Severity of Lung Injury in Cyclooxygenase-2-Deficient Mice Is Dependent on Reduced Prostaglandin E2 Production

Hodges, Rebecca J.; Jenkins, Gisli; Wheeler‐Jones, Caroline P.D.; Copeman, Danielle M.; Bottoms, Stephen E.; Bellingan, Geoffrey; Nanthakumar, Carmel B.; Laurent, Geoffrey J.; Hart, Stephen L.; Foster, Martyn; McAnulty, Robin J.

doi:10.1016/s0002-9440(10)63423-2

Cited by 109 publications

(95 citation statements)

References 54 publications

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“…1) was similar to that shown for PGE 2 , also in the bleomycin model (16). Of note, multiple groups have demonstrated dysregulation of PGE 2 synthesis (as a result of down-regulation of COX-II expression) in the lung of human patients with pulmonary fibrosis as well as in animal models, which was associated with severity of the disease (42)(43)(44)(45)(46)(47), suggesting that activation of PGE 2 receptors could be an attractive approach for treatment of pulmonary fibrosis. Thus, noscapine could be a novel, nontoxic and orally available agonist of EP 2 receptor signaling with antifibrotic action.…”

Section: Discussionsupporting

confidence: 69%

Antifibrotic Effects of Noscapine through Activation of Prostaglandin E2 Receptors and Protein Kinase A

Kach

Sandbo

et al. 2014

Journal of Biological Chemistry

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Background: Noscapine is a safe orally available anticough medicine also known to bind microtubules and induce cancer cell death. Results: Noscapine inhibits myofibroblast differentiation and pulmonary fibrosis through prostaglandin receptors and activation of PKA. Conclusion: Noscapine is an antifibrotic drug acting through PKA activation via EP 2 prostaglandin receptors. Significance: This study describes a novel antifibrotic function and novel mechanism of action of noscapine.

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Section: Discussionsupporting

confidence: 69%

Antifibrotic Effects of Noscapine through Activation of Prostaglandin E2 Receptors and Protein Kinase A

Kach

Sandbo

et al. 2014

Journal of Biological Chemistry

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“…For example, fibroblasts derived from patients with idiopathic pulmonary fibrosis exhibit down-regulated COX-2 levels and PGE 2 synthetic capacity, and bronchoalveolar lavage PGE levels are lower than in normals (28 -30). Furthermore, reductions in PGE 2 , through deletion of one COX-2 allele or administration of indomethacin, worsens pulmonary fibrosis in experimentally induced pulmonary fibrosis in mice (6,(72)(73)(74). Interestingly, mice are not protected from experimental pulmonary fibrosis under conditions of increased PGE 2 , consistent with the possibility of the existence of a biphasic PGE 2 -fibrosis response in this model (72).…”

Section: Discussionsupporting

confidence: 63%

Prostaglandin E2 Mediates IL-1β-Related Fibroblast Mitogenic Effects in Acute Lung Injury through Differential Utilization of Prostanoid Receptors

White¹,

Ding²,

Moore

et al. 2008

The Journal of Immunology

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The fibroproliferative response to acute lung injury (ALI) results in severe, persistent respiratory dysfunction. We have reported that IL-1β is elevated in pulmonary edema fluid in those with ALI and mediates an autocrine-acting, fibroblast mitogenic pathway. In this study, we examine the role of IL-1β-mediated induction of cyclooxygenase-2 and PGE2, and evaluate the significance of individual E prostanoid (EP) receptors in mediating the fibroproliferative effects of IL-1β in ALI. Blocking studies on human lung fibroblasts indicate that IL-1β is the major cyclooxygenase-2 mRNA and PGE2-inducing factor in pulmonary edema fluid and accounts for the differential PGE2 induction noted in samples from ALI patients. Surprisingly, we found that PGE2 produced by IL-1β-stimulated fibroblasts enhances fibroblast proliferation. Further studies revealed that the effect of fibroblast proliferation is biphasic, with the promitogenic effect of PGE2 noted at concentrations close to that detected in pulmonary edema fluid from ALI patients. The suppressive effects of PGE2 were mimicked by the EP2-selective receptor agonist, butaprost, by cAMP activation, and were lost in murine lung fibroblasts that lack EP2. Conversely, the promitogenic effects of mid-range concentrations of PGE2 were mimicked by the EP3-selective agent, sulprostone, by cAMP reduction, and lost upon inhibition of Gi-mediated signaling with pertussis toxin. Taken together, these data demonstrate that PGE2 can stimulate or inhibit fibroblast proliferation at clinically relevant concentrations, via preferential signaling through EP3 or EP2 receptors, respectively. Such mechanisms may drive the fibroproliferative response to ALI.

