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Commentary: Ahead of the Curve |

The A’s Have It: Developing Apolipoprotein A-I Mimetic Peptides Into a Novel Treatment for Asthma FREE TO VIEW

Xianglan Yao, MD, PhD; Elizabeth M. Gordon, PhD; Amisha V. Barochia, MBBS, MHS; Alan T. Remaley, MD, PhD; Stewart J. Levine, MD
Author and Funding Information

FUNDING/SUPPORT: This work was funded by the Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health (project number 1ZIAHL006054-06).

aLaboratory of Asthma and Lung Inflammation, Cardiovascular and Pulmonary Branch, Division of Intramural Research, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD

bLipoprotein Metabolism Section, Cardiovascular and Pulmonary Branch, Division of Intramural Research, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD

CORRESPONDENCE TO: Stewart J. Levine, MD, National Heart, Lung, and Blood Institute, National Institutes of Health, Bldg 10, Room 6D03, MSC 1590, Bethesda, MD 20892


Copyright 2016, . All Rights Reserved.


Chest. 2016;150(2):283-288. doi:10.1016/j.chest.2016.05.035
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New treatments are needed for patients with asthma who are refractory to standard therapies, such as individuals with a phenotype of “type 2-low” inflammation. This important clinical problem could potentially be addressed by the development of apolipoprotein A-I (apoA-I) mimetic peptides. ApoA-I interacts with its cellular receptor, the ATP-binding cassette subfamily A, member 1 (ABCA1), to facilitate cholesterol efflux out of cells to form nascent high-density lipoprotein particles. The ability of the apoA-I/ABCA1 pathway to promote cholesterol efflux from cells that mediate adaptive immunity, such as antigen-presenting cells, can attenuate their function. Data from experimental murine models have shown that the apoA-I/ABCA1 pathway can reduce neutrophilic airway inflammation, primarily by suppressing the production of granulocyte-colony stimulating factor. Furthermore, administration of apoA-I mimetic peptides to experimental murine models of allergic asthma has decreased both neutrophilic and eosinophilic airway inflammation, as well as airway hyperresponsiveness and mucous cell metaplasia. Higher serum levels of apoA-I have also been associated with less severe airflow obstruction in patients with asthma. Collectively, these results suggest that the apoA-I/ABCA1 pathway may have a protective effect in asthma, and support the concept of advancing inhaled apoA-I mimetic peptides to clinical trials that can assess their safety and effectiveness. Thus, we propose that the development of inhaled apoA-I mimetic peptides as a new treatment could represent a clinical advance for patients with severe asthma who are unresponsive to other therapies.

Figures in this Article

Asthma is a common disease that affects > 7% of the population in the United States. Since the 1970s, administration of inhaled corticosteroids to suppress airway inflammation has been the mainstay of asthma treatment. However, inhaled corticosteroids will only improve lung function in patients with asthma with a phenotype of “type 2-high” inflammation, as indicated by the increased expression of interleukin (IL)-13-inducible genes in airway epithelial cells. These patients with type 2-high asthma have eosinophilic airway inflammation, as well as increases in airway hyperresponsiveness (AHR), mucin gene expression, subepithelial fibrosis, and total immunoglobulin E (IgE) levels. In contrast, almost one-half of patients with asthma have a phenotype of “type 2-low” inflammation and do not exhibit improvements in airflow obstruction in response to treatment with corticosteroids. Therefore, new therapeutic approaches are needed for patients with asthma who do not respond to standard therapies, especially those with severe disease. This clinical problem could be addressed by the development of apolipoprotein A-I (apoA-I)-based therapies.

ApoA-I is the major structural protein of high-density lipoprotein (HDL), which has an important protective role in atherosclerotic vascular disease by mediating reverse cholesterol transport out of cells., In particular, apoA-I, which is synthesized in the liver and small intestine and secreted into the blood, interacts with the ATP-binding cassette subfamily A, member 1 (ABCA1), on cells (eg, macrophages) to facilitate the transfer of excess cellular cholesterol and phospholipids to nascent discoidal HDL particles. Nascent HDL then matures into spheroidal particles by a process involving the esterification and transfer of cholesterol to the hydrophobic HDL particle core by lecithin-cholesterol acyltransferase. These spheroidal HDL particles then promote efflux of additional cholesterol and phospholipids from peripheral cells via the ATP-binding cassette subfamily G, member 1, and the scavenger receptor class B member 1. In addition to its role in reverse cholesterol transport, HDL particles have increasingly been recognized to modulate innate and adaptive immune responses, as well as to have antiinflammatory, antioxidant, antithrombotic, and antifibrotic properties.,, This Ahead of the Curve article reviews the evidence supporting the concept of developing apoA-I mimetic peptides for the treatment of asthma.

