This study describes induction of pulmonary inflammation, production of matrix metalloprotease of type 2 (MMP-2) and type 9 (MMP-9), and emphysema in cadmium (Cd)-exposed rats. Sprague-Dawley rats were randomly distributed into two groups: one placebo-exposed group undergoing saline (NaCl 0.9%) inhalation (n=30) and one Cd-exposed group undergoing cadmium (CdCl(2) 0.1%) inhalation (n=30). The animals of the placebo- and Cd-exposed groups were divided in five subgroups (n=6). Subgroups underwent either a single exposure of 1h or repeated exposures three times weekly for 1h during 3 weeks (3W), 5 weeks (5W), 5 weeks followed by 2 weeks without exposure (5W+2) or 5 weeks followed by 4 weeks without exposure (5W+4). Each animal underwent determination of enhanced pause (Penh) as index of airflow limitation prior to the first exposure as well as before sacrifice. The animals were sacrificed the day after their last exposure. The left lung was fixed for histomorphometric analysis (determination of median interwall distance (MIWD)), whilst bronchoalveolar lavage fluid (BALF) was collected from the right lung. BALF was analyzed cytologically, and MMP-2 and MMP-9 levels were determined by gelatine zymography. Twelve rats previously instilled with pancreatic elastase were used as positive emphysema controls and underwent the same investigations. Cd-exposure induced a significant increase of BALF macrophages, neutrophils and MMP-9 up to 5W+4, whereas MMP-2 gelatinolytic activity returned to baseline levels within 5W. MIWD was significantly increased in all repeatedly Cd-exposed groups and elastase-treated rats. Penh was increased in Cd-exposed rats after a single exposure and after 3W. MMP gelatinolytic activity was significantly correlated with macrophages, neutrophils and Penh. In repeatedly exposed rats, MIWD was positively and significantly correlated with MMP gelatinolytic activity, suggesting that increased MMP-2 and MMP-9 production favours the development of emphysema.

Heat shock transcription factor (HSF)-1 is recognized as a central component of the heat shock response, which protects against various harmful conditions. However, the mechanisms underlying the protection and the role of HSF-1 in these mechanisms have not yet been clearly elucidated. Using HSF-1 knockout mice ( Hsf1−/−), we examined whether heat shock response-mediated lung protection involved an inhibition of the proinflammatory pathway via an interaction between HSF-1 and NF-κB, in response to cadmium insult. The HSF-1-dependent protective effect against intranasal instillation of cadmium (10 and 100 μg/mouse) was demonstrated by the higher protein content (1.2- and 1.4-fold), macrophage (1.6- and 1.9-fold), and neutrophil (2.6- and 1.8-fold) number in bronchoalveolar fluids, higher lung wet-to-dry weight ratio, and more severe lung damage evaluated by histopathology in Hsf1−/−compared with wild-type animals. These responses were associated with higher granulocyte/macrophage colony-stimulating factor (GM-CSF; 1.7-fold) but not TNF-α concentrations in bronchoalveolar fluids of Hsf1−/−mice compared with those of wild-type animals, indicating that HSF-1 behaved as a repressor of specific cytokine production in our model. To further investigate the mechanism of GM-CSF repression, we analyzed the NF-κB activity and IκB stability. The DNA binding NF-κB activity, in particular p50 homodimer activity, was higher in Hsf1−/−mice than in wild-type mice after cadmium exposure. These results provide a first line of evidence that mechanisms of lung protection depending on HSF-1 involve specific cytokine repression via inhibition of NF-κB activation in vivo.

Cadmium (Cd) is known to activate heat shock (HS) response, which is characterized by overexpression of heat shock proteins (Hsps) under the control of heat shock factor 1 (HSF1). The potential protection provided by the HS response, induced by increasing the body temperature of animals before Cd exposure or by Cd itself, against pathophysiological changes occurring after Cd intranasal instillation (1 to 100 microg/mouse) was examined. HSF1-deficient mice were used to evaluate the role of this factor in lung protection. Cd instillation caused dose- and time-dependent changes in the respiratory pattern measured by plethysmography (Penh), and significant increases in lactate dehydrogenase (LDH) activity as well as macrophage and neutrophil counts in bronchoalveolar lavage fluids. HS preconditioning induced Hsp overexpression and reduced the Penh (-30%), LDH (-25%), and neutrophil (-55%) responses to subsequent administration of the highest Cd doses (50 and 100 microg) in wild-type mice. HSF1 deficiency abolished the HS response and its protective effect. In the absence of preconditioning, Hsf1(-/-) mice exhibited higher values of Penh (+70%) and LDH activity (+42%) compared with wild-type animals when exposed to the lowest Cd doses. Higher macrophage (+80%) and neutrophil counts (+115%) were recorded whatever the dose. Western blot analyses indicated that lung protection might be related to the kinetics of HSF1-dependent Hsp70 expression. Altogether, our data demonstrate that HS response elicited both by prior HS and by Cd itself moderates pulmonary injuries due to Cd instillation, and that HSF1 is a major mediator in this protection.

