No description available.

Diss. (sammanfattning) Stockholm : Karol. inst., 2005. / Härtill 4 uppsatser.

Diss. (sammanfattning) Linköping : Linköpings universitet, 2005. / Härtill 4 uppsatser.

Conselho Nacional de Desenvolvimento CientÃfico e TecnolÃgico / CoordenaÃÃo de AperfeiÃoamento de Pessoal de NÃvel Superior / O influxo celular (IC) à sinÃvia participa na fisiopatologia da artrite reumatÃide (AR). Hà controvÃrsias sobre o papel do Ãxido nÃtrico (NO) na modulaÃÃo do influxo de neutrÃfilos para sÃtios inflamatÃrios, seja reduzindo ou estimulando-o. Esse trabalho investigou o efeito de inibidores de Ãxido nÃtrico sintase (NOS) sobre o IC agudo em animais submetidos à artrite ou peritonite induzida por zymosan (AZy ou PZy) ou lipopolissacarÃdeo (ALPS ou PLPS), bem como a participaÃÃo de leucotrieno B4 (LTB4) e da molÃcula de adesÃo intercelular -1 (ICAM-1). Ratos Wistar receberam 10-1000 micrograma de Zy ou 1-10 micrograma de LPS intra-articular (i.a.). Outros grupos receberam 1 mg de Zy ou 10 Âg de LPS intraperitoneal (i.p.). Camundongos selvagens ou geneticamente manipulados (knock out) para ICAM-1 (ICAM-1-/-) receberam 100 Âg de Zy i.a. ou i.p. Esquema dos prÃ-tratamentos (30 minutos antes da artrite ou peritonite): na AZy, L-NAME (1-30 mg/kg; i.p. ou 0,3-1 micromol; i.a), 1400W (1 mg/kg; i.p.) ou Aminoguanidina (Amino) (50 mg/kg; i.p.) em ratos e camundongos receberam L-NAME (3-10 mg/kg;i.p.) ou NG-nitro-L-arginia (Nitro) (50 mg/kg; i.p.). Na PZy, L-NAME (10-30 mg/kg; s.c. ou i.p.) ou 1400W (1 mg/kg; s.c.) foi administrado em ratos e camundongos receberam L-NAME (30 mg/kg; s.c.) ou Nitro (50 mg/kg; s.c.). Na ALPS, ratos receberam L-NAME (10-30 mg/kg; i.p) e, na PLPS, L-NAME (30 mg/kg; s.c.). Controles receberam veÃculo (grupos NT). ApÃs o sacrifÃcio, foram quantificados o IC e LTB4 nos lavados articulares e peritoneais. Na AZy (10-100 micrograma) em ratos, L-NAME (1-3 mg) reduziu o IC (47,4 - 76,6%), quando comparado aos animais NT (p<0,05). Na AZy 1mg, L-NAME (30 mg), 1400W (1 mg) e Amino (50 mg) diminuÃram o IC (57,4%, 74,8% e 76,6%) (p<0,05). L-NAME (0,3 micromol) i.a. tambÃm reduziu o IC (85,3%) (p<0,05). Semelhante aos ratos, camundongos prÃ-tratados com L-NAME (3-10 mg) ou Nitro (50 mg) apresentaram diminuiÃÃo do IC (67,6%, 53,8% e 39,5%) (p<0,05). Contrariamente, na PZy, L-NAME (10-30 mg) e 1400W (1 mg) aumentaram o IC (566,7%, 495,1% e 470,7%) em ratos e L-NAME (30 mg), em camundongos (155,8%) (p<0,05). Nesses, Nitro aumentou o IC, mas nÃo significativamente (p>0,05). L-NAME (10 mg) i.p. tambÃm aumentou o IC (747,6%) (p<0,05). Na ALPS, L-NAME (30 mg) diminuiu o IC nas duas doses de LPS (50,3% e 52,3%) (p<0,05). Na PLPS, L-NAME (30 mg) aumentou o IC (53,4%) (p<0,05). Os inibidores de NOS nÃo alteraram os nÃveis de LTB4. Animais ICAM-1-/- artrÃticos prÃ-tratados ou nÃo com Nitro apresentaram reduÃÃo do IC (57,8% ou 32,1%)(p<0,05). Nos ICAM-1-/- com peritonite prÃ-tratados ou nÃo com Nitro, houve uma reduÃÃo do IC (9,5% e 22,3%), mas nÃo significativa (p>0,05). O NO, particularmente o produzido pela NOSi, reduz o IC agudo na articulaÃÃo, enquanto que o incrementa no peritÃneo. Esse efeito à independente do estÃmulo, da espÃcie, da