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O hidrogênio molecular (H2) exerce efeito antioxidante, anti-apoptótico e antiinflamatório. Nesse estudo testamos a hipótese que o H2 modula as mudanças cardiovasculares, inflamatórias e termorregulatórias na inflamação sistêmica (IS) induzida por lipopolissacarídeo (LPS) em diferentes doses (0,1 ou 1,5 mg/kg, intravenoso, induzindo IS moderada ou severa) em ratos machos Wistar (250-300 g). LPS ou salina foi injetada imediatamente antes do início dos 360 minutos de inalação do H2 (2% H2, 21% O2, balanceado com nitrogênio) ou ar ambiente (21% O2, balanceado com nitrogênio). A temperatura corporal (Tc) foi mensurada por datalogger pré-implantados na cavidade peritoneal. O H2 não causou mudança nos parâmetros cardiovasculares, inflamatórios e na Tc dos ratos controle (tratados com salina). Durante a IS moderada o H2 reduziu o surgimento das citocinas pró-inflamatórias no plasma (TNF-? e IL-6) enquanto causou um aumento da IL-10 plasmática (citocina anti-inflamatória) e preveniu a febre. Durante a IS severa o H2 potencializou a hipotermia e preveniu a febre e a hipotensão. Além disso, o H2 causou uma redução no surgimento das citocinas pró-inflamatórias (TNF-? e IL-1? do plasma) e prostaglandina E2 [(PGE2), no plasma e no hipotálamo], e um aumento da IL-10 plasmática. Esses dados são consistentes com o entendimento que o H2 atenua a febre na IS moderada e durante a IS severa potencializa a hipotermia, previne a hipotensão e exerce um efeito antiinflamatório forte o suficiente para prevenir a febre alterando a sinalização febrigênica e alterando a produção hipotalâmica de PGE2 / Molecular hydrogen (H2) exerts anti-oxidative, anti-apoptotic, and anti-inflammatory effects. Here we tested the hypothesis that H2 modulates cardiovascular, inflammatory, and thermoregulatory changes in systemic inflammation (SI) induced by lipopolysaccharide (LPS) at different doses (0.1 or 1.5 mg/kg, intravenously, to induce mild or severe SI) in male Wistar rats (250-300 g). LPS or saline was injected immediately before the beginning of 360- minute inhalation of H2 (2% H2, 21% O2, balanced with nitrogen) or room air (21% O2, balanced with nitrogen). Deep body temperature (Tb) was measured by dataloggers preimplanted in the peritoneal cavity. H2 caused no change in cardiovascular, inflammatory parameters, and Tb of control rats (treated with saline). During mild SI, H2 reduced plasma surges of proinflammatory cytokines (TNF-? and IL-6) while caused an increase in plasma IL-10 (anti-inflammatory cytokine) and prevented fever. During severe SI, H2 potentiated hypothermia, and prevented fever and hypotension. Moreover, H2 caused a reduction in surges of proinflammatory cytokines (plasma TNF-? and IL-1?) and prostaglandin E2 [(PGE2), in plasma and hypothalamus], and an increase in plasma IL-10. These data are consistent with the notion that H2 blunts fever in mild SI, and during severe SI potentiates hypothermia, prevents hypotension and exerts anti-inflammatory effects strong enough to prevent fever by altering febrigenic signaling and ultimately down-modulating hypothalamic PGE2 production

O hidrogênio molecular (H2) exerce efeito antioxidante, anti-apoptótico e antiinflamatório. Nesse estudo testamos a hipótese que o H2 modula as mudanças cardiovasculares, inflamatórias e termorregulatórias na inflamação sistêmica (IS) induzida por lipopolissacarídeo (LPS) em diferentes doses (0,1 ou 1,5 mg/kg, intravenoso, induzindo IS moderada ou severa) em ratos machos Wistar (250-300 g). LPS ou salina foi injetada imediatamente antes do início dos 360 minutos de inalação do H2 (2% H2, 21% O2, balanceado com nitrogênio) ou ar ambiente (21% O2, balanceado com nitrogênio). A temperatura corporal (Tc) foi mensurada por datalogger pré-implantados na cavidade peritoneal. O H2 não causou mudança nos parâmetros cardiovasculares, inflamatórios e na Tc dos ratos controle (tratados com salina). Durante a IS moderada o H2 reduziu o surgimento das citocinas pró-inflamatórias no plasma (TNF-? e IL-6) enquanto causou um aumento