Optimising experimental research in respiratory diseases: an ERS statement

Experimental models are critical for the understanding of lung health and disease and are indispensable for drug development. However, the pathogenetic and clinical relevance of the models is often unclear. Further, the use of animals in biomedical research is controversial from an ethical perspective.The objective of this task force was to issue a statement with research recommendations about lung disease models by facilitating in-depth discussions between respiratory scientists, and to provide an overview of the literature on the available models. Focus was put on their specific benefits and limitations. This will result in more efficient use of resources and greater reduction in the numb…

Interstitial Lung Disease during ANCA-Associated Vasculitis: A Poor-Prognosis Factor

IF 7.873; International audience

The small heat-shock protein α B-crystallin is essential for the nuclear localization of Smad4: impact on pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is a devastating disease characterized by the proliferation of myofibroblasts and the accumulation of extracellular matrix (ECM) in the lungs. TGF-β1 is the major profibrotic cytokine involved in IPF and is responsible for myofibroblast proliferation and differentiation and ECM synthesis. αB-crystallin is constitutively expressed in the lungs and is inducible by stress, acts as a chaperone and is known to play a role in cell cytoskeleton architecture homeostasis. The role of αB-crystallin in fibrogenesis remains unknown. The principal signalling pathway involved in this process is the Smad-dependent pathway. We demonstrate here that αB-crystallin is stron…

Fibroblast Growth Facor 19, a Downregulated Factor in Idiopathic Pulmonary Fibrosis, Inhibits Mice Lung Fibrosis

Le FGF-9 inhibe la fibrose pleurale induite par un adénovirus chez la souris

La fibrose pulmonaire idiopathique (FPI) est une pathologie incurable et mortelle. Elle debute et predomine dans les regions sous-pleurales. Elle serait la consequence d’une reactivation des voies impliquees dans le developpement pulmonaire et d’une anomalie de communication entre les differentes cellules pulmonaires. Le fibroblast growth factor-9 (FGF-9) est necessaire pour le developpement pulmonaire fœtal. Au cours de la FPI, le FGF-9 est reexprime par les cellules mesotheliales pleurales. L’objectif de ce travail est de determiner l’effet de la surexpression de FGF-9 par les cellules mesotheliales de la plevre au cours du processus fibrosant pulmonaire. Materiel et methodes De souris mâ…

Eight novel variants in the SLC34A2 gene in pulmonary alveolar microlithiasis

BackgroundPulmonary alveolar microlithiasis (PAM) is caused by genetic variants in the SLC34A2 gene, which encodes the sodium-dependent phosphate transport protein 2B (NaPi-2b). PAM is characterised by deposition of calcium phosphate concretions (microliths) in the alveoli leading to pulmonary dysfunction. The variant spectrum of SLC34A2 has not been well investigated and it is not yet known whether a genotype–phenotype correlation exists.MethodsWe collected DNA from 14 patients with PAM and four relatives, and analysed the coding regions of SLC34A2 by direct DNA sequencing. To determine the phenotype characteristics, clinical data were collected and a severity score was created for each va…

FGF-9 overexpression prevents pleural fibrosis induced by intra-pleural adenovirus injection in mice

Introduction: Lung fibrosis is associated with the reactivation of molecular pathways involved in lung development. Mesothelial cells are involved in the fibrotic lung process but their exact role is debated. Fibroblast Growth Factor-9 (FGF-9) is expressed by epithelial cells and visceral pleura during embryonic lung development. Mice homozygous for a targeted disruption of FGF-9 exhibit lung hypoplasia with reduced mesenchyme and early postnatal death. The aim of this study was to evaluate the role of FGF-9 expression by mesothelial cells in the adult lung. We used adenovirus-mediated (FGF-9) gene transfer in mesothelial cells in vivo. Material and Methods: AdFGF9 or a control adenovirus (…

Identification of periplakin as a major regulator of lung injury and repair in mice

IF 12.784 (2016); International audience; Periplakin is a component of the desmosomes that acts as a cytolinker between intermediate filament scaffolding and the desmosomal plaque. Periplakin is strongly expressed by epithelial cells in the lung and is a target antigen for autoimmunity in idiopathic pulmonary fibrosis. The aim of this study was to determine the role of periplakin during lung injury and remodeling in a mouse model of lung fibrosis induced by bleomycin. We found that periplakin expression was downregulated in the whole lung and in alveolar epithelial cells following bleomycin-induced injury. Deletion of the Ppl gene in mice improved survival and reduced lung fibrosis developm…

Inhibition of HSP27 blocks fibrosis development and EMT features by promoting Snail degradation

Idiopathic pulmonary fibrosis (IPF) is a devastating disease characterized by myofibroblast proliferation. Transition of epithelial/mesothelial cells into myofibroblasts [epithelial-to-mesenchymal transition (EMT)] occurs under the influence of transforming growth factor (TGF)-β1, with Snail being a major transcription factor. We study here the role of the heat-shock protein HSP27 in fibrogenesis and EMT. In vitro, we have up- and down-modulated HSP27 expression in mesothelial and epithelial cell lines and studied the expression of different EMT markers induced by TGF-β1. In vivo, we inhibited HSP27 with the antisense oligonucleotide OGX-427 (in phase II clinical trials as anticancer agent)…

Le FGF-9 inhibe la fibrose pleurale viro-induite chez la souris

La fibrose pulmonaire idiopathique (FPI) est une pathologie mortelle, predominante en zone sous-pleurale. Elle serait en partie due a une reactivation des voies impliquees dans le developpement pulmonaire. Le Fibroblast Growth Factor-9 (FGF-9) est reexprime par les cellules mesotheliales lors de la FPI. Nous avons determine l’effet de la surexpression de FGF-9 par les cellules mesotheliales chez la souris. Des souris C56/Bl6 ont recu une injection intrapleurale unique de serum physiologique (groupe Phy) ou un adenovirus recombine exprimant le FGF-9 humain (groupe AdFGF-9) ou un adenovirus controle (groupe Adcont), a la concentration de 1 × 108 pfu/mL. Les souris ont ete sacrifiees a j3, j5,…