FoxO3a is a transcription factor that regulates various cellular functions such as cell cycle or cell death. However, its role in the innate immune response is not clear. I investigated the impact of FoxO3a signaling on the immune response during infection with Salmonella Typhimurium (ST). My results revealed that FoxO3a regulated the homeostasis of myeloid cells in the spleen and blood of mice during steady-state. Following infection of macrophages with ST, FoxO3a signaling promoted the expression of pro-inflammatory cytokines such as IL12 and TNFα, but inhibited the expression of the anti-inflammatory cytokine IL10. Phenotypic analysis revealed that FoxO3a signaling had no effect on classical macrophage polarization into M1 vs M2 phenotypes, although it appeared to regulate mitochondrial function during infection with ST. Inflammatory responses are critical during infection with virulent intracellular pathogens, and these results provide new insights into the role of FoxO3a signaling in inflammatory responses.

In mammals endogenous, self sustained oscillators, known as circadian clocks, have evolved as a result of day night cycles, with a period close to 24 hours, and are involved in many physiological processes; such as sleep wake cycles, metabolic and hormonal activity. The suprachiasmatic nucleus (SCN), is the central oscillator, and is synchronised to the external environment by light, via the eye. It has been demonstrated that peripheral clocks, too, contain the circadian oscillator, with tissues such as the lung, liver, heart and kidney as well as many isolated cell types remaining rhythmic, in culture, for many days. However, these peripheral oscillators require a signal from the central oscillator in order to co-ordinate a synchronised time. Leading candidates in the relay of this information are the circulating glucocorticoid hormones corticosterone (rodents) or cortisol (man), which are known to have potent effects on the peripheral clock, both in-vivo and in-vitro. Further to this, glucocorticoids have been used for many decades to suppress the symptoms of inflammation, a by product of many human diseases.This thesis aims to address the temporal regulation of the peripheral clock by the endogenous glucocorticoid, corticosterone, using a transgenic mouse harbouring a luciferase conjugated clock reporter, and circadian reporter cell lines. It also aims to address the relative contribution of the two closely related nuclear hormone receptors, the glucocorticoid and mineralocorticoid receptors. A further aim of the work with glucocorticoid signalling was to design a flow-though culture system, in order to address the effects of the endogenous pulsatile release of glucocorticoids on the peripheral oscillator. This thesis also aims to characterise the inflammatory response in relation to its circadian characteristics; its relationship with corticosterone and the effect of inflammation on the central clock components. Finally, this thesis aims to investigate a potential input/output of the clock, a member of the family of C/EBP transcription factors, C/EBP alpha, and whether it is under endogenous circadian control and regulated by glucocorticoids.Work in this thesis has shown that glucocorticoids dynamically regulate the peripheral clock at all phases of the circadian cycle and that this regulation occurs mainly through the glucocorticoid receptor; yet the mineralocorticoid receptor does have a function in the immediate response to glucocorticoid administration. Furthermore, as a result of the initial temporal profile after corticosterone addition, on the clock protein PERIOD2, I have shown transient regulation of the clock through Caveolin-1 based signalling. There is also a significant circadian component to the inflammatory response, which appears, at least in part, to be REV-ERB alpha mediated, and the inflammatory response also has profound effects on circadian gene expression in the periphery. A functional flow-through system was designed and a working model produced, albeit with technical difficulties, to address glucocorticoid pulsing and circadian timing but much more work is needed for effects to be fully understood. C/EBP alpha appears not to be under circadian regulation nor under direct glucocorticoid regulation, at least in peripheral models used here.

