Antenatal Inflammation Reduces Expression of Caveolin-1 and Influences Multiple Signaling Pathways in Preterm Fetal Lungs

University Children's Hospital, University of Würzburg, Germany.
American Journal of Respiratory Cell and Molecular Biology (Impact Factor: 3.99). 05/2011; 45(5):969-76. DOI: 10.1165/rcmb.2010-0519OC
Source: PubMed


Bronchopulmonary dysplasia (BPD), associated with chorioamnionitis, results from the simultaneous effects of disrupted lung development, lung injury, and repair superimposed on the developing lung. Caveolins (Cavs) are implicated as major modulators of lung injury and remodeling by multiple signaling pathways, although Cavs have been minimally studied in the injured developing lung. We hypothesized that chorioamnionitis-associated antenatal lung inflammation would decrease the expression of Cav-1 in preterm fetal lungs.Wetested whether changes occurred in the transcription factors Smad2/3, Smad1/5, Stat3, and Stat1, andwealso studied the activation of acid-sphingomyelinase (a-SMase) with the generation of ceramide, along with changes in the expression of heme oxygenase - 1 (HO-1) as indicators of possible Cav-1 - mediated effects. Fetal sheep were exposed to 10 mg of intra-amniotic endotoxin or saline for 2, 7, or 2 + 7 days before preterm delivery at 124 days of gestation. The expression of Cav-1 and HO-1 and the phosphorylation of Smad and Stat were evaluated by real-time PCR, Western blotting, and/or immunohistochemistry. The activity of a-SMase and the concentrations of ceramide were measured. Intra-amniotic endotoxin decreased Cav-1 mRNA and protein expression in the lungs, with a maximum reduction of Cav-1 mRNA to 50% ± 7% of the control value (P<0.05), and of Cav-1 protein expression to20%±5%of the control value (P < 0.05). Decreased concentrations of Cav-1 were associated with the elevated phosphorylation of Smad2/3, Stat3, and Stat1, but not of Smad1/5. The expression of HO-1, a-SMase activity, and ceramide increased. Antenatal inflammation decreased the expression of Cav-1 in the preterm fetal lung. The decreased expression of Cav-1 was associated with the activation of the Smad2/3, Stat, anda-SMase/ ceramidepathways, andwiththe increasedexpression of HO-1. The decreased concentrations of Cav-1 and changes in other signaling pathways may contribute to BPD.


Available from: Jennifer J Collins
    • "Caveolins are implicated as major modulators of lung injury and remodeling by multiple signaling pathways. It has been demonstrated that antenatal lung inflammation can decrease the concentrations of caveolins, thus contributing to BPD.[27] Moreover, fetal innate immune responses to lipopolysaccharide (LPS)-induced chorioamnionitis would alter postnatal systemic immune and airway responsiveness determining decreased airway reactivity and changes in lymphocytes.[28] "
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    ABSTRACT: Previous studies have shown that the transforming growth factor (TGF)β/Alk1/Smad1 signaling pathway is constitutively activated in a subset of systemic sclerosis (SSc) fibroblasts and this pathway is a critical regulator of CCN2 gene expression. Caveolin-1 (cav-1), an integral membrane protein and the main component of caveolae, has also been implicated in SSc pathogenesis. This study was undertaken to evaluate the role of caveolin-1 in Smad1 signaling and CCN2 expression in healthy and SSc dermal fibroblasts. We show that a significant subset of SSc dermal fibroblasts has up-regulated cav-1 expression in vitro, and that cav-1 up-regulation correlates with constitutive Smad1 phosphorylation. In addition, basal levels of phospho-Smad1 were down-regulated after inhibition of cav-1 in SSc dermal fibroblasts. Caveolin-1 formed a protein complex with Alk1 in dermal fibroblasts, and this association was enhanced by TGFβ. By using siRNA against cav-1 and adenoviral cav-1 overexpression we demonstrate that activation of Smad1 in response to TGFβ requires cav-1 and that cav-1 is sufficient for Smad-1 phosphorylation. We also show that cav-1 is a positive regulator of CCN2 gene expression, and that it is required for the basal and TGFβ-induced CCN2 levels. In conclusion, this study has revealed an important role of cav-1 in mediating TGFβ/Smad1 signaling and CCN2 gene expression in healthy and SSc dermal fibroblasts.
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