Intratracheally administered titanium dioxide or carbon black nanoparticles do not aggravate elastase-induced pulmonary emphysema in rats.

International audienceABSTRACT: BACKGROUND: Titanium dioxide (TiO2) and carbon black (CB) nanoparticles (NPs) have biological effects that could aggravate pulmonary emphysema. The aim of this study was to evaluate whether pulmonary administration of TiO2 or CB NPs in rats could induce and/or aggravate elastase-induced emphysema, and to investigate the underlying molecular mechanisms. METHODS: On day 1, Sprague-Dawley rats were intratracheally instilled with 25 U kg1 pancreatic porcine elastase or saline. On day 7, they received an intratracheal instillation of TiO2 or CB (at 100 and 500 mug) dispersed in bovine serum albumin or bovine serum albumin alone. Animals were sacrificed at days 8 or 21, and bronchoalveolar lavage (BAL) cellularity, histological analysis of inflammation and emphysema, and lung mRNA expression of heme oxygenase-1 (HO-1), interleukin-1beta (IL-1beta), macrophage inflammatory protein-2, monocyte chemotactic protein-1, and matrix metalloprotease (MMP)-1, and -12 were measured. In addition, pulmonary MMP-12 expression was also analyzed at the protein level by immunohistochemistry. RESULTS: TiO2 NPs per se did not modify the parameters investigated, but CB NPs increased perivascular/peribronchial infiltration, and macrophage MMP-12 expression, without inducing emphysema. Elastase administration increased BAL cellularity, histological inflammation, HO-1, IL-1beta and macrophage MMP-12 expression and induced emphysema. Exposure to TiO2 NPs did not modify pulmonary responses to elastase, but exposure to CB NPs aggravated elastase-induced histological inflammation without aggravating emphysema. CONCLUSIONS: TiO2 and CB NPs did not aggravate elastase-induced emphysema. However, CB NPs induced histological inflammation and MMP-12 mRNA and protein expression in macrophages

Analyse génotypique et fonctionnelle des cardiomyocytes issus de la différenciation précoce des cellules souches embryonnaires murines

Les cellules souches embryonnaires (ES) de par leur pluripotence constituent un excellent modèle pour étudier les stades précoces de la différenciation cardiaque. Ce travail a permis la caractérisation phénotypique, " génotypique " et fonctionnelle des cardiomyocytes issus de la différenciation des cellules murines ES R1 à différentes étapes de cette différenciation. D'une part, le profil d'expression génique et les études électrophysiologiques montrent que les progéniteurs cardiaques dérivés des cellules ES à des stades précoces de différenciation présentent les caractéristiques des cellules cardiaques de type pacemaker. D'autre part, les cardiomyocytes isolés à des stades de différenciation plus tardifs présentent un profil génotypique de type atrial. Les résultats obtenus à partir de co-culture de cardiomyocytes dérivés des ES et de cardiomyocytes néonataux d'origine atriale ou ventriculaire suggèrent une capacité d'adaptation de ces cardiomyocytes en fonction de la niche tissulaire.The embryonic stem cells (ES) by their pluripotence constitute an appropriate model to study the early events leading to cardiac cellular differentiation. In the present study, we investigated at different steps of the in vitro differentiation, the genomic and functionnal expression of murine ES-derived cardiomyocytes. The results of gene expression profile by semi quantitative and electrophysiological studies, allowed us to demonstrate that these cardiac cells at an early stage of differentiation have properties similar to those described in native cardiac pacemaker. Moreover, those isolated at a later stage have an atrial-like gene expression profile in our culture conditions. The results obtained by co-culturing neonatal atrial or ventricular cardiomyocytes with ES-derived cardiac cells suggest that cells have the ability to modify their phenotype depending on their environment. This environment may condition the final phenotype expression of ES-derived cardiac cells.NANTES-BU Médecine pharmacie (441092101) / SudocPARIS-BIUP (751062107) / SudocSudocFranceF

Interaction of matrix metalloproteinases with pulmonary pollutants.

International audienceAn air pollutant consists of any atmospheric substance that may harm humans, animals, vegetation or material. Various air pollutants have been reported, differing in their physicochemical characteristics. They can be grouped into four categories: gaseous pollutants (e.g. ozone, sulfur dioxide, oxides of nitrogen, carbon monoxide and volatile organic compounds), persistent organic pollutants, heavy metals (e.g. cadmium, lead and mercury) and particulate matter (coarse, fine and ultrafine). These pollutants can reach the respiratory system, eliciting pulmonary and/or systemic effects. These effects include inflammation, tissue remodelling and carcinogenesis: all phenomena where matrix metalloproteases (MMPs) play critical roles, given their broad effects on matrix remodelling and modulation of inflammation and cell signalling. Moreover, since expression and activity of MMPs can be induced by such stimuli, the hypothesis has been raised that MMPs could be involved in the health effects of pollutants. Until now, the implication of MMPs in these effects has been studied only for some pollutants and for a restricted selection of MMPs (mainly MMP-1, -2, -9 and -12), while evidence for a link between MMP induction/activation and health effects remains scarce. A larger number of studies is, therefore, needed in order to better understand the implication of MMPs in health effects associated with air pollution

Secreted phospholipase A2 XIIA triggers a mitochondrial damage-induced senescence in chronic obstructive pulmonary disease fibroblasts

