonary vasoconstriction (HPV) of rat small intrapulmonary arteries (IPA). The p38 MAPK inhibitors SB-203580 and SB-202190 strongly inhibited PGF2α-induced vasoconstriction, with IC50s of 1.6 and 1.2 μM, whereas the inactive analog SB-202474 was ∼30-fold less potent. Both transient and sustained phases of HPV were suppressed by SB-203580, but not by SB-202474 (both 2 μM). Western blot analysis revealed that PGF2α (20 μM) increased phosphorylation of p38 MAPK and of heat shock protein 27 (HSP27), and this was abolished by SB-203580 but not by SB-202474 (both 2 μM). Endothelial denudation or blockade of endothelial nitric oxide (NO) synthase with Nω-nitro-l-arginine methyl ester (l-NAME) significantly suppressed the relaxation of PGF2α-constricted IPA by SB-203580, but not by SB-202474. Similarly, the inhibition of HPV by SB-203580 was prevented by prior treatment with l-NAME. SB-203580 (2 μM), but not SB-202474, enhanced relaxation-induced by the NO donor S-nitroso- N-acetylpenicillamine (SNAP) in endothelium-denuded IPA constricted with PGF2α. In α-toxin-permeabilized IPA, SB-203580-induced relaxation occurred in the presence but not the absence of the NO donor sodium nitroprusside (SNP); SB-202474 was without effect even in the presence of SNP. In intact IPA, neither PGF2α- nor SNAP-mediated changes in cytosolic free Ca2+ were affected by SB-203580. We conclude that p38 MAPK contributes to PGF2α- and hypoxia-induced constriction of rat IPA primarily by antagonizing the underlying Ca2+-desensitizing actions of NO.

scholarly journals The Expanding Role of p38 Mitogen-Activated Protein Kinase in Programmed Host Cell Death

2019 ◽  
Vol 12 ◽  
pp. 117863611986459 ◽  
Author(s):  
Jessica Gräb ◽  
Jan Rybniker
Keyword(s):  
Protein Kinase ◽  
Host Cell ◽  
P38 Mapk ◽  
Bacterial Infections ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Host Cell Apoptosis ◽  
Mitogen Activated Protein ◽  
P38 Mapk Inhibitors ◽  
Mapk Inhibitors

The p38 mitogen-activated protein kinase (MAPK) is involved in a multitude of essential cellular processes. The kinase is activated in response to environmental stresses, including bacterial infections and inflammation, to regulate the immune response of the host. However, recent studies have demonstrated that pathogens can manipulate p38 MAPK signaling for their own benefit to either prevent or induce host cell apoptosis. In addition, there is evidence demonstrating that p38 MAPK is a potent trigger of pathogen-induced necrosis driven by mitochondrial membrane disruption. Given the large number of p38 MAPK inhibitors that have been tested in clinical trials, these findings provide an opportunity to repurpose these drugs for improved control of infectious diseases.

P38 MAPK: critical molecule in thrombin-induced NF-κB-dependent leukocyte recruitment

2003 ◽  
Vol 284 (4) ◽  
pp. H1095-H1103 ◽  
Author(s):  
Jaswinder Kaur ◽  
Richard C. Woodman ◽  
Paul Kubes
Keyword(s):  
P38 Mapk ◽  
Umbilical Vein ◽  
Nuclear Factor Κb ◽  
Flow Chamber ◽  
Significant Inhibition ◽  
Leukocyte Recruitment ◽  
P38 Mapk Inhibitors ◽  
Mapk Inhibitors ◽  
Umbilical Vein Endothelial Cells ◽  
Sb 203580

