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

ABSTRACT: 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.

SUBMITTER: Bozinovski S

PROVIDER: S-EPMC3271884 | biostudies-other | 2012 Jan

REPOSITORIES: biostudies-other

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

Bozinovski Steven S Uddin Mohib M Vlahos Ross R Thompson Michelle M McQualter Jonathan L JL Merritt Anne-Sophie AS Wark Peter A B PA Hutchinson Anastasia A Irving Louis B LB Levy Bruce D BD Anderson Gary P GP

Proceedings of the National Academy of Sciences of the United States of America 20120103 3

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 bronchoalveola ...[more]

PMID: 22215599

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Project description:PurposeChronic obstructive pulmonary disease (COPD) is a heterogeneous disease with high morbidity and mortality rates. This study used proteomic profiling of serum to identify the differentially expressed proteins in COPD patients compared with healthy controls, to expand the knowledge of COPD pathogenesis and to ascertain potential new targets for diagnosis and treatment of COPD.MethodsSerum samples were collected from 56 participants (COPD group n = 28; Healthy Control group n = 28). A data-independent acquisition quantitative proteomics approach was used to identify differentially expressed proteins (DEPs) between the two groups. Gene Ontology (GO) functional annotation, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway functional enrichment, and protein-protein interaction analyses of DEPs were conducted to identify their relevant biological processes, cellular components, and related pathways. We used a parallel reaction monitoring (PRM)-based targeted quantitative proteomics approach to validate those findings.ResultsOf 8484 peptides identified by searching the UniProtKB/Swiss-Prot knowledgebase, 867 proteins were quantifiable, of which 20 were upregulated and 35 were downregulated in the COPD group. GO functional annotation indicated that the subcellular localization of most DEPs was extracellular. The top three molecular functions of the DEPs were signaling receptor binding, antigen binding, and immunoglobulin receptor binding. The most relevant biological process was immune response. The transforming growth factor-β signaling pathway, Staphylococcus aureus infection, and hematopoietic cell lineage were the top three pathways identified in the KEGG pathway functional enrichment. Our PRM analyses confirmed the identification of 11 DEPs identified in our data-independent acquisition analyses, 8 DEPs were upregulated and 3 DEPs were downregulated.ConclusionThis study using data-independent acquisition analyses with PRM confirmation of findings identified 11 DEPs in the serum of patients with COPD. These DEPs are potential diagnostic or prognostic biomarkers or may be future targets for the treatment of COPD.

Project description:Neutrophils play a central role in innate immunity, inflammation, and resolution. Unresolving neutrophilia features as a disrupted inflammatory process in the airways of patients with chronic obstructive pulmonary disease (COPD) and severe asthma. The extent to which this may be linked to disease pathobiology remains obscure and could be further confounded by indication of glucocorticoids or concomitant respiratory infections. The formation of neutrophil extracellular traps (NETs) represents a specialized host defense mechanism that entrap and eliminate invading microbes. NETs are web-like scaffolds of extracellular DNA in complex with histones and neutrophil granular proteins, such as myeloperoxidase and neutrophil elastase. Distinct from apoptosis, NET formation is an active form of cell death that could be triggered by various microbial, inflammatory, and endogenous or exogenous stimuli. NETs are reportedly enriched in neutrophil-dominant refractory lung diseases, such as COPD and severe asthma. Evidence for a pathogenic role for respiratory viruses (e.g., Rhinovirus), bacteria (e.g., Staphylococcus aureus) and fungi (e.g., Aspergillus fumigatus) in NET induction is emerging. Dysregulation of this process may exert localized NET burden and contribute to NETopathic lung inflammation. Disentangling the role of NETs in human health and disease offer unique opportunities for therapeutic modulation. The chemokine CXCR2 receptor regulates neutrophil activation and migration, and small molecule CXCR2 antagonists (e.g., AZD5069, danirixin) have been developed to selectively block neutrophilic inflammatory pathways. NET-stabilizing agents using CXCR2 antagonists are being investigated in proof-of-concept studies in patients with COPD to provide mechanistic insights. Clinical validation of this type could lead to novel therapeutics for multiple CXCR2-related NETopathologies. In this Review, we discuss the emerging role of NETs in the clinicopathobiology of COPD and severe asthma and provide an outlook on how novel NET-stabilizing therapies via CXCR2 blockade could be leveraged to disrupt NETopathic inflammation in disease-specific phenotypes.

Dataset Information

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

Publications

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

Similar Datasets

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