Enhanced upregulation of smooth muscle related transcripts by TGF 2 in asthmatic (myo) fibroblasts

Wicks, James; Haitchi, Hans Michael; Holgate, S. T.; Davies, Donna E.; Powell, Robert M.

doi:10.1136/thx.2005.050005

Cited by 52 publications

(37 citation statements)

References 17 publications

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“…Myofibroblast differentiation was assessed using the common myofibroblast marker, a-SMA, by immunocytochemistry, Western blot, Imagestream flow cytometry, and RT-PCR. In addition, the expression of a novel myofibroblast (37). CDDO, 15 d-PGJ 2 , and rosiglitazone all inhibited myofibroblast differentiation, as determined by Western blot for a-SMA ( Figure 1A) and by immunocytochemistry ( Figure E1).…”

Section: Results 15 D-pgj 2 Cddo and Rosiglitazone Inhibit Tgf-b-smentioning

confidence: 99%

Electrophilic Peroxisome Proliferator–Activated Receptor-γ Ligands Have Potent Antifibrotic Effects in Human Lung Fibroblasts

Ferguson¹,

Kulkarni²,

Lehmann³

et al. 2009

Am J Respir Cell Mol Biol

125

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Pulmonary fibrosis is a progressive scarring disease with no effective treatment. Transforming growth factor (TGF)-b is up-regulated in fibrotic diseases, where it stimulates differentiation of fibroblasts to myofibroblasts and production of excess extracellular matrix. Peroxisome proliferator-activated receptor (PPAR) g is a transcription factor that regulates adipogenesis, insulin sensitization, and inflammation. We report here that a novel PPARg ligand, 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid (CDDO), is a potent inhibitor of TGF-b-stimulated differentiation of human lung fibroblasts to myofibroblasts, and suppresses up-regulation of a-smooth muscle actin, fibronectin, collagen, and the novel myofibroblast marker, calponin. The inhibitory concentration causing a 50% decrease in aSMA for CDDO was 20-fold lower than the endogenous PPARg ligand, 15-deoxy-D 12,14 -prostaglandin J 2 (15 d-PGJ 2 ), and 400-fold lower than the synthetic ligand, rosiglitazone. Pharmacologic and genetic approaches were used to demonstrate that CDDO mediates its activity via a PPARg-independent pathway. CDDO and 15 d-PGJ 2 contain an a/b unsaturated ketone, which acts as an electrophilic center that can form covalent bonds with cellular proteins. Prostaglandin A 1 and diphenyl diselenide, both strong electrophiles, also inhibit myofibroblast differentiation, but a structural analog of 15 d-PGJ 2 lacking the electrophilic center is much less potent. CDDO does not alter TGF-b-induced Smad or AP-1 signaling, but does inhibit acetylation of CREB binding protein/p300, a critical coactivator in the transcriptional regulation of TGF-b-responsive genes. Overall, these data indicate that certain PPARg ligands, and other small molecules with electrophilic centers, are potent inhibitors of critical TGF-b-mediated profibrogenic activities through pathways independent of PPARg. As the inhibitory concentration causing a 50% decrease in aSMA for CDDO is 400-fold lower than that in rosiglitazone, the translational potential of CDDO for treatment of fibrotic diseases is high.

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Section: Results 15 D-pgj 2 Cddo and Rosiglitazone Inhibit Tgf-b-smentioning

confidence: 99%

Electrophilic Peroxisome Proliferator–Activated Receptor-γ Ligands Have Potent Antifibrotic Effects in Human Lung Fibroblasts

Ferguson¹,

Kulkarni²,

Lehmann³

et al. 2009

Am J Respir Cell Mol Biol

125

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“…These data have led us to suggest that PPARg agonists are a promising intervention to prevent tobacco smoke-induced asthma in offspring (10,11). It is important to point out that the mesenchymal markers of airway reactivity chosen by us are markers of myofibroblast differentiation (a-SMA and calponin), a hallmark of chronic lung diseases, such as asthma, and/or have been shown to have increased matrix deposition (fibronectin and collagen III) in the subepithelial space of the airways in asthma (18)(19)(20). Furthermore, the other markers used by us, such as b-catenin and LEF-1, are functional intermediates in the Wnt signaling pathway, a key mediator of myogenesis, justifying their inclusion in our analysis (21)(22)(23).…”