Experimental results from murine models of experimental asthma have identified an unexpected role for the apoA-I/ABCA1 pathway in the pathogenesis of asthma. ApoA-I and ABCA1 are both expressed by alveolar epithelial cells and alveolar macrophages in the lung, whereas pulmonary vascular endothelial cells and airway smooth muscle cells also express ABCA1.,,,,, Mice with a genetic deletion of apoA-I have a phenotype of increased lung inflammation and oxidative stress, as well as enhanced AHR and collagen deposition. In addition, levels of HDL, as well as the antioxidant protein paraoxonase 1, are reduced in Apoa1-deficient mice.

Ovalbumin (OVA)-challenged Apoa1-deficient mice have a phenotype consistent with neutrophilic-predominant, type 2-low asthma with an increase in airway neutrophils that involved multiple pathways, including type 1 cytokines (interferon-γ and tumor necrosis factor-α), a type 17 cytokine (IL-17A), a CXC chemokine (CXCL5), a vascular adhesion molecule (vascular cell adhesion molecule-1), and granulocyte-colony stimulating factor (G-CSF). In contrast, type 2 cytokines (IL-4, IL-5, and IL-13) were not increased in this model. The enhanced neutrophilic airway inflammation in OVA-challenged Apoa1-deficient mice was primarily mediated by G-CSF, as administration of a neutralizing anti-GCSF antibody significantly reduced OVA-induced BAL fluid (BALF) neutrophil numbers. This outcome shows that apoA-I can attenuate neutrophilic airway inflammation in type 2-low experimental murine asthma via a G-CSF-dependent mechanism.

ApoA-I can also attenuate lipopolysaccharide (LPS)-mediated neutrophilic airway inflammation. This finding is relevant for asthma: inhalational LPS exposure has been associated with an increased risk for asthma and wheezing in the United States, whereas LPS inhalation by patients with asthma increases sputum neutrophil and CXCL8 levels.,, Furthermore, LPS signaling via Toll-like receptor 4 mediates neutrophilic, as well as eosinophilic, airway inflammatory responses to inhaled antigens in murine models of experimental asthma.,, Several mechanisms have been identified by which apoA-I can suppress LPS-mediated neutrophilic airway inflammation. LPS-challenged Apoa1-deficient mice have increased numbers of BALF neutrophils compared with wild-type mice. Suppression of CXCR2-mediated neutrophil chemotaxis in response to the CC chemokine CCL2 was identified as the mechanism by which apoA-I attenuated LPS-induced neutrophil recruitment to the lung. In addition, apoA-I can directly bind and neutralize LPS, and it can also partner with the LPS-binding protein as another mechanism to neutralize LPS activity.,, Furthermore, apoA-I can directly suppress neutrophil activation, with associated reductions in cellular adhesion, oxidative burst, and degranulation.,

Murine models of experimental asthma have also provided insights into the role of ATP-binding cassette transporters in the pathogenesis of asthma. OVA-challenged Tie2-hABCA1 transgenic mice, which conditionally overexpress the human ABCA1 transporter under the Tie2 promoter in vascular endothelial cells and macrophages, have attenuated neutrophilic airway inflammation, airway epithelial wall thickness, and serum levels of OVA-specific IgE. The attenuated neutrophilic airway inflammation in OVA-challenged Tie2-hABCA1 mice was associated with significant reductions in G-CSF protein expression by pulmonary vascular endothelial cells and alveolar macrophages, as well as reduced G-CSF protein levels in BALF. This outcome suggests that ABCA1 expression by vascular endothelial cells and macrophages may reduce allergen-induced neutrophilic airway inflammation by suppressing production of G-CSF.

