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 associ...

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Detalles Bibliográficos
Autores principales: Bain, William, Tabary, Mohammadreza, Moore, Sara R., An, Xiaojing, Kitsios, Georgios D., McVerry, Bryan J., Ray, Prabir, Ray, Anuradha, Mallampalli, Rama K., Ferreira, Viviana P., Lee, Janet S., Nouraie, S. Mehdi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: European Respiratory Society 2023
Materias:
Original Research Articles
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10291301/
https://www.ncbi.nlm.nih.gov/pubmed/37377659
http://dx.doi.org/10.1183/23120541.00702-2022
Descripción
Sumario: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.

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