L’obésité est une cause majeure de morbi-mortalité dans le monde en raison notamment du risque accru de développement de pathologies cardiovasculaires athéroscléreuses. Elle est en particulier associée à une accumulation de tissu adipeux blanc secrétant une quantité inappropriée de cytokines possédant des effets pléiotropiques sur l’inflammation et le métabolisme : les adipokines dont la leptine, la résistine et l’adiponectine. L’anévrysme de l’aorte abdominale (AAA) est une dilatation localisée et permanente de plus de 50% du diamètre de l’aorte abdominale. Il a longtemps été considéré comme une complication de l’athérosclérose. Cependant, cette théorie a été mise à l’épreuve récemment. Très peu d’études se sont intéressées à la prévalence et aux facteurs de risque d’AAA chez les patients coronariens. Dans une première partie, nous avons montré dans une population de 217 patients opérés d’un pontage aorto-coronarien pour une athérosclérose coronarienne sévère que la prévalence de l’AAA atteint 24% si l’on considère les hommes avec un tabagisme actif ou ancien et présentant de manière concomitante une atteinte athéroscléreuse d’autres lits vasculaires (sténose carotidienne ou artérite oblitérante des membres inférieurs), pour une prévalence de seulement 4,4% en l’absence de ces facteurs de risque. Dans la population générale, le dépistage d’un AAA est recommandé seulement chez les hommes âgés de 65 à 75 ans ayant des antécédents de tabagisme. Aucune donnée n’existe sur le dépistage des AAA chez les patients coronariens. Dans la seconde partie de ce travail, nous avons donc réalisé une revue de la littérature sur les facteurs de risque prédictifs d’AAA chez les patients coronariens. Malgré le nombre réduit d’études, la prévalence de l’AAA est plus élevée dans une population atteinte d’athérosclérose coronarienne que dans la population générale. Certains facteurs de risques traditionnels de l’athérosclérose (tabagisme, âge et atteinte athéroscléreuse d’autres lits vasculaires) maintiennent chez ces patients une association significative avec l’AAA. Un AAA n’est probablement donc pas une simple complication de l’athérosclérose et l’intérêt du dépistage de l’AAA dans cette population spécifique de patients mérite d’être approfondi. Une inflammation transmurale chronique caractérise à la fois le développement de l’athérosclérose et de l’AAA. Nous avons évalué l’association des taux plasmatiques des 3 principales adipokines (résistine, leptine et adiponectine) avec la prévalence de l’AAA dans notre population de patients coronariens sévères. Nous avons montré que seul le taux plasmatique de résistine était indépendamment associé à l’AAA et corrélé au diamètre infra-rénal de l’aorte. Cette corrélation disparaissait dans le groupe des AAA. Ainsi la résistine pourrait être associée à la pathogenèse de l’AAA, indépendamment de son implication dans le processus inflammatoire à l’origine de l’athérosclérose. Enfin, la quatrième partie de notre travail a porté sur le rôle de la leptine dans le développement de lésions athéroscléreuses de l’artère carotidienne. Dans un protocole clinico-biologique incluant des patients atteints d’une athérosclérose carotidienne symptomatique ou pas, nécessitant une endartérectomie (n=146), nous avons montré pour la première fois que les taux plasmatiques et intra-plaques de leptine sont significativement plus bas chez les patients asymptomatiques que chez les patients symptomatiques, ce qui a été confirmé par analyse multivariée. Les taux de leptine plasmatiques et intra plaques sont positivement corrélés à un phénotype stable de la plaque (ratio collagène/macrophages élevé). Nous avons également montré qu’in vitro, la leptine induit initialement une réponse de migration sur les CMLV (0-20 ng/mL), puis de prolifération (20 à 75 ng/mL). [...] / Obesity is associated with a higher risk of atherosclerotic cardiovascular pathologies and accordingly entails a great deal of morbidity and mortality. Central to obesity is the accumulation of large amounts of white adipose tissue, which inappropriately secretes bioactive molecules involved in a state of local and systemic low grade inflammation as well as metabolic anomalies. These molecules are the adipokines including leptin, resistin and adiponectin. An abdominal aortic aneurysm (AAA) is a localized and permanent aortic dilation, exceeding 50% of the adjacent normal aortic wall diameter. AAA has long been considered an atherosclerotic complication, a theory which has recently been challenged. Only a few studies have evaluated the prevalence and risk factors of AAA in coronary artery disease (CAD) patients. In the first part of our work, we dealt with 217 patients undergoing coronary artery bypass grafting for severe CAD. In men aged less than 75 years with a smoking history, AAA prevalence reached 24% if they had concomitant peripheral