Experiments performed by several laboratories have independently shown that administration of apoA-I or apoA-I mimetic peptides can attenuate the manifestations of allergen-induced experimental asthma. First, intranasal administration of the 5A apoA-I mimetic peptide to OVA-challenged Apoa-I knockout mice suppressed increases in neutrophilic airway inflammation. Similarly, administration of the apoA-I mimetic peptide, L-4F, to wild-type mice that received inhaled LPS reduced the number of BALF neutrophils. Second, systemic administration of the 5A apoA-I mimetic peptide coincident with intranasal administration of house dust mite to wild-type A/J mice significantly reduced the induction of airway inflammation with decreased numbers of BALF eosinophils, lymphocytes, and neutrophils. This reduction in airway inflammation was associated with decreases in type 2 cytokines (IL-4, IL-5, and IL-13), IL-17A, CC chemokines (CCL7, CCL11, CCL17, and CCL24), alternative macrophage activation, AHR, and mucous cell metaplasia. Third, intranasal administration of the D4F apoA-I mimetic peptide in a murine model of OVA-induced experimental asthma reduced airway inflammation, AHR, transforming growth factor-β, and lung collagen deposition, as well as total IgE and pro-inflammatory HDL in plasma. Lastly, intranasal administration of full-length human apoA-I to house dust mite-challenged mice reduced airway inflammation, with decreases in BALF eosinophils, neutrophils, lymphocytes, and macrophages, as well as AHR and lung levels of the airway epithelial cell-derived cytokines, IL-25, IL-33, and thymic stromal lymphopoietin, which promote allergic inflammation. Administration of apoA-I also increased the expression of airway epithelial cell tight junction proteins, as well as levels of lipoxin A4, an antiinflammatory and pro-resolving lipid mediator. Collectively, these experiments support the concept of developing apoA-I-based treatment approaches for asthma (Fig 1).

Figure 1
Figure Jump LinkFigure 1 Administration of apolipoprotein A-I mimetic peptides or human apolipoprotein A-I to murine models of experimental asthma attenuates both neutrophilic and eosinophilic airway inflammation, as well as airway hyperresponsiveness and airway remodeling. G-CSF = granulocyte-colony stimulating factor; IFN = interferon; IL = interleukin; TNF = tumor necrosis factor; TSLP = thymic stromal lymphopoietin; VCAM-1 = vascular cell adhesion molecule 1; ZO-1 = zonula occludens-1.Grahic Jump Location

An important mechanism by which the apoA-I/ABCA1 pathway may modulate the pathogenesis of asthma involves cholesterol efflux out of antigen-presenting cells that mediate adaptive immunity. Reduction of cellular cholesterol levels diminishes receptor localization to lipid raft domains and thereby attenuates signaling. For example, Abca1/Abcg1 double knockout mice have enhanced signaling via the IL-3/granulocyte-macrophage-CSF receptor, with resultant increases in blood neutrophils and monocytes, as well as bone marrow hematopoietic stem cells, common myeloid progenitor cells, and granulocyte-monocyte progenitor cells., The enhanced responsiveness to IL-3 and granulocyte-macrophage-CSF was caused by increased clustering of the common β subunit of the IL-3/granulocyte-macrophage-CSF receptor within lipid rafts that formed in response to excess cellular cholesterol. Treatment of murine antigen-presenting cells (eg, dendritic cells, macrophages, B cells) with apoA-I or HDL increases cholesterol efflux and decreases the abundance of membrane lipid raft domains, which thereby reduces MHC class II density and attenuates T-cell activation. Similarly, treatment of dendritic cells with recombinant HDL composed of apoA-I and lipids in a murine model of antigen-induced arthritis reduced cell surface expression of co-stimulatory molecules and attenuated the ability of dendritic cells to activate IFN-γ-producing Th1 cells, as well as IL-17-producing Th17 cells, via an ABCA1- and scavenger receptor class B member 1-dependent pathway.

Additional mechanisms have been identified by which apoA-I may modulate immune cell function. ApoA-I can inhibit the differentiation of human peripheral blood mononuclear cells into dendritic cells by increasing the production of IL-10 and prostaglandin E2. In hypercholesterolemic Ldlr/Apoa1 double knockout mice, administration of lipid-free apoA-I increased the number of regulatory T cells and decreased the number of effector/effector memory T cells in lymph nodes. However, in a murine model of normocholesterolemic systemic lupus erythematosus, apoA-I overexpressing transgenic mice exhibited a reduction in Th1 cells that was independent of cholesterol or changes in regulatory T cells or dendritic cells. Instead, apoA-I increased the production of oxidized metabolites of linoleic acid (eg, hydroxyoctadecadienoic acids) and arachidonic acid (eg, hydroxyeicosatetraenoic acids) that activate peroxisome proliferator-activated receptor-γ. These studies suggest that the mechanism by which apoA-I regulates T-cell function may be context dependent and modified in the setting of hypercholesterolemia and obesity. In addition, apoA-I blocks the contact-mediated activation of monocytes by stimulated T cells, with a resultant decrease in tumor necrosis factor-α and IL-1β. The role of the apoA-I/ABCA1 pathway in modifying innate and adaptive immune responses in patients with asthma, however, has yet to be defined.

