The role of hypothalamic hydrogen sulphide modulating LPS tolerance

Author(s)

Bruna Maitan Santos

• Document type: Doctoral Thesis
• Press: Ribeirão Preto.
• Institution: Universidade de São Paulo (USP). Faculdade de Medicina de Ribeirão Preto (PCARP/BC)
• Defense date: 2020-03-20

Examining board members

Luiz Guilherme de Siqueira Branco; Luciane Helena Gargaglioni Batalhão; Rafael Simone Saia

• Advisor: Luiz Guilherme de Siqueira Branco

Abstract

Fever is by definition a regulated increase in body temperature produced in defense of the organism against a pathogen. The interaction of the pathogen with the immune system generates the release of cytokines and prostaglandins (mediators of inflammation) that activate central regions involved in the control of body temperature (Tb), with the anteroventral preoptic area (AVPO) being the most important hierarchically region in thermoregulation. The systemic administration of lipopolysaccharide (LPS - an endotoxin extracted from the cell wall of Gbacteria) in rats is the most used model to induce fever. Repeated administration causes tolerance to LPS which can be characterized by the immune system\'s refractory response to the endotoxin, i.e., absence of the febrile response produced in response to the endotoxin immune challenge. Our laboratory characterized the role of gas neuromodulators nitric oxide (NO) and carbon monoxide (CO) in tolerance to LPS, but there are no reports on the possible participation of hydrogen sulfide (H2S - another endogenous gasotransmitter). The present project tests the hypothesis that H2S, endogenously produced at AVPO, participates in LPS tolerance. Methods: Rats with central cannulas (drug microinjection) and datatalogger (body temperature recording) received a low dose of lipopolysaccharide (LPS; 100 γg.kg- 1 intraperitoneally) daily, for four consecutive days. CBS expression and H2S production rate in AVPO were evaluated, along with the analysis of febrile signaling. Tolerant rats received an inhibitor of H2S synthesis (AOA, 100 pmol 1 γL-1 icv) or its vehicle on 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 PGE2 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