artery disease or carotid artery stenosis, vs 4.4% in the absence of either condition. AAA screening is only recommended in men, aged 65 to 75 years, with a history of smoking. Na data are available on the need for AAA screening among CAD patients. The second part of our work is a review on the prevalence and risk factors of AAA in CAD patients. Despite a limited number of studies, AAA seems to be more prevalent among CAD patients compared to the global population. Only some traditional atherosclerosis risk factors remain significantly associated with AAA (smoking, age, atherosclerosis of other vascular beds). Accordingly, AAA may not be pressed into a simple scheme as just an atherosclerotic complication. The benefit of AAA screening in this specific sub-population needs to be further assessed. Both AAA and atherosclerosis share chronic arterial wall inflammation. Hence, in the 3rd part of the current work, we measured circulating levels of the 3 main adipokines (leptin, resistin and adiponectin) and assessed their relationship with the presence of AAA among our precited severe CAD male patients. Only serum resistin levels were independently associated with AAA, and correlated with infra renal aortic diameter. This correlation disappeared in the AAA range. Eventually, resistin could be associated with AAA pathogenesis, independently of its implication in atherosclerosis – related inflammation. The fourth and final part of our work has acknowledged the role of leptin in the development of atherosclerotic carotid artery stenosis. We included 146 patients scheduled for carotid endarterectomy for asymptomatic versus symptomatic carotid artery stenosis. We reported, for the first time, that serum and intra–plaque leptin levels were significantly lower in symptomatic patients compared to asymptomatic patients. This result was confirmed by multivariate analysis. Circulating and intra plaque levels were positively correlated to a stable plaque phenotype (high collagen/macrophage ratio). In vitro, leptin induced an initial migratory response on vascular smooth muscle cells (VSMC) at the concentration range of 0 to 20 ng/mL, followed by a proliferative response (20 to 75 ng/mL). At higher concentrations (100 ng/mL), leptin brought about VSMC apoptosis. Leptin could thus play an active role in carotid plaque stabilization, via its effects on VSMC. Several conclusions can be drawn. AAA is not a mere atherosclerotic complication. On one side, resistin could actively influence the development and progression of AAA. On the opposite side, leptin could promote atherosclerotic plaque stabilization, via its effects on VSMC migration and proliferation.

La prévalence de l’obésité est en net progrès et constitue un problème majeur de santé publique. Cette pathologie est d’autant plus dangereuse qu’elle s’accompagne d’un cluster de désordres métaboliques dont l’inflammation chronique de bas grade et la résistance à l’insuline, principal facteur de risque du diabète de type 2. Les études montrent que la consommation d’un régime hyper lipidique (HFD) représente la cause majeure qui expose à l’obésité et aux pathologies qui lui sont associées. L’obésité induite par un régime HFD s’associe en effet à une inflammation hypothalamique ainsi qu’une altération des circuits neuronaux régissant le contrôle de la balance énergétique, ces altérations sont propices aux développements de résistances à l’insuline et à la leptine. De récentes études montrent que la consommation d’un régime HFD de quelques jours seulement s’accompagne d’une inflammation hypothalamique transitoire, antérieure à l’installation de l’obésité et à l’inflammation périphérique. Ces résultats suggèrent que l’inflammation hypothalamique précoce représente une étape critique dans le développement de l’obésité et de ses altérations. Les médiateurs et les voies de signalisations impliqués dans l’installation de l’inflammation hypothalamique ne sont pas totalement élucidées. Chez les rongeurs, la résistine est associée à l’inflammation et l’insulino-résistance au cours de l’obésité. Bien que majoritairement produite par le tissu adipeux, les études montrent que la résistine est également exprimée par l’hypothalamus ; toutefois, peu d’études renseignent sur son action au niveau central. Notre équipe a démontré chez le rat, qu’une perfusion centrale de résistine altère fortement la sensibilité à l’insuline via l’activation du récepteur TLR4 et l’induction des principales voies de l’inflammation. Dans ce contexte, l’objectif de cette étude a été d’investiguer le rôle de la voie résistine/TLR4 dans l’installation de l’inflammation hypothalamique associée au régime HFD. Nous montrons pour la première fois que, chez la souris, la consommation d’un régime HFD provoque une augmentation de l’expression génique de la résistine dans l’hypothalamus dès 3 jours de régime