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| Author(s): |
Patrícia Passaglia
Total Authors: 1
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| Document type: | Doctoral Thesis |
| Press: | Ribeirão Preto. |
| Institution: | Universidade de São Paulo (USP). Faculdade de Medicina de Ribeirão Preto (PCARP/BC) |
| Defense date: | 2019-08-19 |
| Examining board members: |
Evelin Capellari Carnio;
José Carlos Farias Alves Filho;
Helio Cesar Salgado;
Maria José Campagnole dos Santos
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| Advisor: | Evelin Capellari Carnio |
| Abstract | |
Currently, it has been investigated the participation of sympathetic efferent component of inflammatory reflex in system immune modulation in inflammatory experimental models. This modulation involves: (a) the peripheral signal immune transmission for central nervous system (CNS) through afferent vagal activation by proinflammatory cytokines; (b) immune signal processing by nucleus tractus solitarius (NTS) and activation of others areas, such as the rostral ventrolateral medulla (RVLM) and the paraventricular nucleus of the hypothalamus (PVN); (c) the nerves splanchnic and splenic activation resulting in immunodepression. Angiotensin-(1-7) [Ang-(1-7)] has been pointed as important anti-inflammatory neuropeptide in a number of inflammatory models. However, a possible action of Ang-(1-7) on sympathetic efferent axis to inflammatory response control in endotoxemia has not been described in the literature. Thus, the aim of this study was to determine whether the Ang-(1-7) can modulate the systemic inflammatory response in endotoxemic animals via a central mechanism, and whether this effect is mediated by a sympathetic circuit. In this way, we used male Wistar rats (215-220 g) submitted to stereotaxic (for central administration), jugular vein cannulation (for endovenous administration) and femoral artery (for blood pressure and heart ratio measurement) surgeries. Furthermore, was performed a chemical sympathectomy induced by systemic administration of 6-OHDA (100 mg/Kg) for 24 h. Endotoxemia was induced by systemic administration of lipopolysaccharide (LPS) (1.5 mg/Kg) in accordance with experimental protocol assessed. LPS was induced increase in corticosterone and AVP plasma concentration and central Ang-(1-7) administration (0.3 nmol 2 ?L) was not able to change this effect.. We also observed that Ang-(1-7) central administration, via Mas receptor (A779, selective antagonist, 3 nmol 2 ?L) was able to attenuate serum and tissue (spleen and liver) of the tumor necrosis factor alpha (TNF-?), interleukin-1? (IL-1?), interleukin-6 (IL-6) and NO concentration LPS-induced and increased interleukin-10 (IL-10) and the chemical sympathectomy abolished this anti-inflammatory. Similar profile was observed in in vitro protocol where the LPS dose (1 ?g/mL, for 24 h) induced TNF-? synthesis and protein expression of inducible oxide nitric synthase (iNOS) enzyme, whereas these effects were attenuated by noradrenaline (NE; 0.1 ?M) stimulation in peritoneal macrophages culture. In a second in vivo protocol we verified that mean blood pressure was restored by Ang-(1-7) without affecting the tachycardia LPS-induced. When the effect of LPS treatment was analyzed, rings of thoracic aorta artery of endotoxemic rats, we observed a low resistance in response to NE and this effect was dependent on perivascular adipose tissue (PVAT) NO secretion and vascular hyperpolarization, while Ang-(1-7) central administration was able to restore the vascular responsiveness. In another in vitro protocol, using vascular smooth muscle cells (VSMC) culture we observed that NO and TNF-? PVAT production LPS-induced (for 1 h) may have caused decrease of calcium (Ca+2) cytoplasmatic concentration. Concomitant stimulation of NE and LPS stimulation have reduced proinflammatory effect of LPS on PVAT and increased intracellular Ca+2 concentration ([iCa+2]) in VSMC. Taken together, these data suggest that Ang-(1-7), via Mas receptor, controls the sympathetic component of inflammatory reflex and exerts anti-inflammatory effect on spleen, liver and PVAT resulting in vascular responsiveness and blood pressure recovery, wich could be responsible, at least in part, for the improvement in survival in rats treated with LPS (AU) | |
| FAPESP's process: | 14/22477-6 - Participation of angiotensin-(1-7) in the regulation of synthesis and release of vasopressin during endotoxemia |
| Grantee: | Patrícia Passaglia |
| Support Opportunities: | Scholarships in Brazil - Doctorate |