The apoA-I/ABCA1 pathway may also modulate the function of airway structural cells in asthma. For example, ABCA1 mediates the efflux of cholesterol and phospholipids from human airway smooth muscle cells in response to activation of liver X receptors (LXR-α and LXR-β), which are nuclear receptors that induce the expression of both ABCA1 and ATP-binding cassette subfamily G, member 1. This scenario suggests that modulation of cholesterol homeostasis in airway smooth muscle cells by ABCA1 may directly influence the pathologic manifestations of asthma. Taken collectively, the ability of apoA-I to interact with the ABCA1 transporter and promote efflux of cholesterol out of both immune and structural cells represents a mechanism by which asthma severity may be modified.

Studies have begun to investigate the role of apoA-I in human subjects with asthma. For example, apoA-I levels in BALF were found to be decreased in patients with mild to moderate asthma who were not being treated with asthma medications. Similarly, protein levels of apoA-I were reduced in the lungs of wild-type mice that had been sensitized and challenged with OVA. The reduction of apoA-I in BALF from mice and humans suggests that disease severity might be augmented in subjects with asthma due to lower levels of apoA-I in the lung. In addition, apoA-I has been shown to attenuate production of IL-25, IL-33, and thymic stromal lymphopoietin by normal human bronchial epithelial cells in response to cockroach extract or a house dust mite allergen (Der p1).

Clinical studies have also shown an association between higher serum apoA-I levels and less severe airflow obstruction in patients with asthma. An analysis of 14,135 subjects without respiratory disease who participated in the Third National Health and Nutrition Examination Survey found that serum levels of both apoA-I and HDL were positively correlated with FEV1. Recently, we reported a cross-sectional analysis of 159 subjects with atopic asthma, which similarly showed a positive correlation between FEV1 and serum levels of apoA-I, as well as HDL-cholesterol. Furthermore, serum samples were analyzed by using nuclear magnetic resonance spectroscopy to identify the subset of HDL particles that mediated the association with FEV1. This technique measures the nuclear magnetic resonance proton signal from the terminal methyl group on lipids to determine the amount of each type of lipoprotein particle and also categorizes lipoprotein particles based on size. This analysis identified that the subset of large HDL particles, but not the small- or medium-sized HDL particles, were specifically associated with higher FEV1 in subjects with asthma. Interestingly, the concentration of large HDL particles has also been associated with a reduction in risk of cardiovascular disease in healthy women.

We propose that the available data from animal and human studies support the concept of developing apoA-I-based therapies for asthma. One approach for the delivery of apoA-I to the lung for the treatment of asthma is to use apoA-I mimetic peptides, which have successfully attenuated disease activity in murine asthma models.,

ApoA-I mimetic peptides have an amphipathic α- helical structure that resembles the secondary structure of the native apoA-I protein, which is a tandem array of 10 class A amphipathic α-helices that mediate interactions with lipids., ApoA-I mimetic peptides can facilitate reverse cholesterol transfer out of cells, as well as promote antiinflammatory, antioxidant, and other antiatherogenic effects. Advantages of apoA-I mimetic peptides over full-length apoA-I relate to the relative ease and lower cost of synthesis. Murine asthma studies have used the D4F and 5A apoA-I mimetic peptides, whereas additional apoA-I mimetic peptides are actively being developed., The D4F apoA-I mimetic peptide is an 18 amino acid peptide comprised of D-amino acids. The 5A apoA-I mimetic peptide is composed of two 18 amino acid peptides linked by a proline, one of which is a high lipid affinity helix and the other is a low lipid affinity helix. This design allows the 5A peptide to specifically mediate phospholipid efflux from cells via ABCA1 with low associated cellular toxicity. The D4F apoA-I mimetic peptide has already been safely administered orally in clinical trials to human subjects with cardiovascular disease, providing evidence to support the concept that apoA-I mimetic peptide therapy for asthma is potentially feasible., Furthermore, the 5A peptide is currently being developed for human clinical trials of atherosclerotic vascular disease by intravenous administration.

