Prostaglandin D<sub>2</sub>inhibits fibroblast migration

Kohyama, Tadashi; Liu, X.D.; Wen, Fuqiang; Kim, H.J.; Takizawa, Hajime; Rennard, Stephen I.

doi:10.1183/09031936.02.01272001

Cited by 27 publications

(15 citation statements)

References 28 publications

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“…7). This is interesting as PGD 2 is rapidly converted to 15d-PGJ 2 , which is reported to have anti-inflammatory actions and which inhibits fibroblast migration, whereas PGF 2␣ functions to promote neutrophil chemotaxis and thus has proinflammatory effects (2,17,20,31). It thus appears that as well as COX-2, silica must be acting to induce some of the specific prostaglandin synthases but not others.…”

Section: Discussionmentioning

confidence: 99%

Crystalline and amorphous silica differentially regulate the cyclooxygenase-prostaglandin pathway in pulmonary fibroblasts: implications for pulmonary fibrosis

O’Reilly¹,

Phipps²,

Thatcher³

et al. 2005

American Journal of Physiology-Lung Cellular and Molecular Phys

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Inhalation of crystalline (CS) and amorphous silica (AS) results in human pulmonary inflammation. However, silicosis develops only following CS exposure, and the pathogenic mechanisms are poorly understood. This report describes the differential abilities of CS and AS to directly upregulate the early inflammatory mediator COX-2, the recently identified prostaglandin E (PGE) synthase and the downstream mediator PGE 2 in primary human lung fibroblasts. Increased cyclooxygenase (COX)-2 gene transcription and protein production were demonstrated by ribonuclease protection assay, Western blot analysis, and immunocytochemistry. In each case the ability of AS to induce COX-2 exceeded that of CS. Similarly, downstream of COX-2, production of the antifibrotic prostaglandin PGE 2 was induced in a dose-dependent fashion, but AS was significantly more potent (maximal production: CS ϭ 4,710 pg/ml and AS ϭ 7,651 pg/ml). These increases in COX-2 and PGE 2 were preceded by induction of the PGE2 synthase protein, demonstrating the potential role of this novel molecule in silica-mediated inflammation. There was specificity of induction of prostaglandins, as PGF 2␣, but not PGD2, was induced. Using specific COX-2 inhibitors, we showed increased PG production to be dependent on the COX-2 enzyme. Furthermore, stimulation of fibroblasts was particle specific, as silica but not carbon black resulted in fibroblast activation. These results demonstrate that silica can directly stimulate human lung fibroblasts to produce key inflammatory enzymes and prostaglandins. Moreover, they suggest a mechanism to explain the differing fibrogenic potential of CS and AS. The molecules COX-2, PGE synthase, and PGE 2 are identified as effectors in silicosis.

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Section: Discussionmentioning

confidence: 99%

Crystalline and amorphous silica differentially regulate the cyclooxygenase-prostaglandin pathway in pulmonary fibroblasts: implications for pulmonary fibrosis

O’Reilly¹,

Phipps²,

Thatcher³

et al. 2005

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…There is little information on the role of PGD 2 or PGF 2␣ on airway remodeling. PGD 2 acts via DP1 and 2 receptors, both of which are present on ASM and fibroblasts (14,32), whereas PGF 2␣ acts on the FP receptor, which has been detected in lung fibroblasts and has been shown to facilitate bleomycin-induced pulmonary fibrosis (47). Because PGF 2␣ did not alter the deposition of ECM proteins, it is possible that it may not be involved in the regulation of these ECM proteins.…”

Section: L246 Prostaglandins Alter Cellular Matrix Deposition and Cytmentioning

confidence: 99%

Prostaglandins but not leukotrienes alter extracellular matrix protein deposition and cytokine release in primary human airway smooth muscle cells and fibroblasts

