Therapeutic potential of inhaled p38 mitogen-activated protein kinase inhibitors for inflammatory pulmonary diseases

Chopra, Puneet; Kanoje, Vijay; Semwal, Arvind; Ray, Abhijit

doi:10.1517/13543784.17.10.1411

Cited by 53 publications

(50 citation statements)

References 89 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Our initial assessments suggest that the p38 inhibition ameliorates the skull abnormalities in BSS to a lesser degree. Because p38 plays a crucial role in the signaling cascades of diverse cellular processes, systemic p38 inhibition could result in undesired pharmacological activities in different organs, as suggested by previous studies (70). Thus, we performed topical administration on the skin and found obvious improvement of skin abnormalities.…”

Section: Discussionmentioning

confidence: 73%

“…We found that phosphorylated p38 signaling is increased in both the epidermis and calvarial tissues of Fgfr2 +/Y394C mice. It is known that p38 is one of the critical components within the downstream signaling pathways of different tyrosine kinase receptors, which are associated with skin development and disorders, including FGFR, EGFR, and IGF1 receptor (IGF1R) (70). Also, p38 signaling is involved in skin homeostasis or epidermal differentiation (71) and plays an important role in osteoblast differentiation (72,73).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

p38 Inhibition ameliorates skin and skull abnormalities in Fgfr2 Beare-Stevenson mice

Wang¹,

Zhou²,

Oberoi³

et al. 2012

J. Clin. Invest.

View full text Add to dashboard Cite

Beare-Stevenson cutis gyrata syndrome (BSS) is a human genetic disorder characterized by skin and skull abnormalities. BSS is caused by mutations in the FGF receptor 2 (FGFR2), but the molecular mechanisms that induce skin and skull abnormalities are unclear. We developed a mouse model of BSS harboring a FGFR2 Y394C mutation and identified p38 MAPK as an important signaling pathway mediating these abnormalities. Fgfr2 +/Y394C mice exhibited epidermal hyperplasia and premature closure of cranial sutures (craniosynostosis) due to abnormal cell proliferation and differentiation. We found ligand-independent phosphorylation of FGFR2 and activation of p38 signaling in mutant skin and calvarial tissues. Treating Fgfr2 +/Y394C mice with a p38 kinase inhibitor attenuated skin abnormalities by reversing cell proliferation and differentiation to near normal levels. This study reveals the pleiotropic effects of the FGFR2 Y394C mutation evidenced by cutis gyrata, acanthosis nigricans, and craniosynostosis and provides a useful model for investigating the molecular mechanisms of skin and skull development. The demonstration of a pathogenic role for p38 activation may lead to the development of therapeutic strategies for BSS and related conditions, such as acanthosis nigricans or craniosynostosis.

show abstract

Section: Discussionmentioning

confidence: 73%

Section: Discussionmentioning

confidence: 99%

p38 Inhibition ameliorates skin and skull abnormalities in Fgfr2 Beare-Stevenson mice

Wang¹,

Zhou²,

Oberoi³

et al. 2012

J. Clin. Invest.

View full text Add to dashboard Cite

show abstract

“…Novel p38 MAPK inhibitors that are in clinical development for the treatment of COPD hopefully will have fewer side effects. This may be achieved by inhaled delivery, thus limiting systemic exposure (Chopra et al, 2008), or else, as suggested by our data, through the dose-sparing effect of a combination with a corticosteroid, to increase the safety margin.…”

Section: Downloaded Frommentioning

confidence: 83%

Synergistic Effects of p38 Mitogen-Activated Protein Kinase Inhibition with a Corticosteroid in Alveolar Macrophages from Patients with Chronic Obstructive Pulmonary Disease

Armstrong

Harbron²,

Lea³

et al. 2011

J Pharmacol Exp Ther

View full text Add to dashboard Cite

Corticosteroids partially suppress cytokine production by chronic obstructive pulmonary disease (COPD) alveolar macrophages. p38 mitogen-activated protein kinase (MAPK) inhibitors are a novel class of anti-inflammatory drug. We have studied the effects of combined treatment with a corticosteroid and a p38 MAPK inhibitor on cytokine production by COPD alveolar macrophages, with the aim of investigating dose-sparing and efficacy-enhancing effects. Alveolar macrophages from 10 patients with COPD, six smokers, and six nonsmokers were stimulated with lipopolysaccharide (LPS) after preincubation with five concentrations of dexamethasone alone, five concentrations of the p38 MAPK inhibitor 1-(5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-3(4-(2-morpholin-4-ylethoxy)naphthalen-1-yl)urea (BIRB-796) alone, and all combinations of these concentrations. After 24 h, the supernatants were analyzed for interleukin (IL)-8, IL-6, tumor necrosis factor ␣ (TNF␣), granulocyte macrophage-colony-stimulating factor (GM-CSF), IL-1␣, IL-1␤, IL-1ra, IL-10, monocyte chemoattractant protein 3, macrophage-derived chemokine (MDC), and regulated on activation normal T cell expressed and secreted (RANTES). The effect of dexamethasone on p38 MAPK activation was analyzed by Western blotting. Dexamethasone and BIRB-796 both reduced LPSinduced cytokine production in a dose-dependent manner in all subject groups, with no differences between groups. Increasing the concentration of BIRB-796 in combination with dexamethasone produced progressively greater inhibition of cytokine production than dexamethasone alone. There were significant efficacyenhancing benefits and synergistic dose-sparing effects (p Ͻ 0.05) for the combination treatment for IL-8, IL-6, TNF␣, GM-CSF, IL-1ra, IL-10, MDC, and RANTES in one or more subject groups. Dexamethasone had no effect on LPS-induced p38 MAPK activation. We conclude that p38 MAPK activation in alveolar macrophages is corticosteroid-insensitive. Combining a p38 MAPK inhibitor with a corticosteroid synergistically enhances the antiinflammatory effects on LPS-mediated cytokine production by alveolar macrophages from patients with COPD and controls.

show abstract

“…Inhibition of p38 MAPK has thus attracted attention as a therapeutic target for the development of novel anti-inflammatory agents for the treatment of COPD (table 2) [70,71]. Inhibitors that bind competitively at the ATP-binding pocket and target p38a and b but not d or c, potentially offer a broad range of anti-inflammatory effects because the a isoform is the most abundant isoform in inflammatory cells.…”

Section: P38 Mapk Inhibitorsmentioning

confidence: 99%

Emerging anti-inflammatory strategies for COPD

et al. 2012

View full text Add to dashboard Cite

Therapeutic potential of inhaled p38 mitogen-activated protein kinase inhibitors for inflammatory pulmonary diseases

Cited by 53 publications

References 89 publications

p38 Inhibition ameliorates skin and skull abnormalities in Fgfr2 Beare-Stevenson mice

p38 Inhibition ameliorates skin and skull abnormalities in Fgfr2 Beare-Stevenson mice

Synergistic Effects of p38 Mitogen-Activated Protein Kinase Inhibition with a Corticosteroid in Alveolar Macrophages from Patients with Chronic Obstructive Pulmonary Disease

Emerging anti-inflammatory strategies for COPD

Contact Info

Product

Resources

About