Serum amyloid A opposes lipoxin A₄ to mediate glucocorticoid refractory lung inflammation in chronic obstructive pulmonary disease.
Chronic obstructive pulmonary disease (COPD) will soon be the third most common cause of death globally. Despite smoking cessation, neutrophilic mucosal inflammation persistently damages the airways and fails to protect from recurrent infections. This maladaptive and excess inflammation is also refractory to glucocorticosteroids (GC). Here, we identify serum amyloid A (SAA) as a candidate mediator of GC refractory inflammation in COPD. Extrahepatic SAA was detected locally in COPD bronchoalveolar lavage fluid, which correlated with IL-8 and neutrophil elastase, consistent with neutrophil recruitment and activation. Immunohistochemistry detected SAA was in close proximity to airway epithelium, and in vitro SAA triggered release of IL-8 and other proinflammatory mediators by airway epithelial cells in an ALX/FPR2 (formyl peptide receptor 2) receptor-dependent manner. Lipoxin A(4) (LXA(4)) can also interact with ALX/FPR2 receptors and lead to allosteric inhibition of SAA-initiated epithelial responses (pA(2) 13 nM). During acute exacerbation, peripheral blood SAA levels increased dramatically and were disproportionately increased relative to LXA(4). Human lung macrophages (CD68(+)) colocalized with SAA and GCs markedly increased SAA in vitro (THP-1, pEC(50) 43 nM). To determine its direct actions, SAA was administered into murine lung, leading to induction of CXC chemokine ligand 1/2 and a neutrophilic response that was inhibited by 15-epi-LXA(4) but not dexamethasone. Taken together, these findings identify SAA as a therapeutic target for inhibition and implicate SAA as a mediator of GC-resistant lung inflammation that can overwhelm organ protective signaling by lipoxins at ALX/FPR2 receptors.
Department of Pharmacology, University of Melbourne, Parkville, Victoria, Australia 3010. bozis@unimelb.edu.au
Steven
S
Bozinovski
Mohib
M
Uddin
Ross
R
Vlahos
Michelle
M
Thompson
Jonathan L
JL
McQualter
Anne-Sophie
AS
Merritt
Peter A B
PA
Wark
Anastasia
A
Hutchinson
Louis B
LB
Irving
Bruce D
BD
Levy
Gary P
GP
Anderson
D000818:Animals; D001992:Bronchoalveolar Lavage Fluid; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004848:Epithelium / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005938:Glucocorticoids / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism; D044045:Lipoxins / Q000008:administration & dosage / Q000494:pharmacology*; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000187:drug effects; D051379:Mice; D009092:Mucous Membrane / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018375:Neutrophil Activation / Q000187:drug effects; D009504:Neutrophils / Q000187:drug effects / Q000473:pathology; D011014:Pneumonia / Q000150:complications* / Q000188:drug therapy* / Q000473:pathology; D029424:Pulmonary Disease, Chronic Obstructive / Q000150:complications* / Q000188:drug therapy* / Q000473:pathology; D044042:Receptors, Formyl Peptide / Q000378:metabolism; D044067:Receptors, Lipoxin / Q000378:metabolism; D000685:Serum Amyloid A Protein / Q000008:administration & dosage / Q000494:pharmacology*
C105101:FPR2 protein, human; D005938:Glucocorticoids; D016209:Interleukin-8; D044045:Lipoxins; D044042:Receptors, Formyl Peptide; D044067:Receptors, Lipoxin; D000685:Serum Amyloid A Protein; C040527:lipoxin A4