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Serum amyloid A opposes lipoxin A 4 to mediate glucocorticoid refractory lung inflammation in chronic obstructive pulmonary disease
Open accessAbstract
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.
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“A recent article reported that the increase in the serum level of serum amyloid A (SAA) is associated with glucocorticoid resistance [6].”
From Picroside II Isolated from Pseudolysimachion rotundum var. subintegrum Inhibits Glucocorticoid Refractory Serum Amyloid A (SAA) Expression and SAA-induced IL-33 Secretion (2019) · cites this paper as [6]
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“It has been shown that DEX induces SAA expression on its own and synergistically increases LPS-induced SAA expression in THP-1 cells [6].”
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“It has been shown that SAA/IL-33 play a role in the pathology of steroid-resistant lung inflammation [6,15].”
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Metadata
- Authors
- Bozinovski, S., Uddin, M., Vlahos, R., Thompson, M., McQualter, J. L., Merritt, A.-S., Wark, P. A. B., Hutchinson, A., Irving, L. B., Levy, B. D., & Anderson, G. P.
- Affiliations
- The University of Melbourne (AU)
- Brigham and Women's Hospital (US)
- Department of Pharmacology, and
- The Royal Melbourne Hospital (AU)
- John Hunter Hospital (AU)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2012-01-03
- Volume
- 109
- Issue
- 3
- Pages
- 935-940
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3271884
- OpenAlex
- W1969944763
- Cited by
- 163
- References
- 35
- Citations by year
- 2026: 7 · 2025: 10 · 2024: 4 · 2023: 8 · 2022: 11 · 2021: 10 · 2020: 14 · 2019: 9 · 2018: 16 · 2017: 11 · 2016: 12 · 2015: 11 · 2014: 12 · 2013: 21 · 2012: 7
- FWCI
- 13.14
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- RMIT Research Repository (RMIT University Library) (submittedVersion)
- Deakin Research Online (Deakin University) (submittedVersion)
- Figshare (submittedVersion)
- Funders
- National Heart, Lung, and Blood Institute (R01HL090927, HL-68669, P50HL107166, HL090927, R01HL068669)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Chronic Obstructive Pulmonary Disease (COPD) Research
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Asthma and respiratory diseases
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Respiratory Support and Mechanisms
- Keywords
- serum amyloid A, lipoxin A4, chronic obstructive pulmonary disease, glucocorticoid resistance, lung inflammation, neutrophil recruitment, airway epithelial cells, interleukin-8, neutrophil elastase, acute exacerbation, lung macrophages, bronchoalveolar lavage fluid
- MeSH terms
- Serum Amyloid A Protein, Animals, Bronchoalveolar Lavage Fluid, Epithelial Cells, Epithelium, Glucocorticoids, Humans, Lung, Macrophages, Mucous Membrane, Neutrophils, Pneumonia, Interleukin-8, Neutrophil Activation, Pulmonary Disease, Chronic Obstructive, Receptors, Formyl Peptide, Lipoxins, Receptors, Lipoxin, Mice
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