HFD. L’expression de la résistine est diminuée jusqu’au niveau basal après 8 jours et est de nouveau fortement augmentée après 8 semaines de régime HFD. Nous montrons que l’augmentation de l’expression de la résistine est concomitante avec la gliose réactionnelle associée au régime HFD de court terme, connue pour précocement altérer l’équilibre de la balance énergétique. De façon intéressante, nous montrons quel’augmentation de l’expression de la résistine est observée dans les neurones anorexigènes POMC, critiques pour le maintien de l’homéostasie énergétique ainsi que dans les tanycytes dont les prolongements contactent les capillaires fenêtrés du sang porte hypothalamohypophysaire et dont l’importance pour l’équilibre de la balance énergétique a été démontrée. De façon intéressante, nous montrons que la résistine active l’inflammation dans les tanycytes via TLR4 suggérant que la résistine pourrait promouvoir l’inflammation au sein des tanycytes en réponse au régime HFD, et ce même à court terme. De plus, nous montrons qu’une ICV de 3 jours de résistine chez la souris provoque une inflammation hypothalamique ainsi qu’une gliose réactionnelle au sein de l’ARC qui rappellent les effets du régime HFD. De façon intéressante, nos résultats montrent que l’invalidation du récepteur TLR4 aboli l’inflammation et la gliose réactionnelle hypothalamiques induites par l’ICV de résistine. L’ensemble nos données démontrent que la voie résistine/TLR4 pourrait jouer un rôle critique dansl’inflammation hypothalamique associée au régime HFD de court et long terme, quiprédispose à l’obésité. / Obesity is closely linked to a cluster of metabolic disorders including chronic low-grade inflammation and insulin resistance, which constitutes a principal risk factor for type 2 diabetes. In rodents, cumulative evidence support that the consumption of high fat diet (HFD) is among the most important nutritional factors predisposing to obesity associated insulin resistance and low-grade inflammation. Indeed, HFD induces hypothalamic inflammation and deregulates energy homeostasis control through the alteration of hypothalamic insulin and leptin responsiveness, considered as the main anorexigenic hormones. In addition, it has been shown that unlike peripheral inflammation, which occurs as a consequence of obesity, hypothalamic inflammation develops selectively in the hypothalamic arcuate nucleus (ARC) within the first days of HFD exposure. These data suggest that hypothalamic inflammation is a critical step in the early onset of the deregulation of energy homeostasis by HFD. The cellular and molecular mechanisms underlying obesity-induced hypothalamic inflammation are still not fully characterized. In rodents, resistin is described as a causal factor in obesitymediated insulin resistance and type 2 diabetes. Resistin is mainly secreted by adipose tissue in rodents but an endogenous expression of resistin was also reported in the hypothalamus. However, its action at the central level is not fully understood. Our group recently demonstrated that central resistin, via hypothalamic TLR4, promotes overall insulin resistance through the promotion of inflammatory pathway. In this context, we aimed to investigate the role of resistin/TLR4 pathway in HFD-induced hypothalamic inflammation and insulin resistance. In the present study we report for the first time that both short and long term HFD are associated with a significant increase of resistin expression throughout the MBH. Our results revealed a transient increase in resistin mRNA expression in the ARC after 3 days of HFD, followed by a decline to baseline at day 8 and an expression that increases again after 8 weeks of HFD. We showed that the increase of resistin expression is concomitant with short term HFD-induced ARC reactive gliosis, known to early disrupt energy balance and to predispose to obesity. Interestingly, our results revealed that resistin is expressed by POMC neurons which are critical for energy balance and tanycytes that have the specificity to contact both cerebro-spinal fluid and fenestrated capillary in the mediane eminence. Interestingly, we show that resistin induces tanycytes inflammation through TLR4 suggesting that resistin could promote inflammation in tanycytes in response to short term HFD. Additionally, we show that ICV resistin markedly increases inflammatory markers in the hypothalamic arcuate nucleus in association with reactive gliosis involving recruitment of both microglia and astrocytes. Interestingly, we report that the knockdown of TLR4 almost completely abolished resistin-dependent both hypothalamic inflammation and reactive gliosis. Our data demonstrate that restitin/TLR4 pathway could play a critical role in HFD-diet induced hypothalamic inflammation in response to short and long term HFD which predispose to obesity, a hallmark of metabolic syndrome.

