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Inflammation Session 04 − Inflammation 04.001 Nitroxides regulate protein phosphorylation linked to NOX2 complex activity in neutrophils: prototype of a new anti-inflammatory. Ribeiro ACG1, Chavasco LS1, Santos GB1, Cardoso MHM2, Brigagão MRPL1 1UNIFAL − Ciências Exatas, 2UNIFAL − Farmácia Introduction: Reactive oxygen and nitrogen species (ROS/RNS) released by neutrophils through the Nox2 complex are directly associated with the deleterious actions arise during inflammation processes. Nitroxides are synthetic antioxidants that have been used to protect animal tissues from oxidative/nitrosative damage. In this work, 4-hydroxy 2,2,6,6 tetrametilpiperidiniloxil (Tempol) and 2,2,6,6-tetramethyl-1-piperidinyloxy (Tempo) were used to investigate the nitroxide ability to regulate neutrophil protein kinase and phosphatase activities. Also, this modulatory post-translational event was explored directly associated to Nox2 activity. Methods: Inflammatory neutrophils were elicited from mice peritoneal cavity, incubated with nitroxides and then stimulated with phorbol (PMA) or chemotatic peptide (fMLP). Superoxide anion production release was determined spectophotometrically through cytocrome c reduction (550 nm). Neutrophil protein phosphorylation linked to Nox2 activation was evaluated by dot blotting. The kinase activity was assessed by luminescent assays (Kinase-Glo® Luminescent Assays) and the phosphatase activity was analyzed by spectrometric assays (Bioclin® Alkaline Phosphatase Test). Results and Discussion: The results suggest that nitroxides inhibit •- the production of O2 by Nox2 decreasing the phosphorylation of neutrophil proteins elicited by PMA or fMLP, justified by the inactivation of protein kinase and activation of protein phosphatase. Therefore, the nitroxides are possible prototypes of a new class of anti-inflammatory compounds. Bibliography: BABIOR, B.M, Curr Opin Immunol, v.16, p.42, 2004. License authorization number of animal ethic committee: 205/2009. Supported by: CNPq-INCT of Processos Redox in Biomedicina-Redoxoma., FAPEMIG. Thanks: UNIFAL-MG, CNPq-INCT of Processos Redox in Biomedicina-Redoxoma, FAPEMIG 04.002 Periodontitis induces functional alterations in rat aorta. Campi P1, Ceravolo GS1, Martins Porto R1, Maia-Dantas A1, Yamamoto, M1, Teixeira SA1, Carvalho MHC1, Herrera BS2, Costa SKP1, Spolidório LC3, Muscará MN1 1ICB-USP Farmacologia, 2FO-UNESP − Patologia, 3UNESP − Patologia Introduction: Periodontitis (P) is a chronic disease characterized by impairment of the periodontal attachment apparatus and bone loss secondary to the intense inflammatory reaction of the host to bacteria. Based on emerging evidences showing that P can affect cardio-circulatory parameters, in this study we evaluated the effects of P on rat blood pressure (BP) and on the “in vitro” reactivity of aorta. Methods: The experimental protocol was approved by the CEEA-ICB (protocol 154, fls. 24, livro 2). Male Wistar rats (180-200 g) received daily oral doses of either etoricoxib (ET; 10 mg/kg) or L-NAME (LN; dissolved in the drinking water at 200 mg/L). On the 3rd.-day treatment, the rats had unilateral (first lower molar) ligature-induced periodontitis; sham (Sh) animals had the ligature placed and immediately removed. After 7 days, the rats were killed and thoracic aorta rings (4 mm length) were prepared and mounted for measurement of isometric tension in isolated tissue baths containing Krebs solution bubbled with O2/CO2, (95/5%) at 37ºC. Dose- tension curves to cumulative noradrenaline (NA) and acetylcholine (ACh; after NA pre- contraction) were obtained. Tail-cuff blood pressure (BP) was measured in all the animals before starting the treatments and 6 days after the ligature procedure. Results: Ligature- induced P had no effect on BP. Both LN and ET treatments resulted in significant BP elevation, but no differences were observed between Sh and P rat responses. The “in vitro” maximum contractile response (Emax) to NA was higher in aorta rings from P animals in comparison with Sh (1.67 ± 0.03 vs. 0.67 ± 0.01g, p<0.001); however, this pattern was reversed when the endothelial layer was rubbed off the rings (Sh: 2.50 ± 0.02 vs. P: 3.07 ± 0.04g, p<0.001). No differences in NA pA2 were observed between Sh and P groups, either in the presence or absence of endothelium. ET treatment resulted in higher NA Emax in aorta from Sh animals (0.67 ± 0.01g vs. 2.40 ± 0.01g, p<0.001), while LN had no significant effects. Both ET and LN treatments significantly lowered NA Emax in aorta from P rats (0.950 ± 0.009g and 1.095 ± 0.003g vs. 1.66 ± 0.03g, p<0,001, respectively). ACh Emax was not different between P and Sh rats and, in both groups, LN treatment lowered ACh Emax (P: 65.1 ± 8.2 vs. 101.9 ± 3.1g, p<0.001; Sh: 56.4 ± 10.6 vs. 97.5 ± 2.2g, p<0,01) and augmented ACh pA2 (P: 7.3 ± 0.1 vs. 6.4 ± 0.1, p<0.01; Sh: 7.5 ± 0.1 vs. 6.6 ± 0.3, p<0.05). ET treatment had no effect on aorta rings from Sh rats, but