International audienceLung fibroblast senescence is involved in the pathophysiology of chronic obstructive pulmonary disease (COPD). However, the mechanisms underlining this phenomenon are still poorly understood. Secreted phospholipases (sPLA2, a subclass of phospholipases) are secreted by senescent cells and can in turn induce senescence. However, their role in fibroblasts senescence in COPD is unknown. Objectives: The aim of this study was to analyze the role of sPLA2 in pulmonary fibroblast senescence. Methods: Fibroblasts were isolated from patients with COPD and control subjects, and senescence markers and inflammatory profile was analyzed. sPLA2 levels were quantified in serum of COPD and controls. Main results: In comparison with non-smokers and smoker controls, senescent lung COPD fibroblasts exhibited a higher mRNA and protein expression of the sPLA2 isoform XIIA and of syndecan 4 (one of its receptors). sPLA2 XIIA induced in turn senescence of non-senescent pulmonary fibroblasts via a pathway involving consecutively syndecan 4, activation of MAPK and p-serine 727 STAT-3, increased mitochondrial ROS production, and activation of AMPK/p53. This pathway was associated with a specific inflammatory secretome (IL-10, IL-12 and TNFα), globally suggesting occurrence of a mitochondrial damage-induced senescence. COPD fibroblasts were more susceptible to this sPLA2 XIIA effect than cells from controls subjects. sPLA2 XIIA levels were significantly higher in serum from COPD patients as compared to controls. Conclusion: sPLA2 XIIA is involved in senescence in COPD and could be a potential target to dampen this process

Telomere Dysfunction and Cell Senescence in Chronic Lung Diseases: Therapeutic Potential

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Titanium Dioxide Nanoparticles Induce Matrix Metalloprotease 1 in Human Pulmonary Fibroblasts Partly via an Interleukin-1β–Dependent Mechanism

International audienceExposure to titanium dioxide (TiO2) nanoparticles (NPs) is associated with lung remodeling, but the underlying mechanisms are unknown. Matrix metalloprotease (MMP)-1 is an important actor in matrix homeostasis and could therefore participate in TiO2 NP effects. Our aim was to evaluate the effects of TiO2 NPs on MMP-1 expression and activity in lung pulmonary fibroblasts and to understand the underlying mechanisms and assess the importance of the physicochemical characteristics of the particles in these effects. Human pulmonary fibroblasts (MRC-5 cell line and primary cells) were exposed to 10 or 100 μg/cm(2) TiO2 (two anatases, two anatase/rutile mix, one rutile NP, and one micrometric) and carbon black (CB) NPs for 6 to 48 hours. We examined cell viability, MMP-1 expression and activity, and the implication of oxidative stress, transforming growth factor (TGF)-β, extracellular MMP inducer, and IL-1β in MMP-1 expression. All TiO2 NPs induced MMP-1 (mRNA and protein expression), repression of procollagen-1, and α-actin expression, but only the two anatase/rutile mix induced MMP-1 activity. Micrometric TiO2 had smaller effects than TiO2 NPs, and CB NPs did not induce MMP-1. MMP-1 induction by TiO2 NPs was not related to TGF-β, oxidative stress, or EMPRIN expression but was related to IL-1β expression, which partly drives MMP-1 induction by two TiO2 NPs (one anatase/rutile mix and the rutile one). Taken together, our results show that TiO2 NPs are potent inducers and regulators of MMP-1 expression and activity, partly via an IL-1β-dependent mechanism. This may explain TiO2 lung remodeling effects

Intratracheally administered titanium dioxide or carbon black nanoparticles do not aggravate elastase-induced pulmonary emphysema in rats

Abstract Background Titanium dioxide (TiO2) and carbon black (CB) nanoparticles (NPs) have biological effects that could aggravate pulmonary emphysema. The aim of this study was to evaluate whether pulmonary administration of TiO2 or CB NPs in rats could induce and/or aggravate elastase-induced emphysema, and to investigate the underlying molecular mechanisms. Methods On day 1, Sprague-Dawley rats were intratracheally instilled with 25 U kg−1 pancreatic porcine elastase or saline. On day 7, they received an intratracheal instillation of TiO2 or CB (at 100 and 500 μg) dispersed in bovine serum albumin or bovine serum albumin alone. Animals were sacrificed at days 8 or 21, and bronchoalveolar lavage (BAL) cellularity, histological analysis of inflammation and emphysema, and lung mRNA expression of heme oxygenase-1 (HO-1), interleukin-1β (IL-1β), macrophage inflammatory protein-2, monocyte chemotactic protein-1, and matrix metalloprotease (MMP)-1, and -12 were measured. In addition, pulmonary MMP-12 expression was also analyzed at the protein level by immunohistochemistry. Results TiO2 NPs per se did not modify the parameters investigated, but CB NPs increased perivascular/peribronchial infiltration, and macrophage MMP-12 expression, without inducing emphysema. Elastase administration increased BAL cellularity, histological inflammation, HO-1, IL-1β and macrophage MMP-12 expression and induced emphysema. Exposure to TiO2 NPs did not modify pulmonary responses to elastase, but exposure to CB NPs aggravated elastase-induced histological inflammation without aggravating emphysema. Conclusions TiO2 and CB NPs did not aggravate elastase-induced emphysema. However, CB NPs induced histological inflammation and MMP-12 mRNA and protein expression in macrophages.</p