Valerie Besnard - Academia.edu (original) (raw)

Papers by Valerie Besnard

Current Opinion in Pulmonary Medicine, 2016

Sarcoidosis is a disease caused by a complex combination of genetic susceptibility, immune networ... more Sarcoidosis is a disease caused by a complex combination of genetic susceptibility, immune networks and infectious and/or environmental agents. The onset and phenotypic variability of sarcoidosis remain poorly elucidated, not only due to the lack of clearly identified causes, but also because it is widely considered that no reliable model of this disease is available. In this review, we discuss the various models of granulomatous diseases in order to challenge this assertion. A large number of models of granulomatous diseases are available, both cellular models used to study the natural history of granulomas and experimental animal models mostly developed in rodents. Although none of the available models fully reproduces sarcoidosis, most of them generate various data supporting key concepts. Selected models with a high level of confidence among those already published may provide various pieces of the sarcoidosis jigsaw puzzle, whereas clinical data can provide other elements. A &amp;#39;systems biology&amp;#39; approach for modelling may be a way of piecing together the various pieces of the puzzle. Finally, experimental models and a systemic approach should be considered to be tools for preclinical evaluation of the efficacy of drugs prior to testing in clinical trials.

Revue des Maladies Respiratoires, 2015

PloS one, 2014

Pulmonary surfactant is required for lung function at birth and throughout postnatal life. Defect... more Pulmonary surfactant is required for lung function at birth and throughout postnatal life. Defects in the surfactant system are associated with common pulmonary disorders including neonatal respiratory distress syndrome and acute respiratory distress syndrome in children and adults. Lipogenesis is essential for the synthesis of pulmonary surfactant by type II epithelial cells lining the alveoli. This study sought to identify the role of pulmonary epithelial SREBP, a transcriptional regulator of cellular lipid homeostasis, during a critical time period of perinatal lung maturation in the mouse. Genome wide mRNA expression profiling of lung tissue from transgenic mice with epithelial-specific deletions of Scap (Scap(Δ/Δ), resulting in inactivation of SREBP signaling) or Insig1 and Insig2 (Insig1/2(Δ/Δ), resulting in activation of SREBP signaling) was assessed. Differentially expressed genes responding to SREBP perturbations were identified and subjected to functional enrichment analys...

Principles of Tissue Engineering, 2014

Principles of Tissue Engineering, 2007

The International Journal of Biochemistry & Cell Biology, 2011

This review focuses on the roles of NADPH oxidase/NOX proteins in idiopathic pulmonary fibrosis (... more This review focuses on the roles of NADPH oxidase/NOX proteins in idiopathic pulmonary fibrosis (IPF) pathophysiology and in the signalling pathways involved in IPF. NOX proteins are membrane-associated multi-unit enzymes that catalyze the reduction of oxygen using NADPH as an electron donor. Recent studies indicate that NOX4 is induced in pulmonary fibroblasts in response to TGF-␤. TGF-␤ or PDGF induce myofibroblast proliferation, differentiation, migration, contractility and extracellular matrix production, through NOX4 and reactive oxygen species dependent SMAD2/3 phosphorylation. NOX4 is increased in pulmonary fibroblasts from IPF patients and deletion of Nox4 in mice prevents bleomycin-induced pulmonary fibrosis. These data strongly suggest that targeting of NOX4 could be a step forward in the treatment of fibrotic lung diseases, by specifically targeting myofibroblasts, a major player in this disease.

Clinica Chimica Acta, 2014

AJP: Lung Cellular and Molecular Physiology, 2007

The ATP-binding cassette (ABC) ABCA3 gene encodes a lipid transporter critical for surfactant fun... more The ATP-binding cassette (ABC) ABCA3 gene encodes a lipid transporter critical for surfactant function at birth. To identify transcription factors that regulate ABCA3 expression in the lung, we identified by bioinformatic and functional analyses two positive regulatory regions, located between bp -2591 and -1102 and bp -1102 and +11, relative to the exon 1 of the Abca3 gene promoter. The distal cassette contains consensus sequences predicting binding to lung transcription factors including FOXA2, CCAAT/enhancer binding protein-alpha (C/EBPalpha), GATA-6, thyroid transcription factor-1 (TTF-1 or Nkx2.1), and nuclear factor of activated T cells-c3 (NFATc3). The activity of the distal region from bp -2591 to -1102 was assessed in HeLa and mouse lung epithelial MLE-15 cells. FOXA2, C/EBPalpha, GATA-6, TTF-1, and NFATc3 increased the activity of the Abca3 luciferase construct in a dose-dependent manner. The distal cassette conferred activation by FOXA2, C/EBPalpha, GATA-6, TTF-1, and NFATc3 in a position- and orientation-independent manner, serving as an enhancer-like regulatory element. The proximal Abca3 promoter region contained multiple sterol responsive element (SRE) binding sites. SRE binding protein (SREBP)-1c significantly increased the activity of the Abca3 luciferase construct in a dose-dependent manner, whereas SREBP-1a and SREBP-2 did not influence the Abca3 promoter activity. Chromatin immunoprecipitation (ChIP) analyses demonstrated the binding of SREBP-1c, C/EBPalpha, and TTF-1 to their respective regulatory elements. Conditional deletion of SREBP cleavage-activating protein (Scap) in respiratory epithelial cells in the mouse lung in vivo inhibited the expression of SREBPs in concert with Abca3. Abca3 gene expression is mediated by discrete cis-acting cassettes that mediate pulmonary cell- and lipid-sensitive pathways regulating surfactant homeostasis.