via de administraÃÃo e da liberaÃÃo de LTB4, alÃm de envolver cÃlulas residentes e/ou migradas. ICAM-1 parece participar do IC nesses modelos, especialmente na artrite, com o NO modulando sua expressÃo na peritonite. / Cell influx (CI) to synovium participates in physiopathology of rheumatoid arthritis (RA). There are controversies about the nitric oxide (NO) action in modulation of neutrophil influx to inflammatory sites, with NO decreasing or increasing it. This study investigated the effect of nitric oxide synthase (NOS) inhibitors on acute CI in animals submitted to arthritis or peritonitis induced by zymosan (ZyA or ZyP) or lipopolysaccharide (LPSA or LPSP), and the participation of leukotriene B4 (LTB4) and intercellular adhesion molecule -1 (ICAM-1). Rats Wistar received Zy (10-1000 micrograme) or LPS (1-10 micrograme) intraarticular (i.a.). Other groups received Zy (1 mg) or LPS (10 Âg) intraperitoneal (i.p.). Wild or ICAM-1-deficient (ICAM-1-/-) mice received Zy (100 Âg) i.a. or i.p. Animals were pre-treated (30 minutes before arthritis or peritonitis): in ZyA, rats received L-NAME (1-30 mg/kg; i.p. or 0.3-1 micromol; i.a), 1400W (1 mg/kg; i.p.) or Aminoguanidine (Amino) (50 mg/kg; i.p.). Mice received L-NAME (3-10 mg/kg;i.p.) or NG-nitro-L-arginine (Nitro) (50 mg/kg; i.p.). In ZyP, L-NAME (10-30 mg/kg; s.c. or i.p.) or 1400W (1 mg/kg; s.c.) was administrated in rats and mice received L-NAME (30 mg/kg; s.c.) or Nitro (50 mg/kg; s.c.). In LPSA, rats received L-NAME (10-30 mg/kg; i.p) and, in LPSP, they received L-NAME (30 mg/kg; s.c.). Controls received vehicle (NT groups). After sacrifice, CI was counted and LTB4 was measured in articular and peritoneal exudates. In ZyA (10-100 Âg), L-NAME (1-3 mg) reduced CI (47.4 â 76.6%) as compared to NT animals (p<0.05). In ZyA (1mg), L-NAME (30 mg), 1400W (1mg) and Amino (50 mg) reduced CI (57.4%, 74.8% and 76.6%, respectively) (p<0.05). L-NAME (0.3 Âmol) i.a. also reduced CI (85.3%) (p<0.05). Similarly, L-NAME (3-10 mg) or Nitro (50 mg) pre-treated mice showed a CI reduction (67.6%, 53.8% and 39.5%) (p<0.05). In contrast, in ZyP, L-NAME (10-30 mg) and 1400W (1 mg) increased CI (566.7%, 495.1% and 470.7%, respectively) in rats and L-NAME (30 mg) in mice (155.8%) (p<0.05). In mice, Nitro increased CI, but not significantly (p>0.05). L-NAME (10 mg) i.p. also increased CI (747.6%) (p<0.05). In LPSA, L-NAME (30 mg) decreased CI in two LPS doses (50.3% and 52.3%) (p<0.05). In LPSP, L-NAME (30 mg) increased the influx (53.4%) (p<0.05). NOS inhibitors didnât change LTB4 levels. Arthritic pre-treated or not with Nitro ICAM-1-/- animals showed a CI reduction (57.8% or 32.1%)(p<0.05). In peritonitis, pre-treated or not with Nitro ICAM-1-/- showed a CI reduction (9.5% and 22.3%), but not significantly (p>0.05). NO, especially that produced by iNOS, reduces the acute CI in articulation while increases it in the peritoneum. This effect is independent of stimulus, species, route of administration and LTB4 liberation. Beyond, it involves resident and/or migrated cells. ICAM-1 appears to participate in CI in these models, especially in arthritis. Besides, NO modulates the expression of ICAM-1 in peritonitis.