da IL-10 plasmática (citocina anti-inflamatória) e preveniu a febre. Durante a IS severa o H2 potencializou a hipotermia e preveniu a febre e a hipotensão. Além disso, o H2 causou uma redução no surgimento das citocinas pró-inflamatórias (TNF-? e IL-1? do plasma) e prostaglandina E2 [(PGE2), no plasma e no hipotálamo], e um aumento da IL-10 plasmática. Esses dados são consistentes com o entendimento que o H2 atenua a febre na IS moderada e durante a IS severa potencializa a hipotermia, previne a hipotensão e exerce um efeito antiinflamatório forte o suficiente para prevenir a febre alterando a sinalização febrigênica e alterando a produção hipotalâmica de PGE2 / Molecular hydrogen (H2) exerts anti-oxidative, anti-apoptotic, and anti-inflammatory effects. Here we tested the hypothesis that H2 modulates cardiovascular, inflammatory, and thermoregulatory changes in systemic inflammation (SI) induced by lipopolysaccharide (LPS) at different doses (0.1 or 1.5 mg/kg, intravenously, to induce mild or severe SI) in male Wistar rats (250-300 g). LPS or saline was injected immediately before the beginning of 360- minute inhalation of H2 (2% H2, 21% O2, balanced with nitrogen) or room air (21% O2, balanced with nitrogen). Deep body temperature (Tb) was measured by dataloggers preimplanted in the peritoneal cavity. H2 caused no change in cardiovascular, inflammatory parameters, and Tb of control rats (treated with saline). During mild SI, H2 reduced plasma surges of proinflammatory cytokines (TNF-? and IL-6) while caused an increase in plasma IL-10 (anti-inflammatory cytokine) and prevented fever. During severe SI, H2 potentiated hypothermia, and prevented fever and hypotension. Moreover, H2 caused a reduction in surges of proinflammatory cytokines (plasma TNF-? and IL-1?) and prostaglandin E2 [(PGE2), in plasma and hypothalamus], and an increase in plasma IL-10. These data are consistent with the notion that H2 blunts fever in mild SI, and during severe SI potentiates hypothermia, prevents hypotension and exerts anti-inflammatory effects strong enough to prevent fever by altering febrigenic signaling and ultimately down-modulating hypothalamic PGE2 production

Neste estudo, avaliou-se o efeito da exposição intermitente à Ang II, levando em consideração uma dose que tenha uma ação não pressora, sobre a liberação de citocinas inflamatórias como a interleucina-6 (IL-6) e fator de crescimento transformante beta (TGFβ), bem como PAI-1 e plasminogênio/plasmina. O estudo foi realizado em camundongos machos C57Bl/6, submetidos ao tratamento com Ang II (30ng/kg), com losartan (30mg/kg) ou uma combinação destes, nos tempos de: 30 minutos, 1, 3 e 10 dias. As avaliações mostraram que a Ang II não altera pressão arterial, sugerindo que os aumentos observados de IL-6 e TGFβ sejam decorrentes de ação direta da Ang II. A Ang II promove aumento tanto agudo de TGFβ, possivelmente associado à ação proteolítica da plasmina e alterações vasculares transitórias compatíveis com aumento de permeabilidade, como crônico de TGFβ, possivelmente associado ao aumento da expressão gênica, levando ao aumento da deposição de colágeno vascular. / This study, evaluated the effect of the intermittent exposure to Angiotensin II (Ang II), taking in account a non-pressor dose on the release of inflammatory cytokines such as interleukin-6 (IL-6), transforming growth factor beta (TGFβ) as well PAI-1 and plasminogen /plasmin. The study was conducted on male mice C57BL/6 subjected to the treatment with angiotensin II (30 ng/kg), losartan (30 mg/kg) or a combination thereof, at times: 30 minutes, 1, 3 and 10 days. The evaluations showed that Ang II did not change blood pressure, suggesting that the increases of IL-6 and TGFβ may be by due to direct action of Ang II. Ang II promotes both acute increase of TGFβ, possibly associated with the proteolytic action of plasmin and transient vascular changes consistent with increased permeability, such as chronic increase of TGFβ, possibly associated with increased gene expression, leading to increased vascular collagen deposition.