Amer J Respir Cell Molec Biol, 2007

ATP-Binding Cassette A3 (ABCA3) is a lamellar body associated lipid transport protein required fo... more ATP-Binding Cassette A3 (ABCA3) is a lamellar body associated lipid transport protein required for normal synthesis and storage of pulmonary surfactant in type II cells in the alveoli. In this study, we demonstrate that STAT3, activated by IL-6, regulates ABCA3 expression in vivo and in vitro. ABCA3 mRNA and immunostaining were decreased in adult mouse lungs in which STAT3 was deleted from the respiratory epithelium (Stat3 D/D mice). Consistent with the role of STAT3, intratracheal IL-6 induced ABCA3 expression in vivo. Decreased ABCA3 and abnormalities in the formation of lamellar bodies, the intracellular site of surfactant lipid storage, were observed in Stat3 D/D mice. Expression of SREBP1a and 1c, SCAP, ABCA3, and AKT mRNAs was inhibited by deletion of Stat3 in type II cells isolated from Stat3 D/D mice. The activities of PI3K and AKT were required for normal Abca3 gene expression in vitro. AKT activation induced SREBP expression and increased the activity of the Abca3 promoter in vitro, consistent with the role of STAT3 signaling, at least in part via SREBP, in the regulation of ABCA3. ABCA3 expression is regulated by IL-6 in a pathway that includes STAT3, PI3K, AKT, SCAP, and SREBP. Activation of STAT3 after exposure to IL-6 enhances ABCA3 expression, which, in turn, influences pulmonary surfactant homeostasis.

American Journal of Respiratory Cell and Molecular Biology, Dec 20, 2012

The Journal of Clinical Investigation, Oct 2, 2006

Pulmonary surfactant proteins and lipids are required for lung function after birth. Lung immatur... more Pulmonary surfactant proteins and lipids are required for lung function after birth. Lung immaturity and resultant surfactant deficiency cause respiratory distress syndrome, a common disorder contributing to morbidity and mortality in preterm infants. Surfactant synthesis increases prior to birth in association with formation of the alveoli that mediate efficient gas exchange. To identify mechanisms controlling perinatal lung maturation, the Calcineurin b1 (Cnb1) gene was deleted in the respiratory epithelium of the fetal mouse. Deletion of Cnb1 caused respiratory failure after birth and inhibited the structural maturation of the peripheral lung. Synthesis of surfactant and a lamellar body-associated protein, ABC transporter A3 (ABCA3), was decreased prior to birth. Nuclear factor of activated T cells (Nfat) calcineurin-dependent 3 (Nfatc3), a transcription factor modulated by calcineurin, was identified as a direct activator of Sftpa, Sftpb, Sftpc, Abca3, Foxa1, and Foxa2 genes. The calcineurin/Nfat pathway controls the morphologic maturation of lungs prior to birth and regulates expression of genes involved in surfactant homeostasis that are critical for adaptation to air breathing.

European Respiratory Journal, Sep 1, 2013

European Respiratory Journal, Sep 1, 2012

Number: 7258 Publication Number: P3770 Abstract Group: 3.3. Mechanisms of Lung Injury and Repair