Thrombin-stimulated endothelium synthesizes numerous adhesion molecules to recruit leukocytes; however, it is unknown which intracellular pathways are responsible for this event. A recent report from our laboratory has shown that thrombin induces E-selectin expression and that blocking nuclear factor-κB (NF-κB) activity partially blocked both E-selectin expression (60%) and leukocyte recruitment. In this study, we systematically assessed the importance of p38 MAPK in thrombin-induced NF-κB activation and E-selectin-dependent leukocyte recruitment. Thrombin caused phosphorylation of p38 MAPK, its substrate ATF-2, and JNK MAPK, but not ERK MAPK. The p38 MAPK inhibitors, SKF86002 and SB-203580 only reduced ATF-2 activity. We treated human umbilical vein endothelial cells with SKF86002, 1 h before thrombin stimulation, and noted inhibition of NF-κB mobilization and complete inhibition of leukocyte rolling and adhesion in a laminar flow chamber. Significant inhibition of leukocyte recruitment and E-selectin expression was also observed with SB-203580. SKF86002 did not affect other systems, including tumor necrosis factor-α-induced E-selectin-dependent leukocyte recruitment. Moreover, thrombin-induced rapid mobilization of P-selectin from Weibel Palade bodies was not p38 MAPK dependent. These data suggest that thrombin induces p38 MAPK activation, which leads to NF-κB mobilization to the nucleus and causes the upregulation of E-selectin and subsequent leukocyte recruitment.

scholarly journals Peripheral Injection of SB203580 Inhibits the Inflammatory-Dependent Synthesis of Proinflammatory Cytokines in the Hypothalamus

2014 ◽  
Vol 2014 ◽  
pp. 1-10 ◽  
Author(s):  
Andrzej P. Herman ◽  
Agata Krawczyńska ◽  
Joanna Bochenek ◽  
Hanna Antushevich ◽  
Anna Herman ◽  
...  
Keyword(s):  
Gene Expression ◽  
P38 Mapk ◽  
Proinflammatory Cytokines ◽  
Inflammatory Diseases ◽  
Competitive Inhibitor ◽  
Mitogen Activated Protein Kinase ◽  
Mitogen Activated Protein ◽  
P38 Mapk Inhibitors ◽  
Mapk Inhibitors ◽  
P38 Mapk Inhibitor

The study was designed to determine the effects of peripheral injection of SB203580 on the synthesis of interleukin- (IL-) 1β, IL-6, and tumor necrosis factor (TNF)αin the hypothalamus of ewes during prolonged inflammation. Inflammation was induced by the administration of lipopolysaccharide (LPS) (400 ng/kg) over 7 days. SB203580 is a selective ATP-competitive inhibitor of the p38 mitogen-activated protein kinase (MAPK), which is involved in the regulation of proinflammatory cytokines IL-1β, IL-6 and TNFαsynthesis. Intravenous injection of SB203580 successfully inhibited (P<0.01) synthesis of IL-1βand reduced (P<0.01) the production of IL-6 in the hypothalamus. The p38 MAPK inhibitor decreased (P<0.01) gene expression of TNFαbut its effect was not observed at the level of TNFαprotein synthesis. SB203580 also reduced (P<0.01) LPS-stimulated IL-1 receptor type 1 gene expression. The conclusion that inhibition of p38 MAPK blocks LPS-induced proinflammatory cytokine synthesis seems to initiate new perspectives in the treatment of chronic inflammatory diseases also within the central nervous system. However, potential proinflammatory effects of SB203580 treatment suggest that all therapies using p38 MAPK inhibitors should be introduced very carefully with analysis of all expected and unexpected consequences of treatment.

scholarly journals Central SDF-1/CXCL12 expression and its cardiovascular and sympathetic effects: the role of angiotensin II, TNF-α, and MAP kinase signaling

2014 ◽  
Vol 307 (11) ◽  
pp. H1643-H1654 ◽  
Author(s):  
Shun-Guang Wei ◽  
Zhi-Hua Zhang ◽  
Yang Yu ◽  
Robert B. Felder
Keyword(s):  
Angiotensin Ii ◽  
P38 Mapk ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Ang Ii ◽  
Cxcl12 Expression ◽  
Tnf Α ◽  
P38 Mapk Inhibitors ◽  
Mapk Inhibitors ◽  
Stromal Cell Derived Factor