Neste estudo, avaliou-se o efeito da exposição intermitente à Ang II, levando em consideração uma dose que tenha uma ação não pressora, sobre a liberação de citocinas inflamatórias como a interleucina-6 (IL-6) e fator de crescimento transformante beta (TGFβ), bem como PAI-1 e plasminogênio/plasmina. O estudo foi realizado em camundongos machos C57Bl/6, submetidos ao tratamento com Ang II (30ng/kg), com losartan (30mg/kg) ou uma combinação destes, nos tempos de: 30 minutos, 1, 3 e 10 dias. As avaliações mostraram que a Ang II não altera pressão arterial, sugerindo que os aumentos observados de IL-6 e TGFβ sejam decorrentes de ação direta da Ang II. A Ang II promove aumento tanto agudo de TGFβ, possivelmente associado à ação proteolítica da plasmina e alterações vasculares transitórias compatíveis com aumento de permeabilidade, como crônico de TGFβ, possivelmente associado ao aumento da expressão gênica, levando ao aumento da deposição de colágeno vascular. / This study, evaluated the effect of the intermittent exposure to Angiotensin II (Ang II), taking in account a non-pressor dose on the release of inflammatory cytokines such as interleukin-6 (IL-6), transforming growth factor beta (TGFβ) as well PAI-1 and plasminogen /plasmin. The study was conducted on male mice C57BL/6 subjected to the treatment with angiotensin II (30 ng/kg), losartan (30 mg/kg) or a combination thereof, at times: 30 minutes, 1, 3 and 10 days. The evaluations showed that Ang II did not change blood pressure, suggesting that the increases of IL-6 and TGFβ may be by due to direct action of Ang II. Ang II promotes both acute increase of TGFβ, possibly associated with the proteolytic action of plasmin and transient vascular changes consistent with increased permeability, such as chronic increase of TGFβ, possibly associated with increased gene expression, leading to increased vascular collagen deposition.

Toxoplasma gondii est un parasite intracellulaire obligatoire qui infecte plus du tiers de la population mondiale. La toxoplasmose oculaire (TO), qu’elle soit d’origine acquise ou congénitale, est une infection fréquente et redoutable où le pronostic visuel est fortement engagé. La présence du parasite dans le tissu rétinien, ainsi que la réponse immunitaire de l’hôte, qu’il génère participent au développement des lésions. Cependant, les mécanismes physiopathologiques aboutissant à la destruction de la rétine et ceux conduisant à la latence et à la réactivation parasitaires ne sont toujours pas clairement identifiés. De plus, des améliorations des traitements actuels semblent nécessaires afin de traiter au mieux l’ensemble des patients et d’agir également sur la forme latente du parasite et les récidives qui en découlent. Nos travaux sur des modèles murins de la phase aiguë de la TO démontrent que le facteur de virulence parasitaire ROP16 est responsable de l’augmentation de la charge parasitaire et des réponses inflammatoires oculaires Th1 et Th17. De plus, lorsque cette protéine se trouve dans un génotype parasitaire différent de celui d’origine, la pathologie oculaire en est exacerbée. Nous avons également démontré que la cytokine IL-23 participe à la destruction de la rétine et à la multiplication parasitaire. Notre modèle murin de réactivation de la TO met en évidence le rôle protecteur de la voie Th1 à travers l’IFN-γ et celui fortement délétère de la cytokine IL-6. La neutralisation de cette cytokine dans notre modèle diminue la charge parasitaire oculaire ainsi que l’ensemble de la réponse inflammatoire et n’altère en rien la structure rétinienne. Il serait donc très intéressant d’utiliser une thérapie ciblant le récepteur de l’IL-6 afin de contrecarrer les effets des récurrences de la TO. / The obligate intracellular parasite Toxoplasma gondii infects more than one third of the world population. Ocular toxoplasmosis (OT), whether acquired or congenital, is a common and frightening