Effect of PD98059, a Selective MAPK3/MAPK1 Inhibitor, on Acute Lung Injury in Mice

Paola, Rosanna Di; Crisafulli, Concetta; Mazzon, Emanuela; Genovese, Tiziana; Paterniti, Irene; Bramantı, Placido; Cuzzocrea, Salvatore

doi:10.1177/039463200902200409

Cited by 41 publications

(27 citation statements)

References 30 publications

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“…These include the genes for TNF-α, IL-1β and iNOS to name but a few [19]. There is good evidence that IL-1β help to propagate the extension of a local or systemic inflammatory process [20]. We have clearly confirmed a significant increase in the IL-1β production in the pleural 8 days following ligation.…”

Section: Discussionsupporting

confidence: 62%

Effects of Hypericum Perforatum, in a rodent model of periodontitis

Paterniti

Briguglio

Mazzon

et al. 2010

BMC Complement Altern Med

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BackgroundHypericum perforatum is a medicinal plant species containing many polyphenolic compounds, namely flavonoids and phenolic acids. In this study we evaluate the effect of Hypericum perforatum in animal model of periodontitis.MethodsPeriodontitis was induced in adult male Sprague-Dawley rats by placing a nylon thread ligature around the lower 1st molars. Hypericum perforatum was administered at the dose of 2 mg/kg os, daily for eight days. At day 8, the gingivomucosal tissue encircling the mandibular first molar was removed.ResultsPeriodontitis in rats resulted in an inflammatory process characterized by edema, neutrophil infiltration and cytokine production that was followed by the recruitment of other inflammatory cells, production of a range of inflammatory mediators such as NF-κB and iNOS expression, the nitration of tyrosine residues and activation of the nuclear enzyme poly (ADP-ribose) polymerase; apoptosis and the degree of gingivomucosal tissues injury. We report here that Hypericum perforatum exerts potent anti-inflammatory effects significantly reducing all of the parameters of inflammation as described above.ConclusionsTaken together, our results clearly demonstrate that treatment with Hypericum reduces the development of inflammation and tissue injury, events associated with periodontitis.

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Section: Discussionsupporting

confidence: 62%

Effects of Hypericum Perforatum, in a rodent model of periodontitis

Paterniti

Briguglio

Mazzon

et al. 2010

BMC Complement Altern Med

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“…; Calbiochem, San Diego, CA), a potent and selective antagonist of MEK-1, which is the upstream kinase of ERK 1/2 [28], [29]. The dose of PD98059 used is well established and has been widely used in many animal models to block the effect of ERK 1/2 [18], [30], [31], [32], [33], [34]. PD98059 or vehicle (DMSO) was administrated to mice 1 hour before CLP.…”

Section: Methodsmentioning

confidence: 99%

Hydrogen Sulfide and Neurogenic Inflammation in Polymicrobial Sepsis: Involvement of Substance P and ERK-NF-κB Signaling

et al. 2011

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Hydrogen sulfide (H2S) has been shown to induce transient receptor potential vanilloid 1 (TRPV1)-mediated neurogenic inflammation in polymicrobial sepsis. However, endogenous neural factors that modulate this event and the molecular mechanism by which this occurs remain unclear. Therefore, this study tested the hypothesis that whether substance P (SP) is one important neural element that implicates in H2S-induced neurogenic inflammation in sepsis in a TRPV1-dependent manner, and if so, whether H2S regulates this response through activation of the extracellular signal-regulated kinase-nuclear factor-κB (ERK-NF-κB) pathway. Male Swiss mice were subjected to cecal ligation and puncture (CLP)-induced sepsis and treated with TRPV1 antagonist capsazepine 30 minutes before CLP. DL-propargylglycine (PAG), an inhibitor of H2S formation, was administrated 1 hour before or 1 hour after sepsis, whereas sodium hydrosulfide (NaHS), an H2S donor, was given at the same time as CLP. Capsazepine significantly attenuated H2S-induced SP production, inflammatory cytokines, chemokines, and adhesion molecules levels, and protected against lung and liver dysfunction in sepsis. In the absence of H2S, capsazepine caused no significant changes to the PAG-mediated attenuation of lung and plasma SP levels, sepsis-associated systemic inflammatory response and multiple organ dysfunction. In addition, capsazepine greatly inhibited phosphorylation of ERK1/2 and inhibitory κBα, concurrent with suppression of NF-κB activation even in the presence of NaHS. Furthermore, capsazepine had no effect on PAG-mediated abrogation of these levels in sepsis. Taken together, the present findings show that H2S regulates TRPV1-mediated neurogenic inflammation in polymicrobial sepsis through enhancement of SP production and activation of the ERK-NF-κB pathway.

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“…In a previous study, our workgroup has already demonstrated the beneficial effects of PD98059 (2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one), a highly selective inhibitor of MEK1 activation (and, consequently, of the MAP kinase cascade), showing that at a dose of 10 mg/kg, this molecule is efficient in limiting the acute lung injury induced by carrageenan (Di Paola et al 2009). …”

Section: Introductionmentioning

confidence: 98%

MEK inhibition suppresses the development of lung fibrosis in the bleomycin model

Galuppo

Esposito

Mazzon

et al. 2011

Naunyn-Schmiedeberg's Arch Pharmacol

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The extracellular signal-regulated kinase (ERK) cascade has long been known to be central to the activation of cellular processes such as proliferation, differentiation, and oncogenic transformation. The mitogen-activated protein (MAP) serine/threonine family of protein kinases, of which ERK is a member, is activated by a mechanism that includes protein kinase cascades. Mitogen-activated protein kinases (MAPKs) are well-conserved enzymes connecting cell surface receptors to intracellular regulatory targets; they are activated in response to a wide variety of stimuli. The aim of this study was to investigate the effects of PD98059, a highly selective inhibitor of MAP/ERK kinase1 (MEK1) activation, on the development of lung inflammation and fibrosis. Lung injury was induced by intratracheal instillation of bleomycin (1 mg/kg), and PD98059 (10 mg/kg, 10% dimethyl sulfoxide, i.p.) was administrated 1 h after bleomycin instillation and daily for 7 days. PD98059 treatment shows therapeutic effects on pulmonary damage, decreasing many inflammatory and apoptotic parameters, such as (1) cytokine production; (2) IkBα degradation and NF-kB nuclear translocation; (3) iNOS expression; (4) nitrotyrosine and PAR localization; and (5) the degree of apoptosis, as evaluated by Bax and Bcl-2 balance, FAS ligand expression, and terminal deoxynucleotidyl transferase dUTP nick-end labeling staining. In particular, to assess whether PD98059 treatment influences MAPKs pathway, we have also investigated the expression of activated ERK and JNK after bleomycin-induced pulmonary fibrosis, showing that the inhibition of the cascade reduces the inflammatory processes that lead to the appearance of the fibrosis. Taken together, all our results clearly show that PD98059 reduces the lung injury and inflammation due to the intratracheal bleomycin administration in mice.

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Effect of PD98059, a Selective MAPK3/MAPK1 Inhibitor, on Acute Lung Injury in Mice

Cited by 41 publications

References 30 publications

Effects of Hypericum Perforatum, in a rodent model of periodontitis

Effects of Hypericum Perforatum, in a rodent model of periodontitis

Hydrogen Sulfide and Neurogenic Inflammation in Polymicrobial Sepsis: Involvement of Substance P and ERK-NF-κB Signaling

MEK inhibition suppresses the development of lung fibrosis in the bleomycin model

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