Impaired alveolar macrophage 11β-hydroxysteroid dehydrogenase type 1 reductase activity contributes to increased pulmonary inflammation and mortality in sepsis-related ARDS
BackgroundAcute Respiratory Distress Syndrome (ARDS) is a devastating pulmonary inflammatory disorder, commonly precipitated by sepsis. Glucocorticoids are immunomodulatory steroids that can suppress inflammation. Their anti-inflammatory properties within tissues are influenced by their pre-receptor...
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Frontiers Media S.A.
2023-04-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1159831/full |
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| author | Rahul Y. Mahida Siân Lax Christopher R. Bassford Aaron Scott Dhruv Parekh Rowan S. Hardy Babu Naidu Michael A. Matthay Paul M. Stewart Mark C. Cooper Gavin D. Perkins David R. Thickett |
| author_facet | Rahul Y. Mahida Siân Lax Christopher R. Bassford Aaron Scott Dhruv Parekh Rowan S. Hardy Babu Naidu Michael A. Matthay Paul M. Stewart Mark C. Cooper Gavin D. Perkins David R. Thickett |
| author_sort | Rahul Y. Mahida |
| collection | DOAJ |
| description | BackgroundAcute Respiratory Distress Syndrome (ARDS) is a devastating pulmonary inflammatory disorder, commonly precipitated by sepsis. Glucocorticoids are immunomodulatory steroids that can suppress inflammation. Their anti-inflammatory properties within tissues are influenced by their pre-receptor metabolism and amplification from inactive precursors by 11β-hydroxysteroid dehydrogenase type-1 (HSD-1). We hypothesised that in sepsis-related ARDS, alveolar macrophage (AM) HSD-1 activity and glucocorticoid activation are impaired, and associated with greater inflammatory injury and worse outcomes.MethodsWe analysed broncho-alveolar lavage (BAL) and circulating glucocorticoid levels, AM HSD-1 reductase activity and Receptor for Advanced Glycation End-products (RAGE) levels in two cohorts of critically ill sepsis patients, with and without ARDS. AM HSD-1 reductase activity was also measured in lobectomy patients. We assessed inflammatory injury parameters in models of lung injury and sepsis in HSD-1 knockout (KO) and wild type (WT) mice.ResultsNo difference in serum and BAL cortisol: cortisone ratios are shown between sepsis patients with and without ARDS. Across all sepsis patients, there is no association between BAL cortisol: cortisone ratio and 30-day mortality. However, AM HSD-1 reductase activity is impaired in patients with sepsis-related ARDS, compared to sepsis patients without ARDS and lobectomy patients (0.075 v 0.882 v 0.967 pM/hr/106 AMs, p=0.004). Across all sepsis patients (with and without ARDS), impaired AM HSD-1 reductase activity is associated with defective efferocytosis (r=0.804, p=0.008) and increased 30-day mortality. AM HSD-1 reductase activity negatively correlates with BAL RAGE in sepsis patients with ARDS (r=-0.427, p=0.017). Following intra-tracheal lipopolysaccharide (IT-LPS) injury, HSD-1 KO mice demonstrate increased alveolar neutrophil infiltration, apoptotic neutrophil accumulation, alveolar protein permeability and BAL RAGE concentrations compared to WT mice. Caecal Ligation and Puncture (CLP) injury in HSD-1 KO mice results in greater peritoneal apoptotic neutrophil accumulation compared to WT mice.ConclusionsAM HSD-1 reductase activity does not shape total BAL and serum cortisol: cortisone ratios, however impaired HSD-1 autocrine signalling renders AMs insensitive to the anti-inflammatory effects of local glucocorticoids. This contributes to the decreased efferocytosis, increased BAL RAGE concentrations and mortality seen in sepsis-related ARDS. Upregulation of alveolar HSD-1 activity could restore AM function and improve clinical outcomes in these patients. |
| first_indexed | 2024-04-09T15:44:15Z |
| format | Article |
| id | doaj.art-79837288f2f145448fc78353241ec42d |
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| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-04-09T15:44:15Z |
| publishDate | 2023-04-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Immunology |
| spelling | doaj.art-79837288f2f145448fc78353241ec42d2023-04-27T05:01:57ZengFrontiers Media S.A.Frontiers in Immunology1664-32242023-04-011410.3389/fimmu.2023.11598311159831Impaired alveolar macrophage 11β-hydroxysteroid dehydrogenase type 1 reductase activity contributes to increased pulmonary inflammation and mortality in sepsis-related ARDSRahul Y. Mahida0Siân Lax1Christopher R. Bassford2Aaron Scott3Dhruv Parekh4Rowan S. Hardy5Babu Naidu6Michael A. Matthay7Paul M. Stewart8Mark C. Cooper9Gavin D. Perkins10David R. Thickett11Birmingham Acute Care Research Group, Institute of Inflammation and Ageing, University of Birmingham, Birmingham, United KingdomInstitute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, United KingdomDepartment of General Critical Care, University Hospitals Coventry and Warwickshire NHS Trust, Coventry, United KingdomBirmingham Acute Care Research Group, Institute of Inflammation and Ageing, University of Birmingham, Birmingham, United KingdomBirmingham Acute Care Research Group, Institute of Inflammation and Ageing, University of Birmingham, Birmingham, United KingdomInstitute of Clinical Sciences, University of Birmingham, Birmingham, United KingdomBirmingham Acute Care Research Group, Institute