title: Glucocorticoids downregulate systemic nitric oxide synthesis and counteract overexpression of hepatic heme oxygenase-1 during endotoxin tolerance.
abstract: Heme oxygenase (HO)-1 has antioxidant and cytoprotective properties if properly expressed, whereas nitric oxide (NO) impairs tissue perfusion when greatly increased in the blood circulation. Here we hypothesized that the NO and HO-1 systems are altered during lipopolysaccharide (LPS) tolerance, and that glucocorticoids are crucial modulators of systemic NO production and hepatic HO-1 expression during this intriguing phenomenon of cellular reprogramming. Adrenalectomized (ADX) rats with or without administration of dexamethasone (DEX) were challenged with LPS for 3 consecutive days. The plasma levels of corticosterone and nitrate (NOx), and expression of HO-1 protein were assessed. During tolerance, corticosterone levels were elevated, NOx reduced, and HO-1 overexpressed. ADX rats challenged with LPS for 3 consecutive days exhibited a ~9-fold increase in NOx and a ~6-fold increase in HO-1, reverted by DEX. Our findings strongly support the fact that glucocorticoids downregulate systemic NO synthesis and counteract hepatic HO-1 overexpression during LPS tolerance.
authors.affiliation: a Nursing School of Ribeirão Preto, 14040-902, University of São Paulo, Ribeirão Preto, São Paulo, Brazil.
authors.forename: Renato N
authors.initials: RN
authors.lastname: Soriano
authors.forename: Maria I
authors.initials: MI
authors.lastname: Ravanelli
authors.forename: Marcelo E
authors.initials: ME
authors.lastname: Batalhao
authors.forename: Evelin C
authors.initials: EC
authors.lastname: Carnio
authors.forename: Luiz G S
authors.initials: LG
authors.lastname: Branco
mesh_terms: D000315:Adrenalectomy; D000818:Animals; D003345:Corticosterone / Q000097:blood; D003907:Dexamethasone / Q000008:administration & dosage*; D004195:Disease Models, Animal; D015536:Down-Regulation; D019446:Endotoxemia / Q000097:blood / Q000139:chemically induced / Q000201:enzymology*; D005334:Fever / Q000139:chemically induced / Q000201:enzymology; D005938:Glucocorticoids / Q000008:administration & dosage*; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism*; D020249:Hormone Replacement Therapy; D007279:Injections, Subcutaneous; D008070:Lipopolysaccharides; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D009566:Nitrates / Q000097:blood; D009569:Nitric Oxide / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors; D015854:Up-Regulation
chemical_list: D005938:Glucocorticoids; D008070:Lipopolysaccharides; D009566:Nitrates; C440499:lipopolysaccharide, Escherichia coli O111 B4; D009569:Nitric Oxide; D003907:Dexamethasone; D006419:Heme Oxygenase (Decyclizing); C491523:Hmox1 protein, rat; D003345:Corticosterone