The role of pro-opiomelanocortin in the ACTH–cortisol dissociation of sepsis
Abstract Background Sepsis is typically hallmarked by high plasma (free) cortisol and suppressed cortisol breakdown, while plasma adrenocorticotropic hormone (ACTH) is not increased, referred to as ‘ACTH–cortisol dissociation.’ We hypothesized that sepsis acutely activates the hypothalamus to genera...
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BMC
2021-02-01
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| Series: | Critical Care |
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| Online Access: | https://doi.org/10.1186/s13054-021-03475-y |
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| author | Arno Téblick Sarah Vander Perre Lies Pauwels Sarah Derde Tim Van Oudenhove Lies Langouche Greet Van den Berghe |
| author_facet | Arno Téblick Sarah Vander Perre Lies Pauwels Sarah Derde Tim Van Oudenhove Lies Langouche Greet Van den Berghe |
| author_sort | Arno Téblick |
| collection | DOAJ |
| description | Abstract Background Sepsis is typically hallmarked by high plasma (free) cortisol and suppressed cortisol breakdown, while plasma adrenocorticotropic hormone (ACTH) is not increased, referred to as ‘ACTH–cortisol dissociation.’ We hypothesized that sepsis acutely activates the hypothalamus to generate, via corticotropin-releasing hormone (CRH) and vasopressin (AVP), ACTH-induced hypercortisolemia. Thereafter, via increased availability of free cortisol, of which breakdown is reduced, feedback inhibition at the pituitary level interferes with normal processing of pro-opiomelanocortin (POMC) into ACTH, explaining the ACTH–cortisol dissociation. We further hypothesized that, in this constellation, POMC leaches into the circulation and can contribute to adrenocortical steroidogenesis. Methods In two human studies of acute (ICU admission to day 7, N = 71) and prolonged (from ICU day 7 until recovery; N = 65) sepsis-induced critical illness, POMC plasma concentrations were quantified in relation to plasma ACTH and cortisol. In a mouse study of acute (1 day), subacute (3 and 5 days) and prolonged (7 days) fluid-resuscitated, antibiotic-treated sepsis (N = 123), we further documented alterations in hypothalamic CRH and AVP, plasma and pituitary POMC and its glucocorticoid-receptor-regulated processing into ACTH, as well as adrenal cortex integrity and steroidogenesis markers. Results The two human studies revealed several-fold elevated plasma concentrations of the ACTH precursor POMC from the acute to the prolonged phase of sepsis and upon recovery (all p < 0.0001), coinciding with the known ACTH–cortisol dissociation. Elevated plasma POMC and ACTH–corticosterone dissociation were confirmed in the mouse model. In mice, sepsis acutely increased hypothalamic mRNA of CRH (p = 0.04) and AVP (p = 0.03) which subsequently normalized. From 3 days onward, pituitary expression of CRH receptor and AVP receptor was increased. From acute throughout prolonged sepsis, pituitary POMC mRNA was always elevated (all p < 0.05). In contrast, markers of POMC processing into ACTH and of ACTH secretion, negatively regulated by glucocorticoid receptor ligand binding, were suppressed at all time points (all p ≤ 0.05). Distorted adrenocortical structure (p < 0.05) and lipid depletion (p < 0.05) were present, while most markers of adrenocortical steroidogenic activity were increased at all time points (all p < 0.05). Conclusion Together, these findings suggest that increased circulating POMC, through CRH/AVP-driven POMC expression and impaired processing into ACTH, could represent a new piece in the puzzling ACTH–cortisol dissociation. |
| first_indexed | 2024-12-14T11:16:58Z |
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| institution | Directory Open Access Journal |
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| language | English |
| last_indexed | 2024-12-14T11:16:58Z |
| publishDate | 2021-02-01 |
| publisher | BMC |
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| series | Critical Care |