infection which can strongly impair the visual function. OT is considered as a major cause of posterior uveitis and retinochoroiditis is its most common manifestation. The presence of the parasite in the retina as well as the immune response it generates in the host are two factors involved in the development of ocular lesions. However, up to now, the pathophysiological mechanisms leading to the destruction of the retina and those implied in the parasite latency and reactivation have not been clearly identified. Morever, improvements of current treatments are necessary in order to give all patients a better care but also to fight the parasite latent form and relapses they may cause. Our mouse models of OT acute phase have demonstrated that the parasite virulence factor ROP16 is responsible for the parasite load increase and the Th1 and Th17 ocular inflammatory responses. When this protein is in a different genotype than its original one – this has been made possible by recombining strains – the ocular pathology is more severe. We also showed that the IL-23 cytokine was involved in the destruction of the retina and in parasite multiplication. Our mouse model of OT reactivation highlighted the protective role of the Th1 pathway through IFN-γ as well as the highly deleterious IL-6 cytokine. By neutralizing this cytokine in our model, we reduced the ocular parasite load and the global inflammatory response without modifying the retinal structure. It would be very interesting to elaborate a therapy targeting the IL-6 receptor in order to counter the effects of OT recurrences.

La cryothérapie est utilisée de manière large et empirique à visée adjuvante dans les rhumatismes inflammatoires, avec un niveau de preuve faible. Dans une revue systématique de la littérature, en poolant les données de 6 études non contrôlées, nous avons pu démontrer que la cryothérapie (locale ou corps entier) appliquée deux fois par jour pendant 7 à 15 jours réduisait significativement l'EVA douleur et le score d'activité DAS25 dans la polyarthrite rhumatoïde. La cryothérapie locale (glace ou gaz froide) montrait par ailleurs des effets taille intra-classes supérieurs à ceux obtenus en utilisant la cryothérapie corps entier. L'objectif de ce travail était de mesurer les effets de la cryothérapie locale sur al douleur, l'inflammation synoviale et systémique chez les patients arthritiques et dans le modèle murin d'arthrite à l'adjuvant. Dans les études randomisées CDRI et ALGGAR, nous avons évalué les effets de deux applications locales de froid (glace versus gaz froid) sur la douleur, l'activité Doppler et les taux protéiques de cytokines intra-articulaires controlatéraux non souffrant d'arthrites de genou non septiques. Les genoux arthritiques controlatéraux non traités étaient utilisés comme contrôles. Nous avons par ailleurs étudié in vitro les effets de l'hypothermie modérée (30°C pendant 2heures) sur l'expression protéique des cytokines dans un modèle de culture de rotules de rats arthritiques. Nous avons enfin étudié in vitro dans l'arthrite à l'adjuvant les effets de l'application sub-chronique de glace ou de gaz froid (2 fois par jour pendant 14 jours versus contrôles arthritiques non traités) sur le score d'arthrite, le diamètre de cheville, la transcription des gènes codant pour les cytokines pro-inflammatoires dans les pattes arrières (Q-RT-PCR) et l'expression protéique des cytokines dans le plasma (Multiplex et ELISA) après 14 jours de traitement. Dans l'étude CDRI, la cryothérapie locale (glace et gaz froid) réduisait significativement l'EVA douleur ainsi que le score Doppler dans les genoux traités, ces effets persistant le lendemain des deux applications. Dans une analyse intermédiaire des résultats de l'étude ALGGAR, en combinant les deux groupes de traitement (glace et gaz de froid), nous avons observé une baisse des taux d'IL-6, d'IL-1β et de VEGF dans le liquide