The chemokine stromal cell-derived factor-1 (SDF-1/CXCL12) and its receptors are expressed by neurons and glial cells in cardiovascular autonomic regions of the brain, including the hypothalamic paraventricular nucleus (PVN), and contribute to neurohumoral excitation in rats with ischemia-induced heart failure. The present study examined factors regulating the expression of SDF-1 in the PVN and mechanisms mediating its sympatho-excitatory effects. In urethane anesthetized rats, a 4-h intracerebroventricular (ICV) infusion of angiotensin II (ANG II) or tumor necrosis factor-α (TNF-α) in doses that increase mean blood pressure (MBP) and sympathetic drive increased the expression of SDF-1 in PVN. ICV administration of SDF-1 increased the phosphorylation of p44/42 mitogen-activated protein kinase (MAPK), JNK, and p38 MAPK in PVN, along with MBP, heart rate (HR), and renal sympathetic nerve activity (RSNA), but did not affect total p44/42 MAPK, JNK, and p38 MAPK levels. ICV pretreatment with the selective p44/42 MAPK inhibitor PD98059 prevented the SDF-1-induced increases in MBP, HR, and RSNA; ICV pretreatment with the selective JNK and p38 MAPK inhibitors attenuated but did not block these SDF-1-induced excitatory responses. ICV PD98059 also prevented the sympatho-excitatory response to bilateral PVN microinjections of SDF-1. ICV pretreatment with SDF-1 short-hairpin RNA significantly reduced ANG II- and TNF-α-induced phosphorylation of p44/42 MAPK in PVN. These findings identify TNF-α and ANG II as drivers of SDF-1 expression in PVN and suggest that the full expression of their cardiovascular and sympathetic effects depends upon SDF-1-mediated activation of p44/42 MAPK signaling.

scholarly journals Impact of p38 MAP Kinase Inhibitors on LPS-Induced Release of TNF-α in Whole Blood and Primary Cells from Different Species

2015 ◽  
Vol 36 (6) ◽  
pp. 2237-2249 ◽  
Author(s):  
Sarah Fehr ◽  
Anke Unger ◽  
Elke Schaeffeler ◽  
Sonja Herrmann ◽  
Stefan Laufer ◽  
...  
Keyword(s):  
P38 Mapk ◽  
Whole Blood ◽  
Ex Vivo ◽  
P38 Map Kinase ◽  
Mitogen Activated Protein Kinase ◽  
Primary Cells ◽  
Interspecies Differences ◽  
Tnf Α ◽  
P38 Mapk Inhibitors ◽  
Mapk Inhibitors

Background/Aims: Inhibition of p38 mitogen-activated protein kinase (p38 MAPK) is promising for the treatment of inflammatory disorders, however, the efficacy of p38 MAPK inhibitors in clinical trials is limited so far. Since functional sensitivity of p38 MAPK is commonly predicted by preclinical species, we systematically investigated interspecies differences including human tissue. Methods: Ex vivo test models were established using whole blood and primary cells from different species such as mice, rats, pigs and humans to compare LPS-induced TNF-α inhibition of four different p38 MAPK reference inhibitors SB 203580, BIRB-796, Pamapimod, and a Losmapimod analogue as well as a proprietary imidazole-based p38 MAPK Inhibitor. Results: All analysed p38 MAPK inhibitors resulted in significant inhibition of LPS-induced TNF-α release but with high interspecies differences for dose sensitivity. IC50 values from human whole blood and PBMC showed significant higher sensitivity towards p38 MAPK inhibition compared with data from pig and rat. Conclusion: Inhibition of TNF-α release by p38 MAPK inhibitors can be reliably identified in well-established laboratory species such as rat or mouse. However, our data indicate that animal models appear to be limited for valid prediction of the inhibitory potential for TNF-α release in humans. Thus, human tissues should be considered early in the drug development process of p38 MAPK inhibitors.

scholarly journals p38 MAPK Signaling in Pemphigus: Implications for Skin Autoimmunity