Anaemia frequently accompanies chronic inflammatory diseases like rheumatoid arthritis and cancer. It is postulated to result primarily from the suppression of erythropoiesis by inflammatory cytokines. A contributing factor could be the inhibition of erythropoietin synthesis which may also be mediated by cytokines. Erythropoietin is the hormone which regulates erythropoiesis. The aims of this project were to investigate whether cytokines can indeed suppress erythropoietin production, and to determine whether the erythropoietin response in experimental models of acute and chronic inflammation was appropriate for the associated anaemia. Macrophage-conditioned medium, interleukin-1β, interleukin-6, tumour necrosis factor-α, and neopterin were assayed for inhibition of erythropoietin synthesis by HepG2 cells in culture. All, except neopterin, effected dose-dependent reductions in the secretion of the hormone. Interleukin-1β and tumour necrosis factor-α down-regulated erythropoietin gene transcription, whereas interleukin-6 inhibited a post-transcriptional process. Rats with acute inflammation developed a mild anaemia which evoked an increase in their serum levels of erythropoietin. The serum erythropoietin levels were optimal, since rats with acute inflammation and severe phenylhydrazine-induced anaemia did not have lower levels of the hormone than controls with a similar degree of anaemia, but without acute inflammation. Erythropoietin is, therefore, not an acute phase reactant. Mice with cancer developed a progressive anaemia which was not due to bone marrow invasion by tumour cells. During the first fourteen days after inoculating them with cancer cells, the mice responded by increasing their serum levels of erythropoietin as the anaemia worsened. The erythropoietin response was appropriate when compared to mice with the same degree of phenylhydrazine-induced anaemia. Erythropoietin levels measured in mice with tumours older than fourteen days were significantly lower than those of control mice with the same degree of experimental anaemia. These animals were very cachectic, suggesting that a blunted erythropoietin response may depend on disease activity.

Atherosclerosis is a chronic inflammatory and lipid disorder caused by the buildup of cholesterol-loaded cells of monocyte and muscle cell origin in the arterial intima. While the relationship between excess cholesterol and macrophage behavior is well observed, the molecular mechanisms linking the two remain unclear. Therefore, characterizing the pathways from changes in intracellular cholesterol to the resulting inflammatory output is key to understanding the behavioral changes observed in human macrophages in vitro. We identified that THP-1 macrophages acutely depleted of cholesterol increase the expression of JMJD3, an H3K27me3 demethylase. By using IL-10 as a marker for immune-modulating genes and TNF-α as a marker for pro-inflammatory genes, cholesterol-depleted THP-1 macrophages responded inconsistently to LPS and echinomycin, an inhibitor of HIF-1α, as determined by RT-qPCR and ELISA. Further studies investigating other regulators and outputs of macrophage behavior linked to cellular cholesterol modification are required.

Typical Parkinson’s Disease (PD) is a complex disease that arises from a combination of factors including genetics, environment, gene-environment interactions, sex and age. How these factors interact has yet to be elucidated. We have previously published roles for PD-linked genes in response to microbial infections in an effort to model gene-environment interactions in PD. Mutations in the GBA1 gene, encoding a protein that confers glucocerebrosidase (GCase) activity, represent the commonest risk factor for PD development. In the present study, we sought to understand the role of murine Gba1 in microbial infection. GCase activity was found to be sex- and organ-dependent in young adult mice carrying the p.D409V mutation. Mice carrying Gba1 p.D409V knock-in mutations did not show altered immune outcomes in response to Influenza virus H1N1, bacterial Salmonella typhimurium, or serial infections of the two. In response to Vesicular Stomatitis Virus (VSV), p.D409V mice survived at a higher rate overall compared to their wild type littermates, while homozygous males survived at a higher rate compared to wild type males in a sex-dependent manner. Heterozygous females had a lower viral load in the lung after VSV infection. GCase activity was found to be altered in VSV-infected p.D409V mice in a sex-and organ-dependent manner. Taken together, this study identifies a possible role for Gba1 in host response to an acute neurotropic infection and highlights the importance of exploring sex-dependent outcomes in Gba1-focused studies.