| spelling | doaj.art-1868c4833b1c4bb998bc76a47e0fc75b2022-12-21T23:03:56ZengBMCCritical Care1364-85352021-02-0125111410.1186/s13054-021-03475-yThe role of pro-opiomelanocortin in the ACTH–cortisol dissociation of sepsisArno Téblick0Sarah Vander Perre1Lies Pauwels2Sarah Derde3Tim Van Oudenhove4Lies Langouche5Greet Van den Berghe6Clinical Division and Laboratory of Intensive Care Medicine, Department of Cellular and Molecular Medicine, KU LeuvenClinical Division and Laboratory of Intensive Care Medicine, Department of Cellular and Molecular Medicine, KU LeuvenClinical Division and Laboratory of Intensive Care Medicine, Department of Cellular and Molecular Medicine, KU LeuvenClinical Division and Laboratory of Intensive Care Medicine, Department of Cellular and Molecular Medicine, KU LeuvenClinical Division and Laboratory of Intensive Care Medicine, Department of Cellular and Molecular Medicine, KU LeuvenClinical Division and Laboratory of Intensive Care Medicine, Department of Cellular and Molecular Medicine, KU LeuvenClinical Division and Laboratory of Intensive Care Medicine, Department of Cellular and Molecular Medicine, KU LeuvenAbstract Background Sepsis is typically hallmarked by high plasma (free) cortisol and suppressed cortisol breakdown, while plasma adrenocorticotropic hormone (ACTH) is not increased, referred to as ‘ACTH–cortisol dissociation.’ We hypothesized that sepsis acutely activates the hypothalamus to generate, via corticotropin-releasing hormone (CRH) and vasopressin (AVP), ACTH-induced hypercortisolemia. Thereafter, via increased availability of free cortisol, of which breakdown is reduced, feedback inhibition at the pituitary level interferes with normal processing of pro-opiomelanocortin (POMC) into ACTH, explaining the ACTH–cortisol dissociation. We further hypothesized that, in this constellation, POMC leaches into the circulation and can contribute to adrenocortical steroidogenesis. Methods In two human studies of acute (ICU admission to day 7, N = 71) and prolonged (from ICU day 7 until recovery; N = 65) sepsis-induced critical illness, POMC plasma concentrations were quantified in relation to plasma ACTH and cortisol. In a mouse study of acute (1 day), subacute (3 and 5 days) and prolonged (7 days) fluid-resuscitated, antibiotic-treated sepsis (N = 123), we further documented alterations in hypothalamic CRH and AVP, plasma and pituitary POMC and its glucocorticoid-receptor-regulated processing into ACTH, as well as adrenal cortex integrity and steroidogenesis markers. Results The two human studies revealed several-fold elevated plasma concentrations of the ACTH precursor POMC from the acute to the prolonged phase of sepsis and upon recovery (all p < 0.0001), coinciding with the known ACTH–cortisol dissociation. Elevated plasma POMC and ACTH–corticosterone dissociation were confirmed in the mouse model. In mice, sepsis acutely increased hypothalamic mRNA of CRH (p = 0.04) and AVP (p = 0.03) which subsequently normalized. From 3 days onward, pituitary expression of CRH receptor and AVP receptor was increased. From acute throughout prolonged sepsis, pituitary POMC mRNA was always elevated (all p < 0.05). In contrast, markers of POMC processing into ACTH and of ACTH secretion, negatively regulated by glucocorticoid receptor ligand binding, were suppressed at all time points (all p ≤ 0.05). Distorted adrenocortical structure (p < 0.05) and lipid depletion (p < 0.05) were present, while most markers of adrenocortical steroidogenic activity were increased at all time points (all p < 0.05). Conclusion Together, these findings suggest that increased circulating POMC, through CRH/AVP-driven POMC expression and impaired processing into ACTH, could represent a new piece in the puzzling ACTH–cortisol dissociation.https://doi.org/10.1186/s13054-021-03475-ySepsisPituitaryAdrenalAdrenocorticotropic hormonePro-opiomelanocortinGlucocorticoid receptor |
| spellingShingle | Arno Téblick Sarah Vander Perre Lies Pauwels Sarah Derde Tim Van Oudenhove Lies Langouche Greet Van den Berghe The role of pro-opiomelanocortin in the ACTH–cortisol dissociation of sepsis Critical Care Sepsis Pituitary Adrenal Adrenocorticotropic hormone Pro-opiomelanocortin Glucocorticoid receptor |
| title | The role of pro-opiomelanocortin in the ACTH–cortisol dissociation of sepsis |
| title_full | The role of pro-opiomelanocortin in the ACTH–cortisol dissociation of sepsis |
| title_fullStr | The role of pro-opiomelanocortin in the ACTH–cortisol dissociation of sepsis |
| title_full_unstemmed | The role of pro-opiomelanocortin in the ACTH–cortisol dissociation of sepsis |
| title_short | The role of pro-opiomelanocortin in the ACTH–cortisol dissociation of sepsis |
| title_sort | role of pro opiomelanocortin in the acth cortisol dissociation of sepsis |
| topic | Sepsis Pituitary Adrenal Adrenocorticotropic hormone Pro-opiomelanocortin Glucocorticoid receptor |
| url | https://doi.org/10.1186/s13054-021-03475-y |
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