Factor H preserves alternative complement function during ARDS, linked to improved survival
Background Effective regulation of complement activation may be crucial to preserving complement function during acute respiratory distress syndrome (ARDS). Factor H is the primary negative regulator of the alternative pathway of complement. We hypothesised that preserved factor H levels are associa...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
European Respiratory Society
2023-06-01
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| Series: | ERJ Open Research |
| Online Access: | http://openres.ersjournals.com/content/9/3/00702-2022.full |
| _version_ | 1797689332315717632 |
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| author | William Bain Mohammadreza Tabary Sara R. Moore Xiaojing An Georgios D. Kitsios Bryan J. McVerry Prabir Ray Anuradha Ray Rama K. Mallampalli Viviana P. Ferreira Janet S. Lee S. Mehdi Nouraie |
| author_facet | William Bain Mohammadreza Tabary Sara R. Moore Xiaojing An Georgios D. Kitsios Bryan J. McVerry Prabir Ray Anuradha Ray Rama K. Mallampalli Viviana P. Ferreira Janet S. Lee S. Mehdi Nouraie |
| author_sort | William Bain |
| collection | DOAJ |
| description | Background
Effective regulation of complement activation may be crucial to preserving complement function during acute respiratory distress syndrome (ARDS). Factor H is the primary negative regulator of the alternative pathway of complement. We hypothesised that preserved factor H levels are associated with decreased complement activation and reduced mortality during ARDS.
Methods
Total alternative pathway function was measured by serum haemolytic assay (AH50) using available samples from the ARDSnet Lisofylline and Respiratory Management of Acute Lung Injury (LARMA) trial (n=218). Factor B and factor H levels were quantified using ELISA using samples from the ARDSnet LARMA and Statins for Acutely Injured Lungs from Sepsis (SAILS) (n=224) trials. Meta-analyses included previously quantified AH50, factor B and factor H values from an observational registry (Acute Lung Injury Registry and Biospecimen Repository (ALIR)). Complement C3, and complement activation products C3a and Ba plasma levels were measured in SAILS.
Results
AH50 greater than the median was associated with reduced mortality in meta-analysis of LARMA and ALIR (hazard ratio (HR) 0.66, 95% CI 0.45–0.96). In contrast, patients in the lowest AH50 quartile demonstrated relative deficiency of both factor B and factor H. Relative deficiency of factor B (HR 1.99, 95% CI 1.44–2.75) or factor H (HR 1.52, 95% CI 1.09–2.11) was associated with increased mortality in meta-analysis of LARMA, SAILS and ALIR. Relative factor H deficiency was associated with increased factor consumption, as evidenced by lower factor B and C3 levels and Ba:B and C3a:C3 ratios. Higher factor H levels associated with lower inflammatory markers.
Conclusions
Relative factor H deficiency, higher Ba:B and C3a:C3 ratios and lower factor B and C3 levels suggest a subset of ARDS with complement factor exhaustion, impaired alternative pathway function, and increased mortality, that may be amenable to therapeutic targeting. |
| first_indexed | 2024-03-12T01:44:10Z |
| format | Article |
| id | doaj.art-3243b63a7e464800b085d884997730f5 |
| institution | Directory Open Access Journal |
| issn | 2312-0541 |
| language | English |
| last_indexed | 2024-03-12T01:44:10Z |
| publishDate | 2023-06-01 |
| publisher | European Respiratory Society |
| record_format | Article |
| series | ERJ Open Research |
| spelling | doaj.art-3243b63a7e464800b085d884997730f52023-09-09T13:53:54ZengEuropean Respiratory SocietyERJ Open Research2312-05412023-06-019310.1183/23120541.00702-202200702-2022Factor H preserves alternative complement function during ARDS, linked to improved survivalWilliam Bain0Mohammadreza Tabary1Sara R. Moore2Xiaojing An3Georgios D. Kitsios4Bryan J. McVerry5Prabir Ray6Anuradha Ray7Rama K. Mallampalli8Viviana P. Ferreira9Janet S. Lee10S. Mehdi Nouraie11 Acute Lung Injury Center of Excellence, Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA Acute Lung Injury Center of Excellence, Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA Department of Medical Microbiology and Immunology, University of Toledo College of Medicine and Life Sciences, Toledo, OH, USA Acute Lung Injury Center of Excellence, Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA Acute Lung Injury Center of Excellence, Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA Acute Lung Injury Center of Excellence, Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA Acute Lung Injury Center of Excellence, Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA Acute Lung Injury Center of Excellence, Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA Department of Medical Microbiology and Immunology, University of Toledo College of Medicine and Life Sciences, Toledo, OH, USA Acute Lung Injury Center of Excellence, Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA Acute Lung Injury Center of Excellence, Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA Background Effective regulation of complement activation may be crucial to preserving complement function during acute respiratory distress syndrome (ARDS). Factor H is the primary negative regulator of the alternative pathway of complement. We hypothesised that preserved factor H levels are associated with decreased complement activation and reduced mortality during ARDS. Methods Total alternative pathway function was measured by serum haemolytic assay (AH50) using available samples from the ARDSnet Lisofylline and Respiratory Management of Acute Lung Injury (LARMA) trial (n=218). Factor B and factor H levels were quantified using ELISA using samples from the ARDSnet LARMA and Statins for Acutely Injured Lungs from Sepsis (SAILS) (n=224) trials. Meta-analyses included previously quantified AH50, factor B and factor H values from an observational registry (Acute Lung Injury Registry and Biospecimen Repository (ALIR)). Complement C3, and complement activation products C3a and Ba plasma levels were measured in SAILS. Results AH50 greater than the median was associated with reduced mortality in meta-analysis of LARMA and ALIR (hazard ratio (HR) 0.66, 95% CI 0.45–0.96). In contrast, patients in the lowest AH50 quartile demonstrated relative deficiency of both factor B and factor H. Relative deficiency of factor B (HR 1.99, 95% CI 1.44–2.75) or factor H (HR 1.52, 95% CI 1.09–2.11) was associated with increased mortality in meta-analysis of LARMA, SAILS and ALIR. Relative factor H deficiency was associated with increased factor consumption, as evidenced by lower factor B and C3 levels and Ba:B and C3a:C3 ratios. Higher factor H levels associated with lower inflammatory markers. Conclusions Relative factor H deficiency, higher Ba:B and C3a:C3 ratios and lower factor B and C3 levels suggest a subset of ARDS with complement factor exhaustion, impaired alternative pathway function, and increased mortality, that may be amenable to therapeutic targeting.http://openres.ersjournals.com/content/9/3/00702-2022.full |
| spellingShingle | William Bain Mohammadreza Tabary Sara R. Moore Xiaojing An Georgios D. Kitsios Bryan J. McVerry Prabir Ray Anuradha Ray Rama K. Mallampalli Viviana P. Ferreira Janet S. Lee S. Mehdi Nouraie Factor H preserves alternative complement function during ARDS, linked to improved survival ERJ Open Research |
| title | Factor H preserves alternative complement function during ARDS, linked to improved survival |
| title_full | Factor H preserves alternative complement function during ARDS, linked to improved survival |
| title_fullStr | Factor H preserves alternative complement function during ARDS, linked to improved survival |
| title_full_unstemmed | Factor H preserves alternative complement function during ARDS, linked to improved survival |
| title_short | Factor H preserves alternative complement function during ARDS, linked to improved survival |
| title_sort | factor h preserves alternative complement function during ards linked to improved survival |
| url | http://openres.ersjournals.com/content/9/3/00702-2022.full |
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