L'exposition de tout organisme a des temperatures elevees induit l'expression cellulaire rapide et transitoire de proteines specifiques, les proteines de choc thermique (Hsps pour heat shock proteins). Cette des cellules au choc thermique ou heat shock response a ete initialement decouverte chez la drosophile. Les genes hsps furent parmi les premiers genes eucaryotes a etre clones et utilises comme paradigme dans l'etude des mecanismes de regulation transcriptionnelle faisant intervenir l'activation d'un ou plusieurs heat shock factors (HSFs). C'est plus recemment que l'etude des fonctions des Hsps, particulierement Hsp70, a debute. Le role protecteur de celle-ci, lie a sa fonction de chaperon proteique, a ete deduit d'experiences montrant que l'induction de l'expression de Hsp70 lors d'un stress etait associee au developpement d'une tolerance cellulaire vis-a-vis d'un stress ulterieur. En plus d'un interet fondamental pour la comprehension de la reponse au choc thermique, deux axes de recherche appliquee se sont developpes visant a investiguer la possibilite d'utiliser l'expression de Hsp70 comme biomarqueur de souffrance cellulaire d'une part et, d'autre part, d'exploiter ses fonctions comme moyen de protection des cellules contre divers types d'agressions. Cette revue decrit l'historique des decouvertes sur la reponse au choc thermique, le mecanisme regulant l'expression de Hsp70 ainsi que les perspectives interessantes s'ouvrant a l'utilisation de l'expression de Hsp70 en tant que biomarqueur et outil therapeutique.

The exposure of any organism to high temperature induces rapid and transient cellular overexpression of specific proteins, the heat shock proteins (Hsps). This response, called heat shock response, was initially discovered in Drosophila. The genes hsps were among the first eukaryotic genes to be cloned and whose regulation, which involves activation of heat shock factor (HSF), was elucidated. More recently, study of Hsp functions, particularly Hsp70, started. Their protective role, related to their molecular chaperon function, was inferred from experiments showing that Hsp70 expression, induced by a first stress, results in a cellular tolerance to second stress. Better understanding of the heat shock response had led to the development of two search fields on Hsp70 expression : (1) its use as biomarker of cellular stress and (2) the exploitation of its cytoprotective functions against various insults. This review includes historic of the research on the heat shock response, description of regulation mechanism of Hsp70 expression, and the interesting perspectives allocated to Hsp70 as biomarker and therapeutic tool.

The aim of this study was to investigate the role of particle number, total surface area, mass and surface chemical groups in (K(f,c)) changes. The lung effects of four different fine (110 nm) and ultrafine (24 nm) polystyrene particles have been tested in an isolated perfused rabbit lung model. Pulmonary microvascular permeability (K(f,c)) modifications were measured in response to intratracheal particle challenge. Polystyrene particles, mainly located in alveolar spaces and macrophages, induced a K(f,c) increase that was related to the total surface area and number of particles rather than to the instilled mass. Moreover, the positively charged amine-modified polystyrene particles were more effective in the K(f,c) response than the negatively charged carboxylate-modified polystyrene particles. We concluded that particle number and diameter that mathematically equally determined total surface area do not have the same importance in explaining the biological effects observed and that particle number could be an alternative to total surface area to describe the particle exposure. Furthermore, surface properties of polystyrene particles need to be considered to investigate the microvascular permeability changes measured in our model.

Knowledge about cervids are rapidly growing. This work aims to present the more recent scientific information on reproductive physiology and endocrinology of the cervids: anatomy of the genital tract, length of breeding season, parameters and endocrinology of the reproductive cycle, endocrinology of pregnancy. It also aims to highlight differences between cervids and domestic ruminants such as embryonic diapause observed in Capreolus capreolus.