Because medications can be directly delivered to the respiratory system by inhalation, it would be reasonable for clinical trials of apoA-I mimetic peptides in asthma to utilize this approach, in which they could potentially directly interact with ABCA1 transporters expressed by lung cells.

Based on the emerging body of evidence from preclinical murine models regarding the protective role of apoA-I in asthma, as well as human translational studies that have shown an association between serum apoA-I levels and FEV1 in patients with asthma, we propose that a reasonable next step is to advance apoA-I mimetic peptides from the laboratory to clinical trials in which their safety and efficacy can be evaluated. Furthermore, clinical trials of inhaled apoA-I mimetic peptides can establish whether this method represents an effective therapeutic approach for asthma. In particular, we propose that the development of apoA-I mimetic peptides could represent an important clinical advance as a new treatment for patients with severe asthma who are refractory to standard treatment with corticosteroids. This option could be particularly relevant for patients with asthma and a type 2-low phenotype of neutrophilic-predominant airway inflammation because therapies do not currently exist for these individuals. ApoA-I mimetic peptides could additionally represent a treatment option for patients with type 2-high asthma eosinophilic-predominant airway inflammation.

Financial/nonfinancial disclosures: A. T. R. is the holder of patents issued regarding the 5A apoA-I mimetic peptide. None declared (X. Y., E. M. G., A. V. B., S. J. L.).

Role of sponsors: The sponsor had no role in the design of the study, the collection and analysis of the data, or the preparation of the manuscript.

National Current Asthma Prevalence (2014). Centers for Disease Control and Prevention website.http://www.cdc.gov/asthma/most_recent_data.htm. Accessed June 28, 2016.
 
Gauthier M. .Ray A. .Wenzel S.E. . Evolving concepts of asthma. Am J Respir Crit Care Med. 2015;192:660-668 [PubMed]journal. [CrossRef] [PubMed]
 
Woodruff P.G. .Modrek B. .Choy D.F. .et al T-helper type 2-driven inflammation defines major subphenotypes of asthma. Am J Respir Crit Care Med. 2009;180:388-395 [PubMed]journal. [CrossRef] [PubMed]
 
Kingwell B.A. .Chapman M.J. .Kontush A. .Miller N.E. . HDL-targeted therapies: progress, failures and future. Nat Rev Drug Discov. 2014;13:445-464 [PubMed]journal. [CrossRef] [PubMed]
 
Rosenson R.S. .Brewer H.B. Jr..Davidson W.S. .et al Cholesterol efflux and atheroprotection: advancing the concept of reverse cholesterol transport. Circulation. 2012;125:1905-1919 [PubMed]journal. [CrossRef] [PubMed]
 
Catapano A.L. .Pirillo A. .Bonacina F. .Norata G.D. . HDL in innate and adaptive immunity. Cardiovasc Res. 2014;103:372-383 [PubMed]journal. [CrossRef] [PubMed]
 
Navab M. .Reddy S.T. .Van Lenten B.J. .Fogelman A.M. . HDL and cardiovascular disease: atherogenic and atheroprotective mechanisms. Nat Rev Cardiol. 2011;8:222-232 [PubMed]journal. [CrossRef] [PubMed]
 
Osei-Hwedieh D.O. .Amar M. .Sviridov D. .Remaley A.T. . Apolipoprotein mimetic peptides: mechanisms of action as anti-atherogenic agents. Pharmacol Ther. 2011;130:83-91 [PubMed]journal. [CrossRef] [PubMed]
 
Dai C. .Yao X. .Keeran K.J. .et al Apolipoprotein A-I attenuates ovalbumin-induced neutrophilic airway inflammation via a granulocyte colony-stimulating factor-dependent mechanism. Am J Respir Cell Mol Biol. 2012;47:186-195 [PubMed]journal. [CrossRef] [PubMed]
 
Kim T.H. .Lee Y.H. .Kim K.H. .et al Role of lung apolipoprotein A-I in idiopathic pulmonary fibrosis: antiinflammatory and antifibrotic effect on experimental lung injury and fibrosis. Am J Respir Crit Care Med. 2010;182:633-642 [PubMed]journal. [CrossRef] [PubMed]
 