Les récepteurs couplés de protéines G (RCPG) sont des capteurs biologiques polyvalents responsables de la majorité des réponses cellulaires aux hormones et neurotransmetteurs ainsi que des sens de la vue, de l'odorat et du goût. La transduction des signaux est associée à un ensemble de changements dans la structure tertiaire des récepteurs entraînant l'activation de partenaires intracellulaires dont les protéines G. La dimérisation est un élément central du mode de fonctionnement des RCPG ; cependant, son influence sur la façon dont le signal est transmis est encore mal définie.Nous avons utilisé ici le récepteur BLT1 du leucotriène B4 comme modèle afin d'analyser les changements de conformation au cours de l'activation. Pour cela, nous avons produit le récepteur suivant une approche qui consiste à l'exprimer dans les corps d'inclusion bactériens puis à le renaturer à l'aide de détergents et/ou surfactants originaux. L'accès au récepteur purifié nous a permis de montrer que la protéine G induit une asymétrie dans les changements de conformation au sein de l'homodimère de BLT1. De plus, nous avons pu établir que l'activation de la protéine G se fait essentiellement par le protomère ayant fixé l'agoniste (cis-activation). Enfin, nous avons montré que la forme monomérique du récepteur est parfaitement capable d'induire l'activation de la protéine G, même si le dimère apporte une modulation de la réponse. Ceci indique qu'un monomère de récepteur possède tous les déterminants moléculaires nécessaires à la transmission du signal. L'ensemble de ces résultats apporte un éclairage nouveau sur la façon dont les dimères de RCPG fonctionnent et peuvent moduler la réponse biologique. / G-protein coupled receptors are versatile biological sensors that are responsible for the majority of cellular responses to hormones and neurotransmitters as well as for the sense of sight, smell and taste. Signal transduction is associated with a set of changes in the tertiary structure of the receptor that are recognized by the associated intracellular partners, in particular the G proteins. There is compelling evidence that GPCR can assemble as dimers but the way these assemblies function at the molecular level is still under investigation.We used here the leukotriene B4 receptor BLT1 as a model to analyze the conformational changes occurring during activation. To this end, we first produced the receptor in E. coli inclusion bodies and subsequently folded it back to its native state in vitro using original membrane mimetics. Using the purified dimeric receptor, we showed that (i) the G protein induces an asymmetric arrangement of the BLT1 homodimer where each of the protomers is in a distinct conformation, and (ii) the G protein is cis-activated, i.e. the protomer that binds the agonist also activates Gα. Finally, we brought evidence that, although the dimer fully activates its G protein partner, the monomer has per se all the molecular determinant for an efficient functioning. All these data are original evidence that sheds light into the way GPCR dimers are activated and in turn modulate G protein-mediated signaling.