Ferritin is a protein principally known for its role in iron storage. We have previously shown that ferritin can bind high-molecular-weight kininogen (HK). Upon proteolytic cleavage by the protease kallikrein, HK releases the proinflammatory peptide bradykinin (BK) and other biologically active products, such as two-chain high-molecular-weight kininogen, HKa. At inflammatory sites, HK is oxidized, which renders it a poor substrate for kallikrein. However, oxidized HK remains a good substrate for elastase and tryptase, thereby providing an alternative cleavage mechanism for HK during inflammation. Here we report that ferritin can retard the cleavage of both native HK and oxidized HK by elastase and tryptase. Initial rates of cleavage were reduced 45-75% in the presence of ferritin. Ferritin is not a substrate for elastase or tryptase and does not interfere with the ability of either protease to digest a synthetic substrate, suggesting that ferritin may impede HK cleavage through direct interaction with HK. Immunoprecipitation and solid phase binding studies reveal that ferritin and HK bind directly with a Kd of 134 nM. To test whether ferritin regulates HK cleavage in vivo, we used THP-1 cells, a human monocyte/macrophage cell line that has been used to model pulmonary inflammatory cells. We observed that ferritin impedes the cleavage of HK by secretory proteases in stimulated macrophages. Furthermore, ferritin, HK, and elastase are all present in or on alveolar macrophages in a mouse model of pulmonary inflammation. Collectively, these results implicate ferritin in the modulation of HK cleavage at sites of inflammation.

Rheumatoid arthritis (RA) is a systemic and inflammatory disease that has been associated with an increased morbidity and mortality in cardiovascular disease (CVD). Low aerobic capacity is one of the strongest independent risk factors for CVD and all-cause mortality in the general population. In patients with longstanding RA, low aerobic capacity has been related with a worse cardiovascular profile and an increased risk of CVD mortality. As a consequence of this, low aerobic capacity might provide an additional risk factor for CVD in patients with RA. The aim of this thesis was to describe the associations between aerobic capacity and risk factors for CVD as well as disease activity in patients with early RA, and also the effects of intensive exercise therapy on traditional risk factors for CVD and disease activity in patients with longstanding RA. Paper I, a cross-sectional study including 67 patients with early RA, mean (SD) age 53.1 (14.4), assessments of aerobic capacity, CVD risk factors, disease activity and functional ability were taken. Data were analysed for the associations between aerobic capacity and CVD risk factors and disease activity. In paper II, an intervention study, including 13 patients with RA, median age (Q1-Q3) 57 (44-64) years, aerobic capacity, pulse wave analysis (PWA), CVD risk factors, and disease activity were analysed for changes after 10 weeks of intensive exercise therapy. Additional follow-up was made after 25 weeks. In paper I, the mean (SD) aerobic capacity was 31.6 (8.7) ml O2/kg/min. CVD risk factors and disease activity were all in favour of patients with higher aerobic capacity. In a multiple regression model, adjusted for age and sex, aerobic capacity was significantly associated with percent body fat (β=-0.502, 95%CI=-0.671;-0.333) and triglycerides (β=-2.365, 95%CI=-4.252;-0.479). In paper II, intensive exercise over ten weeks was shown to be a feasible method to significantly improve aerobic capacity (p=≤0.05), systolic blood pressure (p=≤0.01) and the number of tender joints (p=≤0.05). No detrimental effect on disease activity was recorded. This thesis adds further knowledge of aerobic capacity and its associations with CVD risk factors and disease activity in patients with RA. Also, intensive exercise therapy was a feasible intervention to improve CVD risk factors. To include assessment of aerobic capacity in regular clinical practice may improve patient management as well as patient outcome in patients with RA. / Bakgrund: Reumatoid artrit (RA, ledgångsreumatism) är en kronisk inflammatorisk sjukdom som i första hand angriper leder, men kan även påverka inre organ. Typiska symptom är ledsvullnad, smärta, morgonstelhet och nedsatt funktion i lederna. Patienter med RA har