Burgess

Brock

et al. 2012

American Journal of Physiology-Lung Cellular and Molecular Phys

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Prostaglandins but not leukotrienes alter extracellular matrix protein deposition and cytokine release in primary human airway smooth muscle cells and fibroblasts. Am J Physiol Lung Cell Mol Physiol 303: L239-L250, 2012. First published May 25, 2012 doi:10.1152/ajplung.00097.2012.-Eicosanoids are lipid-signaling mediators released by many cells in response to various stimuli. Increasing evidence suggests that eicosanoids such as leukotrienes and prostaglandins (PGs) may directly mediate remodeling. In this study, we assessed whether these substances could alter extracellular matrix (ECM) proteins and the inflammatory profiles of primary human airway smooth muscle cells (ASM) and fibroblasts. PGE 2 decreased both fibronectin and tenascin C in fibroblasts but only fibronectin in ASM. PGD 2 decreased both fibronectin and tenascin C in both ASM and fibroblasts, whereas PGF 2␣ had no effect on ECM deposition. The selective PGI2 analog, MRE-269, decreased fibronectin but not tenascin C in both cell types. All the PGs increased IL-6 and IL-8 release in a dose-dependent manner in ASM and fibroblasts. Changes in ECM deposition and cytokine release induced by prostaglandins in both ASM and fibroblasts were independent of an effect on cell number. Neither the acute nor repeated stimulation with leukotrienes had an effect on the deposition of ECM proteins or cytokine release from ASM or fibroblasts. We concluded that, collectively, these results provide evidence that PGs may contribute to ECM remodeling to a greater extent than leukotrienes in airway cells.

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“…Certain prostaglandins, such as prostacyclin and related analogs prostaglandin (PG) E 2 and PG D 2 , inhibit pulmonary fibroblast migration, proliferation, and collagen synthesis (Keerthisingam et al, 2001;Kohyama et al, 2002;Vancheri et al, 2004). Those agents all activate receptors coupled to G s , implying that cAMP is a negative regulator of fibroblast function.…”

mentioning

confidence: 99%

Fibrotic Lung Fibroblasts Show Blunted Inhibition by cAMP Due to Deficient cAMP Response Element-Binding Protein Phosphorylation

Liu

Sun²,

Ostrom³

2005

J Pharmacol Exp Ther

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Pulmonary fibroblasts regulate extracellular matrix production and degradation; thus, they are critical for maintenance of lung structure, function, and repair. In pulmonary fibrosis, fibroblasts produce excess collagen and form fibrotic foci that eventually impair lung function, but the mechanisms responsible for these alterations are not known. Receptors coupled to the stimulation of cAMP production can inhibit activation of fibroblasts and thereby are antifibrotic. To test whether this signaling pathway is altered in pulmonary fibrosis, we compared the ability of normal adult human pulmonary fibroblasts to generate and respond to cAMP with that of cells isolated from lungs with idiopathic pulmonary fibrosis. Serum-and transforming growth factor (TGF)-␤-stimulated cell proliferation was inhibited ϳ50% by forskolin and ϳ100% by prostaglandin (PG) E 2 in the normal cells but substantially less in the diseased cells. Collagen synthesis was also inhibited Ͼ50% by the same drugs in the normal cells but significantly less so in the diseased cells, despite responding with similar increases in cAMP production. Although expression of protein kinase A (PKA) and cAMPstimulated PKA activity were similar in both the normal and diseased cell types, forskolin-and PGE 2 -stimulated cAMP response element-binding protein (CREB) phosphorylation was decreased in the diseased cell lines compared with the normal cells. cAMP-mediated activation and TGF-␤-mediated inhibition of CREB DNA binding was also diminished in the diseased cells. Thus, pulmonary fibroblasts derived from patients with pulmonary fibrosis are refractory to the inhibition by cAMP due to altered activity of components distal to the activity of PKA, in particular the phosphorylation of CREB.

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Prostaglandin D₂inhibits fibroblast migration

Cited by 27 publications

References 28 publications

Crystalline and amorphous silica differentially regulate the cyclooxygenase-prostaglandin pathway in pulmonary fibroblasts: implications for pulmonary fibrosis

Crystalline and amorphous silica differentially regulate the cyclooxygenase-prostaglandin pathway in pulmonary fibroblasts: implications for pulmonary fibrosis

Prostaglandins but not leukotrienes alter extracellular matrix protein deposition and cytokine release in primary human airway smooth muscle cells and fibroblasts

Fibrotic Lung Fibroblasts Show Blunted Inhibition by cAMP Due to Deficient cAMP Response Element-Binding Protein Phosphorylation

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Prostaglandin D2inhibits fibroblast migration

Cited by 27 publications

References 28 publications

Crystalline and amorphous silica differentially regulate the cyclooxygenase-prostaglandin pathway in pulmonary fibroblasts: implications for pulmonary fibrosis

Crystalline and amorphous silica differentially regulate the cyclooxygenase-prostaglandin pathway in pulmonary fibroblasts: implications for pulmonary fibrosis

Prostaglandins but not leukotrienes alter extracellular matrix protein deposition and cytokine release in primary human airway smooth muscle cells and fibroblasts

Fibrotic Lung Fibroblasts Show Blunted Inhibition by cAMP Due to Deficient cAMP Response Element-Binding Protein Phosphorylation

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Prostaglandin D₂inhibits fibroblast migration