Gegenstand der Dissertationsschrift ist die Untersuchung des Effektes einer Hemmung der Leukotrienbiosynthese auf die Entwicklung des Schädel-Hirn-Traumas (SHT) nach experimenteller fokaler Kontusionsverletzung im Rattenmodell. Die Ergebnisse der Arbeit wurden im Jahre 2011 in einer Publikation veröffentlicht. Das SHT ist eine schwerwiegende globale Erkrankung mit hoher Inzidenz und Mortalität. Diese führt zu hohen Kosten für das Gesundheitssystem, zum einen durch die akute Behandlung im Krankenhaus, zum anderen durch die sich daran anschließenden rehabilitativen Maßnahmen. Nach der primär biomechanischen Verletzung des Hirns, die nicht beeinflussbar ist, bietet die anschließende sekundäre Hirnschädigung aufgrund verschiedener Stoffwechselprozesse Angriffspunkte für eine (medikamentöse) Therapie des SHT. Die sekundären Hirnschäden werden maßgeblich durch die Entwicklung eines perikontusionellen Hirnödems und dem daraus resultierenden Anstieg des intrakraniellen Druckes beeinflusst. Wie in vorangegangenen Untersuchungen gezeigt werden konnte, kam es nach experimentellem SHT zu einem signifikanten Anstieg der Leukotrienwerte im Liquor von Ratten. Dies warf die Frage nach der Rolle der Leukotriene (LT) im posttraumatischen Hirnstoffwechsel bezüglich der Ödementwicklung auf. Ziel dieser Arbeit war der Nachweis einer direkten Beteiligung von Leukotrienen an der sekundären Hirnschädigung und das Aufzeigen eines möglichen therapeutischen Zuganges durch Substitution von Leukotrienbiosynthesehemmern. Dafür wurde bei adulten Ratten ein fokales SHT induziert. Anschließend wurden in zwei Therapiegruppen zwei unterschiedlich wirkende Leukotrieninhibitoren mehrmalig oral verabreicht und die Ausprägung des SHTs nach 24 bzw. 72 Stunden mittels Magnetresonanztomographie (MRT) und immunhistochemischen Aufarbeitung der Hirne mit einer nicht therapierten Kontrollgruppe verglichen. Bei einem dieser LT-Inhibitoren handelte es sich um ein Weihrauchpräparat, das als Nahrungsergänzungsmittel bereits zu erhalten ist und somit auch potentiell am Menschen zur Anwendung kommen kann. Die Ergebnisse waren vielversprechend und zeigten in beiden Therapiegruppen ein verringertes Kontusionsvolumen im MRT und immunhistochemisch einen geringeren Verlust von Neuronen im perikontusionellen Bereich. Somit scheinen Leukotriene einen Anteil an den sekundären Schädigungsprozessen nach SHT zu tragen. Weitere Untersuchungen, vor allem bezüglich eines eventuell verbesserten klinischen Outcome durch Leukotrienbiosynthesehemmung, erscheinen sinnvoll um den potentiellen Einsatz von LT-Synthesehemmstoffen in der Therapie des SHT in Erwägung ziehen zu können.:1. Abkürzungsverzeichnis 2. Bibliographische Beschreibung 3. Einleitung: Schädel-Hirn-Trauma 3.1. Einteilung 3.2. Epidemiologie 3.3 Klinik und Therapie 3.4 Posttraumatisches Hirnödem 3.5 Experimentelles Schädel-Hirn-Trauma 3.6 Leukotriene, MK886 und Boscari 4. Originalpublikation 5. Zusammenfassung der Arbeit 6. Referenzen 7. Anlagen 7.1 Erklärung über die eigenständige Abfassung der Arbeit 7.3 Danksagung

No description available.

Electron crystallography of two-dimensional crystals is a structure-determination method well suited to the study of membrane protein structure-function. Two-dimensional crystals consist of ordered arrays of protein within reconstituted lipid bilayers, an arrangement that mimics the natural membrane environment. In this work we describe our recent progress in the use of this method with three different proteins, each providing a window into a separate paradigm in the electron crystallographic pipeline. Specific crystallization conditions for human leukotriene C₄ synthase (LTC₄S) have previously been determined, but our continued refinement of purification and crystallization has identified a number of additional parameters that greatly affect crystal size and quality, and we have developed a protocol to rapidly and reproducibly grow large, non-mosaic crystals of LTC₄S. The human gamma-glutamyl carboxylase (GGCX) has also been crystallized, but is sensitive to cryo-EM sample preparation conditions and we present here the successful reproduction of crystallization and refinement of cryo-EM sample preparation conditions. Lastly, we describe our crystallization screens with the Vibrio cholerae sodium-pumping NADH:ubiquinone reductase complex (Na⁺-NQR), and identify the factors critical to membrane reconstitution of the complex, a necessary first step towards crystallization. We also describe a semi-quantitative crystal screening protocol we have developed that provides quick and accurate method to assess two- dimensional crystallization trials, and discuss some general observations in optimization of membrane protein purification and two-dimensional crystallization for electron crystallography.

