Inhibition of endogenous glucocorticoid synthesis aggravates lung injury triggered by septic shock in rats

• Published in: International journal of experimental pathology 2015-06, Vol.96 (3), p.133-139
• Main Authors: Incerpi, Erika K., Oliveira, Luiz M., Pereira, Elisângela M., Soncini, Roseli
• Format: Article
• Language: English
• Subjects: Acute Lung Injury - blood; Acute Lung Injury - chemically induced; Acute Lung Injury - pathology; Acute Lung Injury - physiopathology; acute lung injury/acute respiratory distress syndrome; Animals; Corticosterone - biosynthesis; Corticosterone - blood; Disease Models, Animal; Down-Regulation; Enzyme Inhibitors - toxicity; glucocorticoids; Hydrogen Peroxide - metabolism; Inflammation Mediators - metabolism; Lung - drug effects; Lung - metabolism; Lung - pathology; Lung - physiopathology; Male; metyrapone; Metyrapone - toxicity; Original; Oxidative Stress - drug effects; Rats, Wistar; Respiratory Mechanics - drug effects; sepsis; Shock, Septic - complications; Steroid 11-beta-Hydroxylase - antagonists & inhibitors; Steroid 11-beta-Hydroxylase - metabolism; Time Factors
• ISSN: 0959-9673; 1365-2613
• DOI: 10.1111/iep.12113

Summary The aim of this study was to determine the effects of previous administration of metyrapone (met) on the acute lung injury (ALI) induced by caecal ligation and puncture (CLP) and to explore met's relationship with endogenous glucocorticoids (GCs) as measured by inflammatory, oxidative and functional parameters. One hundred and thirty‐five Wistar rats were divided into three main groups: Control (Naïve), Sham and CLP. The animals received pretreatment one hour before surgery. The Naïve group did not undergo any procedure or pretreatment. The Sham group only had the caecum exposed and was pretreated with saline. The CLP group was divided into three pretreatments: metyrapone (CLP met 50 mg/kg i.p.), dexamethasone (CLP dex 0.5 mg/kg i.p.) or saline (CLP sal equivalent volume of 0.9% NaCl). Analyses were performed after 6 and 24 h of sepsis. Previous administration of met significantly increased inflammatory cells, as well as myeloperoxidase (MPO) activity in the lung tissue and alveolar collapsed area, with consequent impairment of respiratory mechanics being observed compared to Sham and Naïve; CLP sal exhibited similar results to those of met. The met reduced corticosterone (CCT) levels and dramatically increased hydrogen peroxide (H2O2) levels in the lung tissue compared to CLP sal. Our results suggest that previous administration of met may have contributed to increased pulmonary oxidative stress and increased mortality by mechanisms dependent of endogenous GC.