Apolipoprotein A1 potentiates lipoxin A4 synthesis and recovery of allergen-induced disrupted tight junctions in the airway epithelium
ABSTRACT Asthma is characterized by chronic airway inflammation triggered by various allergens in the environment. Defects in the bronchial epithelial interface with the external environment are the hallmark of asthma. Apolipoprotein A-1 (ApoA1) or ApoA1 mimetics have demonstrated anti-inflammatory activity and preventive effects in mouse models.
We investigated airway levels of ApoA1 in asthmatics and the possible role of ApoA1 in protection of the bronchial epithelium and in resolution of inflammation in cellular and animal models of asthma.
ApoA1 levels were measured in bronchoalveolar lavage fluid (BALF) from asthmatics and healthy controls. With treatment of ApoA1, mouse model of house dust mite (HDM)-driven asthma and cultured primary bronchial epithelial cells obtained from asthmatics were examined. Tight junction (TJ) expression in the bronchial epithelial cells was assessed by using confocal microscopy and immunoblot.
Asthmatics showed significantly lower ApoA1 levels in bronchoalveolar lavage fluid than did healthy controls. Local ApoA1 treatment significantly decreased lung IL-25, IL-33, and thymic stromal lymphopoietin levels in HDM-challenged mice and inhibited allergen-induced production of these cytokines in cultured primary bronchial epithelial cells. ApoA1 promoted recovery of disrupted TJ proteins zonula occludens-1 and occludin in cultured primary bronchial epithelium obtained from asthmatics. ApoA1-induced increases in the TJ proteins were dependent on increased production of lipoxin A4 (LX A4 ).
ApoA1 enhances resolution of allergen-induced airway inflammation through promoting recovery of damaged TJs in the bronchial epithelium. ApoA1 could be a therapeutic strategy in chronic airway inflammatory diseases that are associated with a defective epithelial barrier, including asthma.
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ABSTRACT: The resolution of the inflammatory response is highly regulated by the timely biosynthesis of a number of endogenous lipid mediators. Among these, lipoxins (LX) and their 15-epimers, aspirin triggered lipoxins (ATL) derived by the lipoxygenase (LO) route of arachidonic acid metabolism. In particular, they are formed and released by cells expressing 5-, 12- and 15-LO such as leukocytes, platelets, vascular endothelium and epithelium, alone or during transcellular interactions. ATL biosynthesis requires cyclooxygenase-2 acetylation by aspirin. LX and ATL exert potent bioactions on leukocytes, vascular and epithelial cells to stop inflammation and promote resolution. They have shown to be beneficial in a broad spectrum of preclinical models of disease as well as in some clinical trials. Counter-regulatory signaling by LXA4 and 15-epi-LXA4 follows the activation of a G protein-coupled receptor, termed ALX/FPR2, which is emerging as a key anti-inflammatory receptor. Copyright © 2015. Published by Elsevier B.V.European journal of pharmacology 04/2015; 760. DOI:10.1016/j.ejphar.2015.03.083 · 2.68 Impact Factor
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ABSTRACT: Apolipoprotein A-I (apoA-I) is an important component of high density lipoprotein particles that mediates reverse cholesterol transport out of cells by interacting with the ATP-binding cassette transporter 1 (ABCA1). ApoA-I has also been shown to attenuate neutrophilic airway inflammation in experimental ovalbumin (OVA)-induced asthma by reducing the expression of granulocyte-colony stimulating factor (G-CSF). Here, we hypothesized that over-expression of the ABCA1 transporter might similarly attenuate OVA-induced neutrophilic airway inflammation. Tie2-hABCA1 mice expressing human ABCA1 under the control of the Tie2 promoter, which is primarily expressed by vascular endothelial cells, but can also be expressed by macrophages, received daily intranasal OVA challenges, 5 days a week for 5 weeks. OVA-challenged Tie2-hABCA1 mice had significant reductions in total bronchoalveolar lavage fluid (BALF) cells that reflected a decrease in neutrophils, as well as reductions in peri-bronchial inflammation, OVA-specific IgE levels and airway epithelial thickness. The reduced airway neutrophilia in OVA-challenged Tie2-hABCA1 mice was associated with significant decreases in G-CSF protein levels in pulmonary vascular endothelial cells, alveolar macrophages and BALF. Intranasal administration of recombinant murine G-CSF to OVA-challenged Tie2-hABCA1 mice for 5 days increased BALF neutrophils to a level comparable to that of OVA-challenged wild type mice. We conclude that ABCA1 suppresses OVA-induced airway neutrophilia by reducing G-CSF production by vascular endothelial cells and alveolar macrophages. These findings suggest that ABCA1 expressed by vascular endothelial cells and alveolar macrophages may play important roles in attenuating the severity of neutrophilic airway inflammation in asthma.American Journal of Respiratory Cell and Molecular Biology 05/2014; DOI:10.1165/rcmb.2013-0264OC · 4.11 Impact Factor
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ABSTRACT: Objectives/HypothesisNasal mucus is a defense barrier against aeroallergens. We recently found apolipoproteins to be elevated in the nasal mucus of allergic rhinitis patients. Apolipoproteins are involved in lipid metabolism, have immunomodulatory properties, and may represent interesting novel biomarkers. This study aims to validate our findings and analyze whether the increased abundance of apolipoproteins in nasal mucus is a local or systemic phenomenon in allergic rhinitis.Study Design: Prospective controlled trial.Methods Nasal mucus of allergic rhinitis patients (n = 10) and healthy controls (n = 12) was collected, tryptically digested, and analyzed by LC-MS/MS. Areas under the curve (AUCs) of the total peptides identified and matched to apolipoproteins were used to compare relative protein abundances of the same protein between groups.ResultsIn a total of 389 identified proteins in nasal mucus, apolipoproteins A-I, A-II, A-IV, and B 100 were detected. Apolipoprotein A-I (mean normalized AUC 1.49% [SEM = 0.5] vs. 0.42% [SEM = 0.2]) and A-II (mean normalized AUC 0.47% [SEM = 0.2] vs. 0.05% [SEM = 0.02]) were significantly more abundant in allergic rhinitis patients than controls (3.6-fold and 9.4-fold, respectively). Apolipoprotein A-IV (mean normalized AUC = 0.01%) and B-100 (mean normalized AUC = 0.02%) were each detected in only one allergic rhinitis patient out of 10. Myeloperoxidase was detected with a mean normalized AUC of 0.06% (SEM = 0.03) in allergic rhinitis patients and 0.18% (SEM = 0.08) in healthy controls without reaching significance.Conclusion This study confirms the significantly higher abundance of apolipoproteins A-I and AII in allergic rhinitis mucus. Their release seems to be triggered by local mechanisms as an antiinflammatory response to allergens.Level of Evidence3b. Laryngoscope, 2014The Laryngoscope 10/2014; 125(3). DOI:10.1002/lary.25003 · 2.03 Impact Factor