<p>Uvod: Pu&scaron;enje predstavlja jedan od najznačajnijih uzroka lo&scaron;e kontrole astme, zbog iritativnog dejstva duvanskog dima na disajne puteve i razvoja rezistencije na inhalatorne kortikosteroide. Stoga je pu&scaron;ače sa astmom često potrebno lečiti kombinovanom antiinflamatornom terapijom, iako je efikasnost ovakvog tretmana jo&scaron; uvek nedovoljno ispitana. Cilj: utvrditi efikasnost kombinovane antiinflamatorne terapije: inhalatorni kortikosteroidi (ICS) u kombinaciji sa dugodelujućim beta2-adrenergičkim agonistima (DDBA) u odnosu na ICS u kombinaciji sa antagonistima leukotrijenskih receptora (ALTR) u postizanju dobre kontrole astme, pobolj&scaron;anju kvaliteta života i plućne funkcije kod pu&scaron;ača u odnosu na nepu&scaron;ače sa astmom. Metod: Pacijenti starosti od 18-50 godina sa astmom (&ge;6meseci), FEV1 većim od 60%, podeljeni su u grupu nepu&scaron;ača &ndash;NP (N=60) i aktivnih pu&scaron;ača &ndash;PU (&le;2 &ge;15 p/g i &ge;10&le;40 cigareta na dan; N=60). Obe grupe su randomizovane u jednu od dve, otvorene, terapijske grupe (ICS uz dodatak DDBA ili ALTR) u trajanju od 24 nedelje. Rezultati: u svakoj od 4 randomizovane grupe (NP-DDBA, NP-ALTR, PU-DDBA, PU-ALTR) je bilo po 30 pacijenata. Tokom 24 nedelje, PU su imali lo&scaron;ije kontrolisanu astmu od NP (p=0,02), bez ralizke između DDBA vs ALTR (0,677 vs 0,634). Konstantno dobru kontrolu astme (ACQ&lt;0,75) tokom 24 nedelje je postiglo 48% NP i 32% PU (p=0,094), bez značajne razlike u odnosu na terapiju (DDBA vs ALTR; p=1,000). NP su imali bolji kvalitet života od PU, ali razlika nije dostigla statističku značajnost (p=0,056)- Kod NP i kod PU u oba modaliteta lečenja (LABA, ALTR) je do&scaron;lo do statistički značajne promene srednjeg skora AQLQ (p&lt;0,001). Povećanje FEV1(%) je bilo statistički značajno i u grupi NP i u grupi PU (p=0,001 vs. p=0,002). Kod pacijenata lečenih DDBA povećenje FEV(%) je bilo na nivou p=0,001, dok je u grupu ALTR bilo na nivou p=0,005. Multivarijantnom analizom je utvrđeno da su nezavisni faktori postizanja dobre kontrole astme BMI&ge;24, nepu&scaron;ač, FEV1&ge;90%, ACQ&le;2,2 i AQLQ&ge;4,2 Zaključak: Kombinovana antiinflamatorna terapija je efikasnija kod NP u odnosu na PU, dok su u populaciji aktivnih pu&scaron;ača, oba dodatna leka (DDBA, ALTR) bila podjednako efikasna u pobolj&scaron;anju kontrole astme, kvaliteta života i plućne funkcije.</p> / <p>Introduction: Smoking is one of the major causes of a bad asthma control, due to negative effects of the tobacco smoke on the airways and consequent resistance to inhalant corticosteroids. Smoking asthmatics should therefore often be treated with combined anti-inflammatory therapy, although the efficacy of this treatment regimen has not been completely examined yet. Objective: To examine the efficacy of the combined anti-inflammatory therapy (ICS combined to LABA vs.LTRA) in achieving a good asthma control, better quality of life and improved lung function in smoking vs. nonsmoking asthmatics. Method: The patients at 18-50 years of age with asthma (&ge;6 months), FEV1 &gt; 60%, were subclassified into the group of nonsmokers &ndash;NS (N=60), and the group of active smokers - SM (&le;2 &ge;15 p/g and &ge;10&le;40 cigarettes a day; N=60). Both groups were randomized into one of the two open therapy groups (ICS combined to DDBA or ALTR), receiving the selected treatment for 24 weeks. Results: Any of the four randomized groups (NS-LABA, NS-LTRA, SM-LABA, SM-LTRA) consisted of 30 patients. During the 24-week period, SM had a worse control of their asthma than NS (p=0.02), but no difference was registered between DDBA vs. ALTR therapy subgroups (0.677 vs. 0.634). Over the 24-week period, a