visat sig ha en ökad risk att insjukna i och avlida i hjärt- och kärlsjukdom. I den allmänna befolkningen har låg syreupptagningsförmåga (kondition) visat sig vara en av de starkaste riskfaktorerna för att insjukna i eller att avlida i hjärt- och kärlsjukdom. Tidigare studier har visat att patienter med RA kan ha låg kondition vilket kan utgöra en riskfaktor för hjärt- och kärlsjukdom även vid RA. Syfte: Syftet med denna avhandling var att beskriva sambanden mellan kondition och riskfaktorer för hjärt- och kärlsjukdom och sjukdomsaktivitet. Ett annat syfte var att studera hur intensiv cykelträning påverkar kondition, traditionella riskfaktorer och sjukdomsaktivitet hos patienter med RA. Metod: Studie I är en tvärsnittsstudie, bestånde av 67 patienter med tidig RA, som hade en medelålder på 53 år. De undersöktes avseende; kondition, riskfaktorer för hjärt- och kärlsjukdom och sjukdomsaktivitet för att analysera samband mellan dessa. Studie II är en träningsstudie, bestående av 13 patienter med RA, med en medianålder på 57 år. Kondition, riskfaktorer för hjärt- och kärlsjukdom och sjukdomsaktivitet analyserades för att se förändringar efter tio veckors intensiv cykelträning samt vid en uppföljning efter 25 veckor. Resultat: I studie I visade den studerade gruppen ett konditionsmedelvärde på 31.6 mL. Sambandsanalyser visade att högre kondition var relaterad till lägre grad av riskfaktorer för hjärt- och kärlsjukdom, samt lägre 10 års risk för hjärt- och kärlsjukdom och sjukdomsaktivitet. I studie II fann vi att tio veckors intensiv cykelträning kan vara en användbar metod för att förbättra kondition, blodtryck och antalet ömma leder. Ingen ökad sjukdomsaktivitet noterades. Slutsatser: Dessa studier bidrar med kunskap om samband mellan kondition och riskfaktorer för hjärt- och kärlsjukdom samt sjukdomsaktiviteten hos patienter med RA. De visar också att intensiv cykelträning kan vara en effektiv metod att förbättra kondition och blodtryck hos patienter med RA.

Indiana University-Purdue University Indianapolis (IUPUI) / Liver fibrosis is the result of different types of chronic liver diseases, such as cholestatic liver disease and nonalcoholic steatohepatitis, among others. Fibrosis, if left unchecked, may progress to the point of cirrhosis – permanently affecting liver function detrimentally and potentially leading to development of hepatocellular carcinoma. Inflammatory response following tissue injury is vital for the initiation of fibrosis; chronic inflammation results in abnormal tissue healing and promotes a pro-fibrogenic response. Activins are cytokines that have been identified as members of the TGFβ superfamily of growth and differentiation factors. Activin A and B, in particular, have been identified as having roles in the pathophysiology of liver disease, but have not been investigated thoroughly. We treated mice with concanavalin A, a potent T-cell mitogen with liver specificity when administered intravenously, and characterized the resulting response to liver injury and how activin A and B are modulated during this acute inflammatory phase. We showed that activin B is highly increased in circulation following inflammation, as well as locally in the liver as well as the spleen. We then neutralized activin A and B via neutralizing antibodies in our concanavalin A-induced liver injury model to determine if inhibition of these ligands may confer protective effects during the acute inflammatory response in liver. Neutralization of either activin A or activin B protected hepatocytes, improved liver function, and significantly reduced circulating cytokines following concanavalin A administration. Finally, we determined whether inhibition of activin A or B might prevent or reverse the development of liver fibrosis after disease has been established. We induced liver fibrosis in mice via the hepatotoxin carbon tetrachloride, and then treated with neutralizing antibodies while still maintaining carbon tetrachloride administration. Neutralization of activin A and B markedly reduced liver fibrosis, protected hepatocytes, and improved liver function. Our findings implicate both activin A and B as major players in the acute inflammatory response to liver injury, as well as during chronic injury and fibrogenesis, and demonstrate the therapeutic potential of targeting these ligands for the treatment of fibrosis in chronic liver diseases.