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“…Table E1 shows the 50 most markedly up-regulated genes. PTGS2, which was increased 3.11-fold (P ¼ 1.12 3 10 27 ) after MMP19 transfection, was chosen for further experiments because of the known antifibrotic potential of PGE2 and the similarity of the response of PTGS2-deficient mice to bleomycin to that of Mmp-19-deficient mice (31). The induction of PTGS2 mRNA was verified by quantitative reverse transcriptase-polymerase chain reaction ( Figure E2).…”

Section: Mmp19 Regulates Ptgs2 Expression In A549 Cellsmentioning

confidence: 99%

Matrix Metalloproteinase-19 Is a Key Regulator of Lung Fibrosis in Mice and Humans

Kovkarova-Naumovski²,

Jara³

et al. 2012

Am J Respir Crit Care Med

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Rationale: Idiopathic pulmonary fibrosis (IPF) is a devastating disease characterized by epithelial phenotypic changes and fibroblast activation. Based on the temporal heterogeneity of IPF, we hypothesized that hyperplastic alveolar epithelial cells regulate the fibrotic response. Objectives: To identify novel mediators of fibrosis comparing the transcriptional signature of hyperplastic epithelial cells and conserved epithelial cells in the same lung. Methods: Laser capture microscope and microarrays analysis were used to identify differentially expressed genes in IPF lungs. Bleomycininduced lung fibrosis was evaluated in Mmp19-deficient and wild-type (WT) mice. The role of matrix metalloproteinase (MMP)-19 was additionally studied by transfecting the human MMP19 in alveolar epithelial cells. Measurements and Main Results: Laser capture microscope followed by microarray analysis revealed a novel mediator, MMP-19, in hyperplastic epithelial cells adjacent to fibrotic regions. Mmp19 2/2 mice showed a significantly increased lung fibrotic response to bleomycin compared with WT mice. A549 epithelial cells transfected with human MMP19 stimulated wound healing and cell migration, whereas silencing MMP19 had the opposite effect. Gene expression microarray of transfected A549 cells showed that PTGS2 (prostaglandin-endoperoxide synthase 2) was one of the highly induced genes. PTGS2 was overexpressed in IPF lungs and colocalized with MMP-19 in hyperplastic epithelial cells. In WT mice, PTGS2 was significantly increased in bronchoalveolar lavage and lung tissues after bleomycin-induced fibrosis, but not in Mmp19 2/2 mice. Inhibition of Mmp-19 by siRNA resulted in inhibition of Ptgs2 at mRNA and protein levels. Conclusions: Up-regulation of MMP19 induced by lung injury may play a protective role in the development of fibrosis through the induction of PTGS2.

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Severity of Lung Injury in Cyclooxygenase-2-Deficient Mice Is Dependent on Reduced Prostaglandin E2 Production

Cited by 109 publications

References 54 publications

Antifibrotic Effects of Noscapine through Activation of Prostaglandin E2 Receptors and Protein Kinase A

Antifibrotic Effects of Noscapine through Activation of Prostaglandin E2 Receptors and Protein Kinase A

Prostaglandin E2 Mediates IL-1β-Related Fibroblast Mitogenic Effects in Acute Lung Injury through Differential Utilization of Prostanoid Receptors

Matrix Metalloproteinase-19 Is a Key Regulator of Lung Fibrosis in Mice and Humans

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