M A Nenke1,2, W Rankin3, M J Chapman4, N E Stevens5, K R Diener5,6, J D Hayball2,5, J G Lewis7, D J Torpy1. 1. Endocrine and Metabolic Unit, Royal Adelaide Hospital, Adelaide, SA, Australia. 2. School of Medicine, University of Adelaide, Adelaide, SA, Australia. 3. Chemical Pathology Directorate, SA Pathology, Adelaide, SA, Australia. 4. Intensive Care Unit, Royal Adelaide Hospital, Adelaide, SA, Australia. 5. Experimental Therapeutics Laboratory, Hanson Institute and Sansom Institute, University of South Australia, Adelaide, SA, Australia. 6. Robinson Research Institute and School of Paediatrics and Reproductive Health, University of Adelaide, Adelaide, SA, Australia. 7. Steroid and Immunobiochemistry Laboratory, Canterbury Health Laboratories, Christchurch, New Zealand.
Abstract
OBJECTIVE: Corticosteroid-binding globulin (CBG) is cleaved by neutrophil elastase converting the high-affinity (haCBG) conformation of CBG to a low-affinity (laCBG) conformation with a ninefold reduced cortisol-binding affinity. These in vitro data suggest that cortisol release by CBG cleavage results in the targeted delivery of cortisol to areas of inflammation. Our objective was to determine whether CBG cleavage alters circulating levels of haCBG and laCBG in vivo in proportion to sepsis severity. DESIGN: Prospective, observational cohort study in an adult tertiary level Intensive Care Unit in Adelaide, Australia. PATIENTS: Thirty-three patients with sepsis or septic shock grouped by illness severity [sepsis, septic shock survivors, septic shock nonsurvivors and other shock]. MEASUREMENTS: Plasma levels of haCBG and laCBG were assessed using a recently developed in-house assay in patients. Plasma total and free cortisol levels were also measured. RESULTS: Plasma total CBG and haCBG levels fell significantly, in proportion to disease severity (P < 0·0001 for both). There was a nonsignificant increase in free and total cortisol as illness severity worsened (P = 0·19 and P = 0·39, respectively). Illness severity was better correlated with haCBG levels than either free or total cortisol levels. CONCLUSIONS: Increasing illness severity in sepsis and septic shock is associated with markedly reduced circulating haCBG concentrations in vivo. We propose that low levels of haCBG in chronic inflammation may limit the availability of cortisol to inflammatory sites, perpetuating the inflammatory process.
OBJECTIVE:Corticosteroid-binding globulin (CBG) is cleaved by neutrophil elastase converting the high-affinity (haCBG) conformation of CBG to a low-affinity (laCBG) conformation with a ninefold reduced cortisol-binding affinity. These in vitro data suggest that cortisol release by CBG cleavage results in the targeted delivery of cortisol to areas of inflammation. Our objective was to determine whether CBG cleavage alters circulating levels of haCBG and laCBG in vivo in proportion to sepsis severity. DESIGN: Prospective, observational cohort study in an adult tertiary level Intensive Care Unit in Adelaide, Australia. PATIENTS: Thirty-three patients with sepsis or septic shock grouped by illness severity [sepsis, septic shock survivors, septic shock nonsurvivors and other shock]. MEASUREMENTS: Plasma levels of haCBG and laCBG were assessed using a recently developed in-house assay in patients. Plasma total and free cortisol levels were also measured. RESULTS: Plasma total CBG and haCBG levels fell significantly, in proportion to disease severity (P < 0·0001 for both). There was a nonsignificant increase in free and total cortisol as illness severity worsened (P = 0·19 and P = 0·39, respectively). Illness severity was better correlated with haCBG levels than either free or total cortisol levels. CONCLUSIONS: Increasing illness severity in sepsis and septic shock is associated with markedly reduced circulating haCBG concentrations in vivo. We propose that low levels of haCBG in chronic inflammation may limit the availability of cortisol to inflammatory sites, perpetuating the inflammatory process.
Authors: Djillali Annane; Stephen M Pastores; Wiebke Arlt; Robert A Balk; Albertus Beishuizen; Josef Briegel; Joseph Carcillo; Mirjam Christ-Crain; Mark S Cooper; Paul E Marik; Gianfranco Umberto Meduri; Keith M Olsen; Bram Rochwerg; Sophia C Rodgers; James A Russell; Greet Van den Berghe Journal: Intensive Care Med Date: 2017-09-21 Impact factor: 17.440
Authors: Emily J Meyer; David J Torpy; Anastasia Chernykh; Morten Thaysen-Andersen; Marni A Nenke; John G Lewis; Harinda Rajapaksha; Wayne Rankin; Steven W Polyak Journal: Protein Sci Date: 2020-11-04 Impact factor: 6.725
Authors: Z Yilmaz; O Eralp Inan; M Kocaturk; A T Baykal; O Hacariz; I Hatipoglu; A Tvarijonaviciute; M Cansev; J Ceron; I H Ulus Journal: BMC Vet Res Date: 2016-09-20 Impact factor: 2.741
Authors: Marni A Nenke; Anna Zeng; Emily J Meyer; John G Lewis; Wayne Rankin; Julie Johnston; Svjetlana Kireta; Shilpanjali Jesudason; David J Torpy Journal: J Endocr Soc Date: 2017-02-13
Authors: Lesley A Hill; Zeynep Sumer-Bayraktar; John G Lewis; Eva Morava; Morten Thaysen-Andersen; Geoffrey L Hammond Journal: Endocr Connect Date: 2019-08 Impact factor: 3.335
Authors: Lesley A Hill; Dimitra A Vassiliadi; Ioanna Dimopoulou; Anna J Anderson; Luke D Boyle; Alixe H M Kilgour; Roland H Stimson; Yoan Machado; Christopher M Overall; Brian R Walker; John G Lewis; Geoffrey L Hammond Journal: J Endocrinol Date: 2019-01-01 Impact factor: 4.286