articulaire arès deux applications. dans les cultures d'explants de rotules de rats arthritiques, l'hypothermie ponctuelle réduisait significativement les taux d'IL-6, IL-17A et IL-1β dans les pattes arrières après 14 jours de traitement. Les deux modalités réduisaient significativement les niveaux plasmatiques d'IL-17A et la glace réduisait en outre les taux d'IL-6 et de VEGF. Nous n'avons observé aucun effet de la cryothérapie locale sur le voie du TNF-α chez l'homme ni chez l'animal. Nos résultats démontrent pour la première fois un effet thérapeutique et anti-inflammatoire de la cryothérapie locale dans l'arthrite. Les effets biologiques était IL-6/IL-147 dépendants et TNF-α indépendants. Des études complémentaires permettront de mieux caractériser les mécanismes moléculaires sous-jacents et de déterminer su la cryothérapie locale pourrait être une alternative aux AINS et corticoïdes dans les rhumatismes inflammatoires. / Cryotheapy i widely and empirically used in an adjuvant setting in inflammatory rheumatic diseases, with a low level of evidence. We performed a systematic review of the literature and, by pooling data from 6 non-controlled studies, we could show that local cryotherapy (local or whole-body cryotherapy) applaied twice a day for 7-15 days significantly reduced the pain VAS and the DAS28 activity score in rheumatoid arthritis. Furthermore, local cryotherapy (ice packs or cold gas) showed significantly greater intra)class effect-sizes compared to whole-body cryotherapy. The aim of this work was to measure the effects of local cryotherapy on pain, synovial and systemic inflammation in arthrici patients and in the murine model of adjuvant-induced arthritis. First, in the CDRI and ALGGAR randomized studies, we evaluated the effects of 2 local cold applications (ice versus cold gas) on pain, power Doppler activity and intra-joint cytokine protein levels in 46 patients suffering from non-septic knee arthritides. Contralateral arthritic knee were used as control. Secondly, we studied the in vitro effects of mild hypothermia (30°C for 2 hours) on cytokine protein expression in a model of cultured arthritic rat patellae. Thidly, we studied the in vitro effects of sub-chronically applied ice or cold gas (twice a day for 14 days versus non-treated arthritic controls) on the arthritis score, the ankle diameter, pro-inflammatory cytokine gene transcription levelsin hind paws (Q-RT-PCR) and cytokine plasma protein levelx (Multiplex and ELISA) after 14 days of treatment. In the CDRI study, local cryotherapy (ice and cold gas) significantly reduced the pain VAS and the power Doppler score in treated kness, and these effects remained significant the day afetr 2 cold applicaitions. In an intermediate analysis of the ALGGAR study results, by pooling the 2 treatment groups, we could show significant decreases in IL-6 protein, IL-1β and VEGF synovial fluid protein levels after 2 cold applicatios. In arthritic rat patella explangt culture experiments, punctual hypothermia significantly reduced IL-6 protein levels. In vivon ice was more efficient on the clinical parameters and better tolerated compared to cold gas. Both techniques significantly reduced IL-6, IL-17A ans IL-1β gene transcription levels in hind paws after 14 days of treatment. Both techniques redcued IL-17A plasma protein levles, while ice also reduced IL-6 and VEGF plasma protein levels. Conversely, we observed no effect of local cryotherapy on the TNF-α pathway, neither in patients nor in our animal model. Here we demonstrate for the first time therapeutic and anti-inflammatory effet-cts of local cryothepary in arthritis. The biological effects were IL-6/IL-17-driven and TNF-α independent. Further studies will help elucidate the underlying molecular mlechanisms involved and detemrine whether local cryotherapy might be a safer alternative to NSAIDs ans corticosteroids in inflammatory rheumatic diseases.