Serum amyloid A opposes lipoxin A4 to mediate glucocorticoid refractory lung inflammation in chronic obstructive pulmonary disease.

Serum amyloid A opposes lipoxin A4 to mediate glucocorticoid refractory lung inflammation in chronic obstructive pulmonary disease.

MedLine Citation:	PMID: 22215599 Owner: NLM Status: Publisher
Abstract/OtherAbstract:	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.

Authors:	Steven Bozinovski; Mohib Uddin; Ross Vlahos; Michelle Thompson; Jonathan L McQualter; Anne-Sophie Merritt; Peter A B Wark; Anastasia Hutchinson; Louis B Irving; Bruce D Levy; Gary P Anderson
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Publication Detail:	Type: JOURNAL ARTICLE Date: 2012-1-3
Journal Detail:	Title: Proceedings of the National Academy of Sciences of the United States of America Volume: - ISSN: 1091-6490 ISO Abbreviation: - Publication Date: 2012 Jan
Date Detail:	Created Date: 2012-1-4 Completed Date: - Revised Date: -
Medline Journal Info:	Nlm Unique ID: 7505876 Medline TA: Proc Natl Acad Sci U S A Country: -
Other Details:	Languages: ENG Pagination: - Citation Subset: -
Affiliation:	Department of Pharmacology, and Department of Medicine, University of Melbourne, Parkville, Victoria, Australia 3010.
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