Increased hypothalamic hydrogen sulphide contributes to endotoxin tolerance by down-modulating PGE(2) production

Author(s)

Santos, Bruna M. ; Francescato, Heloisa D. C. ; Turcato, Flavia C. ; Antunes-Rodrigues, Jose ; Coimbra, Terezila M. ; Branco, Luiz G. S.

• Document type: Journal article
• Source: ACTA PHYSIOLOGICA; v. 228, n. 3, p. 12-pg., 2019-09-15.

Abstract

Aim Whereas some patients have important changes in body core temperature (Tb) during systemic inflammation, others maintain a normal Tb, which is intrinsically associated to immune paralysis. One classical model to study immune paralysis is the use of repeated administration of lipopolysaccharide (LPS), the so-called endotoxin tolerance. However, the neuroimmune mechanisms of endotoxin tolerance remain poorly understood. Hydrogen sulphide (H2S) is a gaseous neuromodulator produced in the brain by the enzyme cystathionine beta-synthase (CBS). The present study assessed whether endotoxin tolerance is modulated by hypothalamic H2S. Methods Rats with central cannulas (drug microinjection) and intraperitoneal datalogger (temperature record) received a low-dose of lipopolysaccharide (LPS; 100 mu g kg(-1)) daily for four consecutive days. Hypothalamic CBS expression and H2S production rate were assessed, together with febrigenic signalling. Tolerant rats received an inhibitor of H2S synthesis (AOA, 100 pmol 1 mu L-1 icv) or its vehicle in the last day. Results Antero-ventral preoptic area of the hypothalamus (AVPO) H2S production rate and CBS expression were increased in endotoxin-tolerant rats. Additionally, hypothalamic H2S inhibition reversed endotoxin tolerance reestablishing fever, AVPO and plasma PGE(2) levels without altering the absent plasma cytokines surges. Conclusion Endotoxin tolerance is not simply a reflection of peripheral reduced cytokines release but actually results from a complex set of mechanisms acting at multiple levels. Hypothalamic H2S production modulates most of these mechanisms. (AU)

• FAPESP's process: 16/09364-3 - Role of endogenous preoptic hydrogen sulfide modulating LPS tolerance.
• Grantee: Bruna Maitan Santos
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 16/17681-9 - Pathophysiological changes during systemic inflammation
• Grantee: Luiz Guilherme de Siqueira Branco
• Support Opportunities: Research Projects - Thematic Grants