title: Apolipoprotein A-I attenuates ovalbumin-induced neutrophilic airway inflammation via a granulocyte colony-stimulating factor-dependent mechanism.
abstract: Apolipoprotein A-I (apoA-I) is a key component of high-density lipoproteins that mediates reverse cholesterol transport from cells and reduces vascular inflammation. We investigated whether endogenous apoA-I modulates ovalbumin (OVA)-induced airway inflammation in mice. We found that apoA-I expression was significantly reduced in the lungs of OVA-challenged, compared with saline-challenged, wild-type (WT) mice. Next, to investigate the role of endogenous apoA-I in the pathogenesis of OVA-induced airway inflammation, WT and apoA-I(-/-) mice were sensitized by intraperitoneal injections of OVA and aluminum hydroxide, followed by multiple nasal OVA challenges for 4 weeks. OVA-challenged apoA-I(-/-) mice exhibited a phenotype of increased airway neutrophils compared with WT mice, which could be rescued by an administration of a 5A apoA-I mimetic peptide. Multiple pathways promoted neutrophilic inflammation in OVA-challenged apoA-I(-/-) mice, including the up-regulated expression of (1) proinflammatory cytokines (IL-17A and TNF-α), (2) CXC chemokines (CXCL5), (3) vascular adhesion molecules (i.e., vascular cell adhesion molecule-1), and (4) granulocyte colony-stimulating factors (G-CSF). Because concentrations of G-CSF in bronchoalveolar lavage fluid (BALF) were markedly increased in OVA-challenged apoA-I(-/-) mice, we hypothesized that enhanced G-CSF expression may represent the predominant pathway mediating increased neutrophilic inflammation. This was confirmed by the intranasal administration of a neutralizing anti-G-CSF antibody, which significantly reduced BALF neutrophilia by 72% in OVA-challenged apoA-I(-/-) mice, compared with mice that received a control antibody. We conclude that endogenous apoA-I negatively regulates OVA-induced neutrophilic airway inflammation, primarily via a G-CSF-dependent mechanism. Furthermore, these findings suggest that apoA-I may play an important role in modulating the severity of neutrophilic airway inflammation in asthma.
authors.affiliation: Cardiovascular and Pulmonary Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892-1590, USA.
authors.forename: Cuilian
authors.initials: C
authors.lastname: Dai
authors.forename: Xianglan
authors.initials: X
authors.lastname: Yao
authors.forename: Karen J
authors.initials: KJ
authors.lastname: Keeran
authors.forename: Gayle J
authors.initials: GJ
authors.lastname: Zywicke
authors.forename: Xuan
authors.initials: X
authors.lastname: Qu
authors.forename: Zu-Xi
authors.initials: ZX
authors.lastname: Yu
authors.forename: Pradeep K
authors.initials: PK
authors.lastname: Dagur
authors.forename: J Philip
authors.initials: JP
authors.lastname: McCoy
authors.forename: Alan T
authors.initials: AT
authors.lastname: Remaley
authors.forename: Stewart J
authors.initials: SJ
authors.lastname: Levine
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000276:immunology / Q000494:pharmacology; D016632:Apolipoprotein A-I / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D001249:Asthma / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D054365:Chemokine CXCL5 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015536:Down-Regulation; D016179:Granulocyte Colony-Stimulating Factor / Q000276:immunology* / Q000378:metabolism; D007249:Inflammation / Q000188:drug therapy* / Q000276:immunology* / Q000378:metabolism; D020381:Interleukin-17 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D008168:Lung / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D010047:Ovalbumin / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015854:Up-Regulation; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics / Q000276:immunology
chemical_list: D057134:Antibodies, Neutralizing; D016632:Apolipoprotein A-I; D054365:Chemokine CXCL5; C094739:Cxcl5 protein, mouse; D020381:Interleukin-17; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; D016179:Granulocyte Colony-Stimulating Factor; D010047:Ovalbumin