Role of the autonomic nervous system in the systemic inflammatory response modulation in unanesthetized rats

Author(s)

Fernanda Brognara Penteado Dias

• Document type: Doctoral Thesis
• Press: Ribeirão Preto.
• Institution: Universidade de São Paulo (USP). Faculdade de Medicina de Ribeirão Preto (PCARP/BC)
• Defense date: 2021-02-03

Examining board members

Helio Cesar Salgado; Fernando Silva Carneiro; Eduardo Moacyr Krieger; Fernanda Luciano Rodrigues

• Advisor: Helio Cesar Salgado

Abstract

Both branches of the autonomic nervous system (parasympathetic and sympathetic) have been associated with the regulation of inflammation. However, there is much to be investigated. In order to explore the role of the autonomic nervous system in the systemic inflammatory response modulation, the present study evaluated: (i) the effects of parasympathetic activation in unanesthetized endotoxemic rats using the aortic depressor nerve electrical stimulation; (ii) the effects of reflex sympathetic activation using the bilateral carotid occlusion (BCO), a physiological approach which involves the baroreflex and chemoreflex mechanisms; (iii) the influence of the baroreceptors and peripheral chemoreceptors, in the systemic inflammatory response, through selective surgical denervation. Male Wistar Hannover rats were used in all protocols, and the systemic inflammation was induced by lipopolysaccharide (LPS) administration. Before start the main protocols, a study of the LPS doses was conducted. Four different doses were tested intravenously: 0.06 mg/kg; 20 mg/kg; 30 mg/kg; and 40 mg/kg. All doses examined induced tachycardia over time, but only the lowest dose (0.06 mg/kg) reduced the arterial pressure, as generally seen in systemic inflammation. In addition, LPS decreased baroreflex sensitivity and changed the autonomic balance regardless of the dose used. Therefore, the next protocols were conducted using 0.06 mg/kg (i.v.) of LPS in order to mimic better the classic hemodynamic responses observed during inflammation. In both protocols, blood samples were collected over 360 min after LPS administration to analyze the cytokines levels in different moments, and all the experiments were performed in unanesthetized rats. In the protocol comprising the parasympathetic activation, the baroreflex was successfully stimulated but was unable to attenuate the increase in plasma cytokines induced by LPS at any of the evaluated moments. Moreover, the autonomic imbalance and the baroreflex sensitivity reduction induced by LPS were not prevented by the baroreflex activation. In the protocol involving the sympathetic activation, the BCO elicited reflex activation of the sympathetic nervous system, reduced the levels of inflammatory cytokines in plasma, including the tumoral necrosis factor (TNF) and the interleukin (IL)-1β, and increased the anti-inflammatory cytokine IL-10, 90 min after LPS administration. In addition, either baroreceptor or chemoreceptor denervation, by itself, decreased the LPS-induced cytokine release, highlighting the role of these peripheral receptors as immunosensors during an immune challenge. Moreover, baroreceptor denervation increased the level of IL-10 in the plasma. Nevertheless, the BCO also did not avoid changes in the autonomic balance and baroreflex sensitivity over time, resulting from the LPS administration. In conclusion, these findings indicate that the parasympathetic activation associated with sympathetic inhibition has no systemic antiinflammatory effects in unanesthetized endotoxemic rats. On the other hand, global reflex activation of the sympathetic system is able to modulate the systemic inflammatory response. Finally, this study also suggests a novel function for the baroreceptors as immunosensors during an immune challenge. (AU)

• FAPESP's process: 17/05163-6 - Role of the parasympathetic and sympathetic autonomic nervous system in the modulation of sepsis in unanesthetized rats
• Grantee: Fernanda Brognara Penteado Dias
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)