of Inflammation and Ageing, University of Birmingham, Birmingham, United KingdomCardiovascular Research Institute, Department of Medicine, and Department of Anaesthesia, University of California San Francisco, San Francisco, California, CA, United StatesSchool of Medicine, University of Leeds, Leeds, United KingdomFaculty of Medicine and Health, University of Sydney, Sydney, NSW, AustraliaWarwick Medical School, University of Warwick, Warwick, United KingdomBirmingham Acute Care Research Group, Institute of Inflammation and Ageing, University of Birmingham, Birmingham, United KingdomBackgroundAcute Respiratory Distress Syndrome (ARDS) is a devastating pulmonary inflammatory disorder, commonly precipitated by sepsis. Glucocorticoids are immunomodulatory steroids that can suppress inflammation. Their anti-inflammatory properties within tissues are influenced by their pre-receptor metabolism and amplification from inactive precursors by 11β-hydroxysteroid dehydrogenase type-1 (HSD-1). We hypothesised that in sepsis-related ARDS, alveolar macrophage (AM) HSD-1 activity and glucocorticoid activation are impaired, and associated with greater inflammatory injury and worse outcomes.MethodsWe analysed broncho-alveolar lavage (BAL) and circulating glucocorticoid levels, AM HSD-1 reductase activity and Receptor for Advanced Glycation End-products (RAGE) levels in two cohorts of critically ill sepsis patients, with and without ARDS. AM HSD-1 reductase activity was also measured in lobectomy patients. We assessed inflammatory injury parameters in models of lung injury and sepsis in HSD-1 knockout (KO) and wild type (WT) mice.ResultsNo difference in serum and BAL cortisol: cortisone ratios are shown between sepsis patients with and without ARDS. Across all sepsis patients, there is no association between BAL cortisol: cortisone ratio and 30-day mortality. However, AM HSD-1 reductase activity is impaired in patients with sepsis-related ARDS, compared to sepsis patients without ARDS and lobectomy patients (0.075 v 0.882 v 0.967 pM/hr/106 AMs, p=0.004). Across all sepsis patients (with and without ARDS), impaired AM HSD-1 reductase activity is associated with defective efferocytosis (r=0.804, p=0.008) and increased 30-day mortality. AM HSD-1 reductase activity negatively correlates with BAL RAGE in sepsis patients with ARDS (r=-0.427, p=0.017). Following intra-tracheal lipopolysaccharide (IT-LPS) injury, HSD-1 KO mice demonstrate increased alveolar neutrophil infiltration, apoptotic neutrophil accumulation, alveolar protein permeability and BAL RAGE concentrations compared to WT mice. Caecal Ligation and Puncture (CLP) injury in HSD-1 KO mice results in greater peritoneal apoptotic neutrophil accumulation compared to WT mice.ConclusionsAM HSD-1 reductase activity does not shape total BAL and serum cortisol: cortisone ratios, however impaired HSD-1 autocrine signalling renders AMs insensitive to the anti-inflammatory effects of local glucocorticoids. This contributes to the decreased efferocytosis, increased BAL RAGE concentrations and mortality seen in sepsis-related ARDS. Upregulation of alveolar HSD-1 activity could restore AM function and improve clinical outcomes in these patients.https://www.frontiersin.org/articles/10.3389/fimmu.2023.1159831/fullalveolar macrophage (AM)ARDS (acute respiratory disease syndrome)sepsis11b-hydroxysteroid dehydrogenase type-1autocrine action |
| spellingShingle | Rahul Y. Mahida Siân Lax Christopher R. Bassford Aaron Scott Dhruv Parekh Rowan S. Hardy Babu Naidu Michael A. Matthay Paul M. Stewart Mark C. Cooper Gavin D. Perkins David R. Thickett Impaired alveolar macrophage 11β-hydroxysteroid dehydrogenase type 1 reductase activity contributes to increased pulmonary inflammation and mortality in sepsis-related ARDS Frontiers in Immunology alveolar macrophage (AM) ARDS (acute respiratory disease syndrome) sepsis 11b-hydroxysteroid dehydrogenase type-1 autocrine action |
| title | Impaired alveolar macrophage 11β-hydroxysteroid dehydrogenase type 1 reductase activity contributes to increased pulmonary inflammation and mortality in sepsis-related ARDS |
| title_full | Impaired alveolar macrophage 11β-hydroxysteroid dehydrogenase type 1 reductase activity contributes to increased pulmonary inflammation and mortality in sepsis-related ARDS |
| title_fullStr | Impaired alveolar macrophage 11β-hydroxysteroid dehydrogenase type 1 reductase activity contributes to increased pulmonary inflammation and mortality in sepsis-related ARDS |
| title_full_unstemmed | Impaired alveolar macrophage 11β-hydroxysteroid dehydrogenase type 1 reductase activity contributes to increased pulmonary inflammation and mortality in sepsis-related ARDS |
| title_short | Impaired alveolar macrophage 11β-hydroxysteroid dehydrogenase type 1 reductase activity contributes to increased pulmonary inflammation and mortality in sepsis-related ARDS |
| title_sort | impaired alveolar macrophage 11β hydroxysteroid dehydrogenase type 1 reductase activity contributes to increased pulmonary inflammation and mortality in sepsis related ards |
| topic | alveolar macrophage (AM) ARDS (acute respiratory disease syndrome) sepsis 11b-hydroxysteroid dehydrogenase type-1 autocrine action |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1159831/full |
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