2013 ◽  
Vol 2013 ◽  
pp. 1-11 ◽  
Author(s):  
Athanasios Mavropoulos ◽  
Timoklia Orfanidou ◽  
Christos Liaskos ◽  
Daniel S. Smyk ◽  
Vassiliki Spyrou ◽  
...  
Keyword(s):  
P38 Mapk ◽  
Inflammatory Responses ◽  
Critical Role ◽  
Pemphigus Vulgaris ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Current Evidence ◽  
Pemphigus Foliaceus ◽  
P38 Mapk Inhibitors ◽  
Mapk Inhibitors

p38 mitogen activated protein kinase (p38 MAPK) signaling plays a major role in the modulation of immune-mediated inflammatory responses and therefore has been linked with several autoimmune diseases. The extent of the involvement of p38 MAPK in the pathogenesis of autoimmune blistering diseases has started to emerge, but whether it pays a critical role is a matter of debate. The activity of p38 MAPK has been studied in great detail during the loss of keratinocyte cell-cell adhesions and the development of pemphigus vulgaris (PV) and pemphigus foliaceus (PF). These diseases are characterised by autoantibodies targeting desmogleins (Dsg). Whether autoantibody-antigen interactions can trigger signaling pathways (such as p38 MAPK) that are tightly linked to the secretion of inflammatory mediators which may perpetuate inflammation and tissue damage in pemphigus remains unclear. Yet, the ability of p38 MAPK inhibitors to block activation of the proapoptotic proteinase caspase-3 suggests that the induction of apoptosis may be a consequence of p38 MAPK activation during acantholysis in PV. This review discusses the current evidence for the role of p38 MAPK in the pathogenesis of pemphigus. We will also present data relating to the targeting of these cascades as a means of therapeutic intervention.

p38 mitogen-activated protein kinase mediates adenosine-induced alterations in myocardial glucose utilization via 5′-AMP-activated protein kinase

2007 ◽  
Vol 292 (4) ◽  
pp. H1978-H1985 ◽  
Author(s):  
Jagdip S. Jaswal ◽  
Manoj Gandhi ◽  
Barry A. Finegan ◽  
Jason R. B. Dyck ◽  
Alexander S. Clanachan
Keyword(s):  
Protein Kinase ◽  
P38 Mapk ◽  
Glucose Utilization ◽  
Glycogen Synthesis ◽  
Mitogen Activated Protein Kinase ◽  
Transient Ischemia ◽  
Mitogen Activated Protein ◽  
P38 Mapk Inhibitors ◽  
Ampk Activity ◽  
Mapk Inhibitors

Adenosine-induced acceleration of glycolysis in hearts stressed by transient ischemia is accompanied by suppression of glycogen synthesis and by increases in activity of adenosine 5′-monophosphate-activated protein kinase (AMPK). Because p38 mitogen-activated protein kinase (MAPK) may regulate glucose metabolism and may be activated downstream of AMPK, this study determined the effects of the p38 MAPK inhibitors SB202190 and SB203580 on adenosine-induced alterations in glucose utilization and AMPK activity. Studies were performed in working rat hearts perfused aerobically following stressing by transient ischemia (2 × 10-min ischemia followed by 5-min reperfusion). Phosphorylation of AMPK and p38 MAPK each were increased fourfold by adenosine, and these effects were inhibited by either SB202190 or SB203580. Neither of these inhibitors directly affected AMPK activity. Attenuation of the adenosine-induced increase in AMPK and p38 MAPK phosphorylation by SB202190 and SB203580 occurred independently of any change in tissue ATP-to-AMP ratio and did not alter glucose uptake, but it was accompanied by an increase in glycogen synthesis and glycogen content and by inhibition of glycolysis and proton production. There was a significant inverse correlation between the rate of glycogen synthesis and AMPK activity and between AMPK activity and glycogen content. These data demonstrate that AMPK is likely downstream of p38 MAPK in mediating the effects of adenosine on glucose utilization in hearts stressed by transient ischemia. The ability of p38 MAPK inhibitors to relieve the inhibition of glycogen synthesis and to inhibit glycolysis and proton production suggests that these agents may restore adenosine-induced cardioprotection in stressed hearts.

scholarly journals Drugs Designed To Inhibit Human p38 Mitogen-Activated Protein Kinase Activation Treat Toxoplasma gondii and Encephalitozoon cuniculi Infection