constantly good asthma control (ACQ&le;0,75) was achieved by 48% of NS and 32% of SM (p=0.094), and no significant difference related to the applied therapy regimen (LABA vs. LTRA; p=1.000). NS had a better life quality than SM, but this difference remained statistically insignificant (p=0.056). Both the NS and the SM group in either treatment modality (LABA, ALTR) had a statistically significant change of the AQLQ score (p&lt;0.001). FEV1 (%) improvement was statistically significant t in both the NS and the SM group (p=0.001 vs. p=0.002). The LABA and LTRA treated patients had their FEV (%) improvement at the level of p=0.001, and p=0.005 respectively. The multivariate analysis has established the following independent factors of a good asthma control: BMI&ge;24, nonsmoker, FEV1&ge;90%, ACQ&le;2.2, and AQLQ&ge;4.2. Conclusion: The combined anti-inflammatory therapy is more efficient in NS than in SM asthmatics, while in the population of active smokers, both additional drugs (LABA, LTRA) were equally efficient in improving asthma control, life quality, and lung function.</p>

O diabetes tipo 1 (DT1) é uma doença metabólica associada a uma inflamação sistêmica de baixo grau, responsável por importantes co-morbidades associadas. Nosso grupo demonstrou que esta inflamação depende dos níveis plasmáticos aumentados de leucotrieno-B4 (LTB4), o qual estimula o eixo Myd88/STAT1 amplificando a resposta dos receptores TLR/IL1&#946 em macrófagos. Isso caracteriza o programa pró-inflamatório M1 nestas células, que requer energia proveniente da glicólise e produz substancias tóxicas como espécies reativas de oxigênio (ROS) e óxido nítrico (NO). Isto pode ser minimizado pela respiração mitocondrial desacoplada à síntese de ATP no metabolismo lipídico. Assim, na primeira parte do trabalho os macrófagos de camundongos (C57Bl/6) DT1, expressaram níveis elevados de marcadores de oxidação de ácidos graxos, o que não foi observado em macrófagos de camundongos diabéticos tratados com o antagonista de LTB4 (u75302). Além disso, o u75302 também reduziu a expressão aumentada de CD36, receptor envolvido na captação de lipídios, assim como aumento de lipídios intracelulares nestas células. Os elevados níveis de triglicérides e ácidos graxos presentes no plasma dos diabéticos também foram reduzidos pelo antagonista u75302, e isso foi consistente com o aparecimento de marcadores de lipólise (Prdm16 e Fgf21) no tecido adiposo branco destes animais. Da mesma forma, u75302 reduziu o consumo de oxigênio dos macrófagos de animais diabéticos. Isso foi consistente com os resultados obtidos em macrófagos de camundongos diabéticos deficientes da UCP1, os quais apresentaram maior peso corporal, maior massa de gordura e metabolismo mitocondrial mais baixo do que diabéticos WT. A perda de gordura também foi recuperada pelo tratamento com u75302 indicando o envolvimento do LTB4 na perda de adiposidade e dislipidemia em DT1. Na segunda parte do trabalho, confirmamos a participação dos leucotrienos na inflamação sistêmica em DT1 induzida por estreptozotocina. Camundongos (129SvE) diabéticos apresentaram níveis sistêmicos elevados das citocinas e este aumento não ocorreu em 129Sve deficientes da enzima 5-lipoxigenase (5LO-/-), responsável pela síntese de leucotrienos. A freqüência de monócitos pró-inflamatórios (CD11b&#43Ly6ChighLy6G-) circulantes estava aumentada em camundongos diabéticos WT mas não nos 5LO-/-. Macrófagos peritoneais residentes de camundongos diabéticos também apresentaram um fenótipo semelhante ao M1 classicamente ativado (alta expressão de Nos2 e Stat1, e alta produção de NO), que não foi revertido com o estímulo de IL4 in vitro ou in vivo. Por outro lado, os macrófagos dos 