SB 239063, a p38 MAPK inhibitor, reduces neutrophilia, inflammatory cytokines, MMP-9, and fibrosis in lung

Underwood, David C.; Osborn, Ruth R.; Bochnowicz, Steven; Webb, Edward F.; Rieman, David J.; Lee, John C.; Romanic, Anne M.; Adams, Jerry L.; Hay, Douglas W. P.; Griswold, Don E.

doi:10.1152/ajplung.2000.279.5.l895

Cited by 284 publications

(215 citation statements)

References 23 publications

Supporting

Mentioning

202

Contrasting

Unclassified

Order By: Relevance

“…These changes in enzymatic activity correlate with up-regulation of MMP-12 mRNA in BAL cells (95% macrophages), and with elevated levels of MMP-9 and MMP-12 mRNA in total lung RNA. Whereas TGF-␤1-induced MMP-9 production has been suggested to be more dependent on Ras/MAPK pathways (43,44), our findings suggest that Smad3 is also important in TGF-␤1 inhibition of MMP-9 expression. Of note, MMP-2 has been shown to be dependent on Smad2, and not Smad3, for stimulated expression (45), consistent with our observation that levels of MMP2 are not changed in Smad3 KO mice.…”

Section: Smad3 Null Mice Develop Emphysematous Alveolar Enlargement Acontrasting

confidence: 44%

Smad3 Null Mice Develop Airspace Enlargement and Are Resistant to TGF-β-Mediated Pulmonary Fibrosis

Bonniaud

Kolb

Galt

et al. 2004

The Journal of Immunology

354

258

View full text Add to dashboard Cite

Transforming growth factor-β1 plays a key role in the pathogenesis of pulmonary fibrosis, mediating extracellular matrix (ECM) gene expression through a series of intracellular signaling molecules, including Smad2 and Smad3. We show that Smad3 null mice (knockout (KO)) develop progressive age-related increases in the size of alveolar spaces, associated with high spontaneous presence of matrix metalloproteinases (MMP-9 and MMP-12) in the lung. Moreover, transient overexpression of active TGF-β1 in lungs, using adenoviral vector-mediated gene transfer, resulted in progressive pulmonary fibrosis in wild-type mice, whereas no fibrosis was seen in the lungs of Smad3 KO mice up to 28 days. Significantly higher levels of matrix components (procollagen 3A1, connective tissue growth factor) and antiproteinases (plasminogen activator inhibitor-1, tissue inhibitor of metalloproteinase-1) were detected in wild-type lungs 4 days after TGF-β1 administration, while no such changes were seen in KO lungs. These data suggest a pivotal role of the Smad3 pathway in ECM metabolism. Basal activity of the pathway is required to maintain alveolar integrity and ECM homeostasis, but excessive signaling through the pathway results in fibrosis characterized by inhibited degradation and enhanced ECM deposition. The Smad3 pathway is involved in pathogenic mechanisms mediating tissue destruction (lack of repair) and fibrogenesis (excessive repair).

show abstract

Section: Smad3 Null Mice Develop Emphysematous Alveolar Enlargement Acontrasting

confidence: 44%

Smad3 Null Mice Develop Airspace Enlargement and Are Resistant to TGF-β-Mediated Pulmonary Fibrosis

Bonniaud

Kolb

Galt

et al. 2004

The Journal of Immunology

354

258

View full text Add to dashboard Cite

show abstract

“…For example, the p38 mitogen-activated protein kinase inhibitor SB 239063 has been shown to inhibit induced lung fibrosis (56), and pentoxifylline, a nonselective inhibitor of phosphodiesterase, inhibits PDGF-induced proliferation and TGF␤1-induced collagen synthesis via a cAMP effector mechanism (57,58). Yet, despite all the effort to develop an effective antagonist for collagen synthesis, there still is no effective treatment for pathogenic fibrosis.…”

Section: Discussionmentioning

confidence: 99%

Halofuginone inhibition of COL1A2 promoter activity via a c‐Jun–dependent mechanism