significantly reduced ACh Emax in aorta rings from P animals (83.9 ± 4.5vs.101.9 ± 3.1%,p<0,05) without changes in ACh pA2 values. Discussion: Based on the above shown results, we can suggest that despite unilateral periodontitis is not enough to induce changes in BP in rats (even under NOS or COX-2 inhibition), endothelial dysfunction secondary to the oral disease is evident from the hyperresponsiveness pattern of aorta rings to NA and the complete reversal of this response by removal of the endothelial layer. In addition, the endothelium-dependent vasorelaxant activity of ACh is significantly dependent on COX-2, which supports a major role for prostacyclin in the maintenance of vascular tone homeostasis during the course of periodontitis. Financial support: CNPq, FAPESP, CAPES. 04.003 Effect of ovariectomy on LPS-induced acute lung inflammation in female mice. Gimenes- Júnior JA1, Ligeiro de Oliveira AP2, Vitoretti LB1, Domingos HV1, Oliveira-Filho RM1, Vargaftig BB1, Tavares de Lima W1 1ICB-USP − Pharmacology, 2ICB-USP − Immunology Introduction: Acute respiratory distress syndrome (ARDS) is a multifactorial disease characterized by acute lung injury, severe hypoxemia, polymorphonuclear cells infiltration and lung edema. Lipopolysaccharides (LPS) from Gram-negative bacteria wall induce acute lung inflammation. Studies from our laboratory showed that female sex hormones (FSH) may exert protective or deleterious effect on Th2 lung inflammation, depending on the levels of FSH at the time of the sensitization to antigen. In this study, we investigated the role exerced by FSH on Th1 lung inflammation induced by LPS. Methods: Seven days after ovariectomy (OVx), female mice (c57Bl/6, n = 5–8/group) were subjected to intranasal instillation of LPS (100 μg/ml, 1 μl/g) or saline (0.9%, 1 μl/g). Twenty-four h thereafter, the animals were euthanized and the cells present in bronchoalveolar lavage (BAL), blood and bone marrow were quantified. Total cell countings were made in Neubauer chambers; differential countings were made upon optical microscopy. Otherwise intact animals were subjected to the same procedures and served as controls (Sham-OVx group). The experiments used in this study were approved by the local Ethics Committee on Animal Experimentation (Certification no. 113, 2009). Results and conclusion: The removal of the ovaries per se did not alter the total number of cells recovered in BAL compared with the control group (OVx: 13 ± 2 vs Sham-OVx: 23 ± 5 x 104 cells). Moreover, LPS increased the total number of cells in both OVx (194 ± 14) and in Sham-OVx groups (127 ± 14 x 104 cells) regarding their respective controls and the basal groups (14 ± 2 x 104 cells). Also, the increase in total cells observed in the OVx+LPS group was significant when compared with Sham-OVx+LPS. We observed an increase in neutrophils and lymphocytes in OVx+LPS (respectively, 146 ± 13 and 24 ± 1 x 104 cells) and in Sham- OVx+LPS (respectively 86 ± 12 and 13 ± 3 x 104 cells) as compared to the untreated groups (OVx: respectively 0.3 ± 0.1 and 3 ± 0.8 / Sham-OVx: respectively 1 ± 0.8 and 3 ± 0.9 x 104 cells). Furthermore, the group OVx+LPS showed a significant increase in the number of these cells as compared to the Sham-OVx group. No changes were observed in the number of macrophages in the lung. OVx induced a fall in bone marrow cells (OVx: 91 ± 30; Sham-OVx: 199 ± 28 x 105 cells). After instillation of LPS this reduction was exacerbated in the OVx group (50 ± 9) compared to Sham-OVx+LPS (212 ± 34 x 105 cells). No changes in the circulating leukocyte countings were detected among the groups. These data suggest that female sex hormones attenuate the LPS-induced lung inflammation. Financial support: FAPESP 09/52782-7 04.004 Initial characterization of toll-like receptor (TLR)4 signaling pathway on pollutant-induced increased neonate mice susceptibility to asthma. Santos KT1, Florenzano J1, Peron JPS2, Muscará MN1, Rizzo LV2, Costa SKP1 1ICB-USP − Farmacologia, 2ICB-USP − Imunologia Introduction: Low air quality, by traffic pollution, has been linked to increased prevalence of allergic diseases in susceptible individuals such as children (Bråbäck et al., Environ Health, 16(8):17;2009). Supporting this evidence, we have recently shown a mouse model of increased asthma susceptibility by using a chemical agent (e.g. 1,2-naphthoquinone; 1,2-NQ) commonly found in diesel exhaust particles (DEP; Santos et al., 41° SBFTE: Eventus. p.17;2009). Objective: This study was designed to characterize the mechanism pathway of 1,2-NQ-evoked increased asthma susceptibility in neonate mice by targeting the toll-like receptor (TLR)4, since these receptors have been involved in DEP-induced airway inflammation DEP (Williams et al., J Allergy Clin Immunol.,119(2):488-97;2007). Methods: Both C57BL/6 wild type (WT) and C57BL10/ScCr natural mutant of TLR4 and IL-12 (MT) neonates mice were used under the approved animal use protocol (ICB/USP: n.
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