2007 ◽  
Vol 51 (12) ◽  
pp. 4324-4328 ◽  
Author(s):  
Shuang Wei ◽  
Benjamin J. Daniel ◽  
Michael J. Brumlik ◽  
Matthew E. Burow ◽  
Weiping Zou ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Toxoplasma Gondii ◽  
P38 Mapk ◽  
Human Fibroblasts ◽  
Mitogen Activated Protein Kinase ◽  
Encephalitozoon Cuniculi ◽  
Mapk Activation ◽  
Mitogen Activated Protein ◽  
P38 Mapk Inhibitors ◽  
Mapk Inhibitors

ABSTRACT We recently showed that the pyridinylimidazoles SB203580 and SB202190, drugs designed to block human p38 mitogen-activated protein kinase (MAPK) activation, also inhibited replication of the medically important intracellular parasite Toxoplasma gondii in cultured human fibroblasts through a direct effect on the parasite. We now show that additional pyridinylimidazole and imidazopyrimidine p38 MAPK inhibitors inhibit intracellular T. gondii replication in vitro and protect mice against fatal T. gondii infection. Mice surviving infection following treatment with p38 MAPK inhibitors were resistant to subsequent T. gondii challenge, demonstrating induction of protective immunity. Thus, drugs originally developed to block human p38 MAPK activation are useful for treating T. gondii infection without inducing significant immunosuppression. MAPK inhibitors combined with either of the approved anti-Toxoplasma drugs sulfadiazine and pyrimethamine resulted in improved survival among mice challenged with a fatal T. gondii inoculum. A MAPK inhibitor also treated mice infected with the Microsporidium parasite Encephalitozoon cuniculi, suggesting that MAPK inhibitors represent a novel class of agents that may have a broad spectrum of antiparasitic activity. Preliminary studies implicate a T. gondii MAPK homologue as the target of drug action, suggesting possibilities for more-selective agents.

Signaling by eNOS through a superoxide-dependent p42/44 mitogen-activated protein kinase pathway

2001 ◽  
Vol 281 (2) ◽  
pp. C544-C554 ◽  
Author(s):  
Weihan Wang ◽  
Shuibang Wang ◽  
Ervant V. Nishanian ◽  
Ana Del Pilar Cintron ◽  
Robert A. Wesley ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
P38 Mapk ◽  
Mapk Pathway ◽  
Mitogen Activated Protein Kinase ◽  
No Donor ◽  
Tnf Α ◽  
Mitogen Activated Protein ◽  
Factor Α ◽  
Reactive Oxygen Species Signaling ◽  
Endothelial Nitric Oxide

Expression of endothelial nitric oxide synthase (eNOS) in transfected U-937 cells upregulates phorbol 12-myristate 13-acetate (PMA)-induced tumor necrosis factor-α (TNF-α) production through a superoxide (O[Formula: see text])-dependent mechanism. Because mitogen-activated protein kinases (MAPK) have been shown to participate in both reactive oxygen species signaling and TNF-α regulation, their possible role in eNOS-derived O[Formula: see text] signal transduction was examined. A redox-cycling agent, phenazine methosulfate, was found to both upregulate TNF-α (5.8 ± 1.0 fold; P = 0.01) and increase the phosphorylation state of p42/44 MAPK (3.1 ± 0.2 fold; P = 0.01) in PMA-differentiated U-937 cells. Although S-nitroso- N-acetylpenicillamine, a nitric oxide (NO) donor, also increased TNF-α production, NO exposure led to phosphorylation of p38 MAPK, not p42/44 MAPK. Upregulation of TNF-α production by eNOS transfection was associated with increases in activated p42/44 MAPK ( P = 0.001), whereas levels of phosphorylated p38 MAPK were unaffected. Furthermore, cotransfection with Cu/Zn superoxide dismutase, which blocks TNF-α upregulation by eNOS, also abolished the effects on p42/44 MAPK. Expression of Gln361eNOS, a mutant that produces O[Formula: see text] but not NO, still resulted in p42/44 MAPK phosphorylation. In contrast, two NADPH binding site deletion mutants of eNOS that lack oxidase activity had no effect on p42/44 MAPK. Finally, PD-98059, a p42/44 MAPK pathway inhibitor, blocked TNF-α upregulation by eNOS ( P = 0.02). Thus O[Formula: see text] produced by eNOS increases TNF-α production via a mechanism that involves p42/44 MAPK activation.

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