The technology of reproduction progressed considerably during the last decade, leading to a certain availability of in vitro methods for fertilisation, oocyte maturation and embryo culture. The most spectacular manipulations are cloning and transgenesis. This review focuses on the early appearance of germinal cell precursors and the long-standing fate of gametes in mammals. The evident complexity and long-term programming of events in gametes and early embryos explain part of the difficulties encountered during the development of in vitro and in vivo methods such as multiple Ovulation and embryo transfer (MOET), oestrus synchronisation, ovulation induction, superovulation, in vitro maturation and fertilisation, cryopreservation, transgenesis, nuclear transfer and cloning) and the occurrence of unexpected alterations of development, e.g. embryonic or fetal mortality, large-weight newborn syndrome and other dysregulations ill imprinting or DNA transmission.

All living systems have evolved mechanisms to maintain homeostasis in the face of rapid environmental changes. When exposed to elevated temperatures, most of the cells activate the synthesis of a specific group of proteins called Heat Shock Proteins (Hsps). This heat shock response, under control of specific transcription factors, the Heat Shock factors (HSF), is an evolutionarily conserved mechanism, from bacteria to humans. Heat Shock Proteins are classified into families according to their molecular weight (Hsp 25, 40, 70, 90, 105). They play the role of molecular chaperones by binding and protecting other molecules (proteins, RNAs). The function of Hsp is to prevent accumulation of non-native proteins either by assisting proper folding of polypeptides or by driving them to proteosome pathway for degradation. Hsps are involved in various pathological processes that are accompanied by protein alterations such as chronic or degenerative diseases. This review describes structural and functional characteristics of the six main Hsps classes. It also focuses on their respective role in highly studied pathologies. The diversity of Hsps implications in these diseases explains that they became recently a strategic target in development of new therapeutic strategies.

Members of heat shock proteins (Hsp70) family have been considered to respond to a large variety of stressful conditions. But it was suggested that, in pulmonary cells, Hsp response depends more closely on the type of stimulus. The lungs are critical organs potentially subjected to air pollution affecting respiratory function and, therefore, these organs are of particular interest with regard to the stress response. To investigate the stress dependence of Hsp70 response in lungs, we created transgenic mice where the firefly luciferase reporter gene is under the control of the murine hsp70-1 promoter and exposed them to different sublethal toxic conditions. For each condition, the level of transgene induction and pulmonary toxicity were assessed. We found that hsp70-1 promoter was stimulated by heat shock and cadmium but not by ozone, paraquat, and parathion, even if these chemicals induced respiratory distress and lung inflammation. Similar observations were made when expression of the endogenous hsp70-1 gene was analyzed, indicating that our transgenic model was accurately detecting hsp70-1 induction. Thereby, it appeared that hsp70-1 response is selective and depends on signaling pathways triggered by the toxicants rather than by their pathologic toxicity per se. Furthermore, because all the chemicals used in our study have been previously described to increase the level of oxidative stress, it indicates that there is no direct and simple correlation between hsp70-1 response and the level of oxidative stress, but more specific oxidative patterns should be involved in Hsp regulation.

Tout organisme est dote de mecanismes lui permettant de resister a de brusques changements de son environnement. Exposees a une temperature anormalement elevee, la plupart des cellules activent l'expression d'une classe particuliere de proteines appelees les proteines de choc thermique (Heat Shock Proteins, Hsps). Cette reponse cellulaire au choc thermique placee sous le controle de facteurs de transcription specifiques, les facteurs de choc thermique (Heat shock factor, HSF) est un mecanisme conserve au travers de l'evolution depuis les bacteries jusqu'a l'homme. Les proteines de choc thermique qui sont divisees en familles designees par leur masse moleculaire (Hsp25, 40, 70, 90, 105) font partie des molecules chaperons qui s'associent a d'autres molecules (proteines, ARNs) et en protegent la destinee. Le role des Hsp est d'empecher l'accumulation de proteines anormales en aidant a conformer correctement les polypeptides ou en les dirigeant vers le proteosome qui les detruit. En tant que chaperons, les Hsp sont impliquees dans de nombreux processus pathologiques qui s'accompagnent d'alterations des proteines comme les maladies chroniques et degeneratives. Cette revue decrit les specificites structurelles et fonctionnelles des six familles principales d'Hsp ainsi que leur intervention a differents niveaux dans les pathologies les mieux etudiees. La multiplicite de l'implication des Hsp dans ces phenomenes pathologiques les designe comme cibles privilegiees dans le developpement de nouvelles strategies therapeutiques.