Section: Discussionmentioning

confidence: 99%

Sex-Specific Perinatal Nicotine-Induced Asthma in Rat Offspring

Liu

Naeem

Tian

et al. 2013

Am J Respir Cell Mol Biol

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Recently, we have suggested that down-regulation of homeostatic mesenchymal peroxisome proliferator-activated receptor g signaling after in utero nicotine exposure might contribute to asthma. Here, we have exploited an in vivo rat model of asthma to determine if the effects of perinatal nicotine exposure on offspring pulmonary function and mesenchymal markers of airway contractility in both tracheal and lung parenchymal tissue are sex specific, and whether the protection afforded by the peroxisome proliferator-activated receptor g agonist, rosiglitazone (RGZ), against the perinatal nicotine-induced effect on offspring lung is also sex specific. Pregnant rat dams received placebo, nicotine, or nicotine plus RGZ daily from Embryonic Day 6 until Postnatal Day 21, at which time lung resistance, compliance, tracheal contractility, and the expression of structural and functional mesenchymal markers of pulmonary contractility were determined. Compared with control animals, perinatal nicotine exposure caused a significant increase in airway resistance and a decrease in airway compliance after a methacholine challenge in both male and female offspring, with more pronounced changes in the males. In contrast to this, the effects of perinatal nicotine exposure on acetylcholine-induced tracheal constriction, along with the expression of its mesenchymal markers, were observed exclusively in the male offspring. Concomitant treatment with RGZ normalized the nicotine-induced alterations in pulmonary function in both sexes, as well as the male-specific effects on acetylcholine-induced tracheal constriction, along with the affected mesenchymal markers. These data suggest that perinatal nicotine exposure causes sex-specific perinatal cigarette smoke exposureinduced asthma, providing a powerful phenotypic model for unequivocally determining the underlying nature of the cell molecular mechanism for this disease.Keywords: nicotine; asthma; pregnancy; peroxisome proliferator-activated receptor g; cigarette smokeThere is strong epidemiologic (1-3) and experimental (4-6) evidence that perinatal exposure to maternal smoking results in detrimental long-term effects on lung growth and function, including significant suppression of alveolarization (7,8), and increased predisposition to asthma (9) in the offspring. Because the mechanisms underlying these adverse pulmonary effects remain incompletely understood, there are no effective preventive or therapeutic interventions. Based on both in vitro and in vivo studies from our laboratory, we have suggested that down-regulation of homeostatic lung mesenchymal peroxisome proliferator-activated receptor (PPAR) g signaling might be a key contributor to chronic lung diseases, such as bronchopulmonary dysplasia and asthma (9-11). We have also shown that perinatal treatment with nicotine increases lung resistance (Rrs), and decreases lung compliance in association with increased tracheal constriction (11), an effect that is blocked by the PPARg agonist, rosiglitazone (RGZ) (11). Mechanistically, we ha...

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“…RNA was extracted using TRIzol reagent (Invitrogen), DNase treated, and reverse-transcribed for quantitative PCR (qPCR) as previously described (16). Genes of interest were normalized to the geometric means of ubiquitin C and phospholipase A2.…”

Section: Rna Extraction and Real-time Quantitative Pcr Analysismentioning

confidence: 99%

Contribution of Bronchial Fibroblasts to the Antiviral Response in Asthma

Bedke

Haitchi

Xatzipsalti

et al. 2009

The Journal of Immunology

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Human rhinoviruses (HRV) are a major cause of asthma exacerbations and hospitalization. Studies using primary cultures suggest that this may be due to impaired production of type I and type III IFNs by asthmatic bronchial epithelial cells. Although epithelial cells are the main target for HRV infection, HRV can be detected in the subepithelial layer of bronchial mucosa from infected subjects by in situ hybridization. Therefore, we postulated that submucosal fibroblasts are also involved in the innate antiviral response to HRV infection in asthma. We found that regardless of subject group, bronchial fibroblasts were highly susceptible to RV1b infection. IL-8 and IL-6 were rapidly induced by either HRV or UV-irradiated virus, suggesting that these responses did not require viral replication. In contrast, RANTES expression was dependent on viral replication. Regardless of disease status, fibroblasts did not respond to HRV infection with significant induction of IFN-␤, even though both groups responded to synthetic dsRNA with similar levels of IFN-␤ expression. Exogenous IFN-␤ was highly protective against viral replication. Our data suggest that fibroblasts respond to HRV with a vigorous proinflammatory response but minimal IFN-␤ expression. Their susceptibility to infection may cause them to be a reservoir for HRV replication in the lower airways, especially in asthmatic subjects where there is reduced protection offered by epithelialderived IFNs. Their ability to support viral replication coupled with their vigorous proinflammatory response following infection may contribute to asthma exacerbations.

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Enhanced upregulation of smooth muscle related transcripts by TGF 2 in asthmatic (myo) fibroblasts

Cited by 52 publications

References 17 publications

Electrophilic Peroxisome Proliferator–Activated Receptor-γ Ligands Have Potent Antifibrotic Effects in Human Lung Fibroblasts

Electrophilic Peroxisome Proliferator–Activated Receptor-γ Ligands Have Potent Antifibrotic Effects in Human Lung Fibroblasts

Sex-Specific Perinatal Nicotine-Induced Asthma in Rat Offspring

Contribution of Bronchial Fibroblasts to the Antiviral Response in Asthma

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