Dai C. .Yao X. .Vaisman B. .et al ATP-binding cassette transporter 1 attenuates ovalbumin-induced neutrophilic airway inflammation. Am J Respir Cell Mol Biol. 2014;51:626-636 [PubMed]journal. [CrossRef] [PubMed]
 
Bates S.R. .Tao J.Q. .Yu K.J. .et al Expression and biological activity of ABCA1 in alveolar epithelial cells. Am J Respir Cell Mol Biol. 2008;38:283-292 [PubMed]journal. [CrossRef] [PubMed]
 
Bortnick A.E. .Favari E. .Tao J.Q. .et al Identification and characterization of rodent ABCA1 in isolated type II pneumocytes. Am J Physiol Lung Cell Mol Physiol. 2003;285:L869-L878 [PubMed]journal. [CrossRef] [PubMed]
 
Delvecchio C.J. .Bilan P. .Nair P. .Capone J.P. . LXR-induced reverse cholesterol transport in human airway smooth muscle is mediated exclusively by ABCA1. Am J Physiol Lung Cell Mol Physiol. 2008;295:L949-L957 [PubMed]journal. [CrossRef] [PubMed]
 
Wang W. .Xu H. .Shi Y. .et al Genetic deletion of apolipoprotein A-I increases airway hyperresponsiveness, inflammation, and collagen deposition in the lung. J Lipid Res. 2010;51:2560-2570 [PubMed]journal. [CrossRef] [PubMed]
 
Nightingale J.A. .Rogers D.F. .Hart L.A. .Kharitonov S.A. .Chung K.F. .Barnes P.J. . Effect of inhaled endotoxin on induced sputum in normal, atopic, and atopic asthmatic subjects. Thorax. 1998;53:563-571 [PubMed]journal. [CrossRef] [PubMed]
 
Thorne P.S. .Kulhankova K. .Yin M. .Cohn R. .Arbes S.J. Jr..Zeldin D.C. . Endotoxin exposure is a risk factor for asthma: the national survey of endotoxin in United States housing. Am J Respir Crit Care Med. 2005;172:1371-1377 [PubMed]journal. [CrossRef] [PubMed]
 
Thorne P.S. .Mendy A. .Metwali N. .et al Endotoxin exposure: predictors and prevalence of associated asthma outcomes in the United States. Am J Respir Crit Care Med. 2015;192:1287-1297 [PubMed]journal. [CrossRef] [PubMed]
 
Eisenbarth S.C. .Piggott D.A. .Huleatt J.W. .Visintin I. .Herrick C.A. .Bottomly K. . Lipopolysaccharide-enhanced, Toll-like receptor 4-dependent T helper cell type 2 responses to inhaled antigen. J Exp Med. 2002;196:1645-1651 [PubMed]journal. [CrossRef] [PubMed]
 
Hammad H. .Chieppa M. .Perros F. .Willart M.A. .Germain R.N. .Lambrecht B.N. . House dust mite allergen induces asthma via Toll-like receptor 4 triggering of airway structural cells. Nat Med. 2009;15:410-416 [PubMed]journal. [CrossRef] [PubMed]
 
McAlees J.W. .Whitehead G.S. .Harley I.T. .et al Distinct Tlr4-expressing cell compartments control neutrophilic and eosinophilic airway inflammation. Mucosal Immunol. 2015;8:863-873 [PubMed]journal. [CrossRef] [PubMed]
 
Madenspacher J.H. .Azzam K.M. .Gong W. .et al Apolipoproteins and apolipoprotein mimetic peptides modulate phagocyte trafficking through chemotactic activity. J Biol Chem. 2012;287:43730-43740 [PubMed]journal. [CrossRef] [PubMed]
 
Emancipator K. .Csako G. .Elin R.J. . In vitro inactivation of bacterial endotoxin by human lipoproteins and apolipoproteins. Infect Immun. 1992;60:596-601 [PubMed]journal. [PubMed]
 
Henning M.F. .Herlax V. .Bakas L. . Contribution of the C-terminal end of apolipoprotein AI to neutralization of lipopolysaccharide endotoxic effect. Innate immunity. 2011;17:327-337 [PubMed]journal. [CrossRef] [PubMed]
 