American Journal of Physiology - Lung Cellular and Molecular Physiology, 2016

Idiopathic pulmonary fibrosis (IPF) is characterized by an accumulation of extracellular matrix p... more Idiopathic pulmonary fibrosis (IPF) is characterized by an accumulation of extracellular matrix proteins and fibroblasts in the distal airways. Key developmental lung signaling pathways are reactivated in IPF. For instance, fibroblast growth factor 9 (FGF9) and FGF18, involved in epithelial-mesenchymal interactions, are critical for lung development. We evaluated the expression of FGF9, FGF18, and FGF receptors (FGFRs) in lung tissue from controls and IPF patients and assessed their effect on proliferation, survival, migration, and differentiation of control and IPF human lung fibroblasts (HLFs). FGF9, FGF18, and all FGFRs were present in the remodeled alveolar epithelium close to the fibroblast foci in IPF lungs. FGFR3 was generally detected in fibroblast foci by immunohistochemistry. In vitro, HLFs mainly expressed mesenchyme-associated FGFR isoforms (FGFR1c and FGFR3c) and FGFR4. FGF9 did not affect fibroblast proliferation, whereas FGF18 inhibited cell growth in control fibroblasts. FGF9 and FGF18 decreased Fas-ligand-induced apoptosis in control but not in IPF fibroblasts. FGF9 prevented transforming growth factor β1-induced myofibroblast differentiation. FGF9 and FGF18 increased the migratory capacities of HLF, and FGF9 actively modulated matrix metalloproteinase activity. In addition, FGFR3 inhibition by small interfering RNA impacted p-ERK activation by FGF9 and FGF18 and their effects on differentiation and migration. These results identify FGF9 as an antiapoptotic and promigratory growth factor on HLF, maintaining fibroblasts in an undifferentiated state. The biological effects of FGF9 and FGF18 were partially driven by FGFR3. FGF18 was a less potent molecule. Both growth factors likely contribute to the fibrotic process in vivo.

American Journal of Physiology Lung Cellular and Molecular Physiology, Jul 1, 1998

Retinoids, including retinol and retinoic acid (RA) derivatives, are important molecules for lung... more Retinoids, including retinol and retinoic acid (RA) derivatives, are important molecules for lung growth and homeostasis. The presence of RA receptors and of RA-binding proteins in the alveolar epithelium led to suggest a role for RA on alveolar epithelial cell replication. In the present study, we examined the effects of RA on proliferation of the stem cells of the alveolar epithelium, the type 2 cells. We showed that treatment of serum-deprived type 2 cells with RA led to a stimulation of cell proliferation, with an increase in cell number in a dose-dependent manner. To gain some insights into the mechanisms involved, we studied the effects of RA on the expression of several components of the insulin-like growth factor (IGF) system that have been shown to be associated with the growth arrest of type 2 cells, mainly the IGF-binding protein-2 (IGFBP-2), IGF-II, and the type 2 IGF receptor. We documented a marked decrease in the expression of these components upon RA treatment. Using conditioned media from RA-treated cells, we provided evidence that the proliferative response of type 2 cells to RA was mediated through production of growth factor(s) distinct from IGF-I. We also showed that RA was able to reduce the decrease in cell number observed when type 2 cells were treated with transforming growth factor (TGF)-beta1. These results together with the known stimulatory effect of TGF-beta1 on IGFBP-2 expression led to suggest that RA may be associated with type 2 cell proliferation through mechanisms interfering with the TGF-beta1 pathway.

American Journal of Physiology Lung Cellular and Molecular Physiology, 2000

Retinoids, including retinol and retinoic acid (RA) derivatives, have been shown to be involved i... more Retinoids, including retinol and retinoic acid (RA) derivatives, have been shown to be involved in the processes of lung development as well as of lung repair after injury. Recently, we have provided evidence that RA could stimulate proliferation of lung alveolar type 2 epithelial cells (E. Nabeyrat, V. Besnard, S. Corroyer, V. Cazals, and A. Clement. Am. J. Physiol. Lung Cell. Mol. Physiol. 275: L71-L79, 1998). To gain some insight into the mechanisms involved in the mitogenic action of RA, we focused in the present study on the effects of RA on the expression of G(1) phase cyclins and their cell cycle-dependent kinases (Cdks). Experiments were performed with serum-deprived cells cultured in the absence and presence of RA. The results showed no effects of RA on the expression of either cyclins or Cdks. In contrast, RA treatment was found to prevent the decrease in cyclin E-Cdk2 activity observed when cells were growth arrested by serum deprivation. The observation that changes in cyclin E-Cdk2 activity were not associated with modifications in the amount of complexes formed led to the suggestion that the Cdk inhibitory protein (CKI) was involved. Study of the CKI p21(CIP1) revealed marked differences in its expression in the absence and presence of RA, with a dramatic downregulation observed in RA-treated cells. Interestingly, immunoprecipitation experiments provided evidence that the decreased levels of p21(CIP1) were associated with a reduced interaction of this CKI with cyclin E-Cdk2 complexes. These data together with previous results obtained in various situations of type 2 cell growth arrest emphasize the role of p21(CIP1) in the control of lung alveolar epithelial cell proliferation.

The American journal of physiology

AJP Lung Cellular and Molecular Physiology

C61. GENE REGULATION DURING DEVELOPMENT AND IN INJURY, 2010

American Journal of Physiology - Lung Cellular and Molecular Physiology, 2001