5LO-/- diabéticos apresentaram o fenótipo de macrófagos M2 alternativamente ativados (alta expressão de Ym1 e Arg1, e alta atividade de arginase). Os animais WT diabéticos tiveram cicatrização deficiente que se correlacionou com uma baixa freqüência de macrófagos M2 (CD45&#43F4/80&#43CD206&#43) nas lesões cutâneas comparado com os demais grupos. Juntos, estes dados sugerem que no DT1 os leucotrienos contribuem para a inflamação sistêmica e reprogramação dos monócitos e macrófagos para perfil inflamatório e isto está associado com aumento do metabolismo energético nestas células. Estas alterações induzidas nos macrófagos pelos níveis elevados de leucotrienos, particularmente LTB4, se correlacionam com a cicatrização deficiente, com a perda de gordura e hiperlipidemia nos camundongos DT1, sugerindo que o LTB4 possa ser um alvo terapêutico no diabetes. / Type 1 diabetes (T1D) is a metabolic disease associated to systemic low grade inflammation, which has an important role in co-morbidities. Our group showed that this inflammation depends on the high systemic levels of leukotriene-B4 (LTB4), which stimulateds MyD88/Stat1 axis, amplifying TLR/IL1&#946 response in macrophages. This characterizes pro inflammatory M1 program, which requires energy from glycolysis, and produces harmful molecules, such as reactive oxygen species (ROS) and nitric oxide (NO). This can be mitigated by mitochondrial respiration uncoupled to ATP synthesis in lipid metabolism. Therefore, in the first part of this study, macrophages from T1D mice (C57Bl/6) expressed high levels of fatty acid oxidation markers, which was not observed in macrophages from T1D mice treated with LTB4 receptor antagonis, u75302. Moreover, u75302 also reduced the high expression od CD36, a receptor involved in lipids uptake, and also reduced intracellular lipids in these cells. The high levels of triglycerides in diabetic plasma were reduced by u75302, and this is consistent with lipolysis markers (Prdm16 and Fgf21) in white adipose tissue of these mice. This was also consistent with results obtained in macrophages from diabetic UCP1 deficient mice, which had higher body weight and lower mitochondrial metabolism then WT diabetics. Fat loss was also recovered by u75302 treatment, indicating an involvement of LTB4 in adiposity loss and dyslipidemia in T1D. In the second part of this study, we confirmed leukotrienes participation in systemic inflammation in T1D streptozotocin-induced. T1D mice (129SvE) increased systemic levels of cytokines, which was not observed in T1D 5-lipoxygenase deficient mice (5LO-/-).The frequency of pro inflammatory monocytes (CD11b&#43Ly6ChighLy6G-) was increased in WT diabetic mice, but not in 5LO-/-. Resident peritoneal macrophages in diabetics had a phenotype similar to M1 classically activated (Nos2 and Stat1 highly expressed, and high production of NO), which was not reversed by IL-4 stimulation in vitro and in vivo. On the other hand, macrophages from diabetic 5LO-/- had a phenotype M2 alternatively activated (Ym1 and Arg1 highly expressed, and high arginase activity). WT diabetic mice had a defective wound healing, which was related to low frequency of M2 (CD45&#43F4/80&#43CD206&#43) macrophages in cutaneous wounds, compared to the other groups. All together, our data suggest that in T1D leukotrienes induce systemic inflammation, and reprogram pro inflammatory phenotype in monocytes and macrophages, and this is related to increased energetic metabolism in these cells. These alteration in macrophages due to leukotrienes effects, mainly LTB4, are correlated to defective healing, with fat loss, and dyslipidemia in T1D mice, suggesting that LTB4 can be a therapeutic target in diabetes.