McGaha¹,

Kodera²,

Spiera³

et al. 2002

Arthritis & Rheumatism

View full text Add to dashboard Cite

Objective. The naturally occurring compound halofuginone has been shown to antagonize collagen synthesis by fibroblasts both in vitro and in vivo. We previously demonstrated that this inhibitory property was related to the ability of halofuginone to disrupt transforming growth factor ␤ signal transduction. The present study further analyzed the ability of halofuginone to affect transcription factors that can regulate type I collagen gene expression by examining its effect on c-Jun, the negative regulator of collagen gene transcription.Methods. The phosphorylation state of c-Jun in the presence of halofuginone was examined via direct Western blotting, and the transcriptional activity of the activator protein 1 (AP-1) binding element via electrophoretic mobility shift assay and luciferase reporter assay. We determined whether the effect of halofuginone on collagen synthesis was dependent on the presence of c-Jun by ectopic expression of a wild-type or dominantnegative c-Jun construct in the presence of halofuginone and assaying ␣2(I) collagen promoter strength via luciferase reporter assay. The effect of halofuginone on ␣2(I) collagen message levels in fibroblasts when wildtype or dominant-negative c-Jun was overexpressed was determined. We also determined whether halofuginone Extracellular matrix (ECM) protein turnover is an important process in the maintenance of connective tissue structure. Consequently, there is a constant low level of collagen synthesis by fibroblasts to maintain the integrity of the ECM. During wound healing, there is a shift in the balance of ECM protein synthesis/degradation that favors an increased deposition of fibrotic material. In the normal state, this shift in the balance is short-lived. In fibrotic disease, however, there appears to

show abstract

“…Heme oxygenase 1 early (Tsuburai et al, 2002) 17 6 HGF early (Umeda et al, 2004) 17 7 SB 239063 early (Underwood et al, 2000) 17 8…”

Section: Idmentioning

confidence: 99%

The bleomycin animal model: A useful tool to investigate treatment options for idiopathic pulmonary fibrosis?

Moeller

Ask

Warburton

et al. 2008

The International Journal of Biochemistry & Cell Biology

841

724

View full text Add to dashboard Cite

Different animal models of pulmonary fibrosis have been developed to investigate potential therapies for idiopathic pulmonary fibrosis (IPF). The most common is the bleomycin model in rodents (mouse, rat and hamster). Over the years, numerous agents have been shown to inhibit fibrosis in this model. However, to date none of these compounds are used in the clinical management of IPF and none has shown a comparable antifibrotic effect in humans. We performed a systematic review of publications on drug efficacy studies in the bleomycin model to evaluate the value of this model regarding transferability to clinical use. Between 1980 and 2006 we identified 246 experimental studies describing beneficial antifibrotic compounds in the bleomycin model. In 221 of the studies we found enough details about the timing of drug application to allow inter-study comparison. 211 of those used a preventive regimen (drug given ≤ day 7 after last bleomycin application), only 10 were therapeutic trials (> 7 days after last bleomycin application). It is critical to distinguish between drugs interfering with the inflammatory and early fibrogenic response from those preventing progression of fibrosis, the latter likely much more meaningful for clinical application. All potential antifibrotic compounds should be evaluated in the phase of established fibrosis rather than in the early period of bleomycin-induced inflammation for assessment of its antifibrotic properties. Further care should be taken in extrapolation of drugs successfully tested in the bleomycin model due to partial reversibility of bleomycin induced fibrosis over time. The use of alternative and more robust animal models, which better reflect human IPF, is warranted.

show abstract

SB 239063, a p38 MAPK inhibitor, reduces neutrophilia, inflammatory cytokines, MMP-9, and fibrosis in lung

Cited by 284 publications

References 23 publications

Smad3 Null Mice Develop Airspace Enlargement and Are Resistant to TGF-β-Mediated Pulmonary Fibrosis

Smad3 Null Mice Develop Airspace Enlargement and Are Resistant to TGF-β-Mediated Pulmonary Fibrosis

Halofuginone inhibition of COL1A2 promoter activity via a c‐Jun–dependent mechanism

The bleomycin animal model: A useful tool to investigate treatment options for idiopathic pulmonary fibrosis?

Contact Info

Product

Resources

About