Abstract
Introduction: Persistent innate immune activation contributes to tissue destruction in chronic obstructive pulmonary disease (COPD). Altered responses to glucocorticosteroids (GC) may further compromise host defense in chronic lung diseases. We previously identified SAA as a GC resistant systemic COPD biomarker and here, characterized its function in orchestrating mucosal inflammatory responses that contribute to neutrophil accumulation.
Methods: Three separate patient cohorts were investigated involving 81 patients.
Results: In a prospective study of competing ALX/FPR2 ligands during COPD exacerbation, circulating SAA levels were markedly and disproportionately increased relative to LXA4. Secreted SAA levels in COPD BAL fluid correlated with interleukin-8 and the neutrophil activation marker, neutrophil elastase. SAA was also detected in COPD lung in close proximity to airway epithelia, and in vitro SAA triggered pro-inflammatory mediator (MCP-1, GM-CSF and IL-8) release by airway epithelial cells in an ALX/FPR2 receptor-dependent manner. Lipoxin A4 (LXA4) blocked SAA initiated epithelial responses via allosteric inhibition at ALX/FPR2 (pA2 13 nM). When administered directly into murine lung, SAA initiated robust acute inflammation that was significantly inhibited by equivalent amounts of 15-epi-LXA4 but not dexamethasone. Tissue macrophages (CD68+) colocalised with lung SAA and the GC dexamethasone markedly increased SAA production by THP-1 macrophages (pEC50 43 nM).
Conclusions: Together, these findings implicate airway SAA production as a mediator of GC resistant lung inflammation that can overwhelm organ protective signaling by lipoxins at ALX/FPR2 receptors.
- © 2011 ERS