Wurfel M.M. .Kunitake S.T. .Lichenstein H. .Kane J.P. .Wright S.D. . Lipopolysaccharide (LPS)-binding protein is carried on lipoproteins and acts as a cofactor in the neutralization of LPS. J Exp Med. 1994;180:1025-1035 [PubMed]journal. [CrossRef] [PubMed]
 
Liao X.L. .Lou B. .Ma J. .Wu M.P. . Neutrophils activation can be diminished by apolipoprotein A-I. Life Sci. 2005;77:325-335 [PubMed]journal. [CrossRef] [PubMed]
 
Blackburn W.D. Jr..Dohlman J.G. .Venkatachalapathi Y.V. .et al Apolipoprotein A-I decreases neutrophil degranulation and superoxide production. J Lipid Res. 1991;32:1911-1918 [PubMed]journal. [PubMed]
 
Yao X. .Dai C. .Fredriksson K. .et al 5A, an apolipoprotein A-I mimetic peptide, attenuates the induction of house dust mite-induced asthma. J Immunol. 2011;186:576-583 [PubMed]journal. [CrossRef] [PubMed]
 
Nandedkar S.D. .Weihrauch D. .Xu H. .et al D-4F, an apoA-1 mimetic, decreases airway hyperresponsiveness, inflammation, and oxidative stress in a murine model of asthma. J Lipid Res. 2011;52:499-508 [PubMed]journal. [CrossRef] [PubMed]
 
Park S.W. .Lee E.H. .Lee E.J. .et al Apolipoprotein A1 potentiates lipoxin A4 synthesis and recovery of allergen-induced disrupted tight junctions in the airway epithelium. Clin Exp Allergy. 2013;43:914-927 [PubMed]journal. [CrossRef] [PubMed]
 
Hansson G.K. .Bjorkholm M. . Tackling two diseases with HDL. Science. 2010;328:1641-1642 [PubMed]journal. [CrossRef] [PubMed]
 
Yvan-Charvet L. .Pagler T. .Gautier E.L. .et al ATP-binding cassette transporters and HDL suppress hematopoietic stem cell proliferation. Science. 2010;328:1689-1693 [PubMed]journal. [CrossRef] [PubMed]
 
Wang S.H. .Yuan S.G. .Peng D.Q. .Zhao S.P. . HDL and ApoA-I inhibit antigen presentation-mediated T cell activation by disrupting lipid rafts in antigen presenting cells. Atherosclerosis. 2012;225:105-114 [PubMed]journal. [CrossRef] [PubMed]
 
Tiniakou I. .Drakos E. .Sinatkas V. .et al High-density lipoprotein attenuates Th1 and th17 autoimmune responses by modulating dendritic cell maturation and function. J Immunol. 2015;194:4676-4687 [PubMed]journal. [CrossRef] [PubMed]
 
Kim K.D. .Lim H.Y. .Lee H.G. .et al Apolipoprotein A-I induces IL-10 and PGE2 production in human monocytes and inhibits dendritic cell differentiation and maturation. Biochem Biophys Res Commun. 2005;338:1126-1136 [PubMed]journal. [CrossRef] [PubMed]
 
Wilhelm A.J. .Zabalawi M. .Owen J.S. .et al Apolipoprotein A-I modulates regulatory T cells in autoimmune LDLr-/-, ApoA-I-/- mice. J Biol Chem. 2010;285:36158-36169 [PubMed]journal. [CrossRef] [PubMed]
 
Black L.L. .Srivastava R. .Schoeb T.R. .Moore R.D. .Barnes S. .Kabarowski J.H. . Cholesterol-independent suppression of lymphocyte activation, autoimmunity, and glomerulonephritis by apolipoprotein A-I in normocholesterolemic lupus-prone mice. J Immunol. 2015;195:4685-4698 [PubMed]journal. [CrossRef] [PubMed]
 
Hyka N. .Dayer J.M. .Modoux C. .et al Apolipoprotein A-I inhibits the production of interleukin-1beta and tumor necrosis factor-alpha by blocking contact-mediated activation of monocytes by T lymphocytes. Blood. 2001;97:2381-2389 [PubMed]journal. [CrossRef] [PubMed]
 
Cirillo D.J. .Agrawal Y. .Cassano P.A. . Lipids and pulmonary function in the Third National Health and Nutrition Examination Survey. Am J Epidemiol. 2002;155:842-848 [PubMed]journal. [CrossRef] [PubMed]
 
Barochia A.V. .Kaler M. .Cuento R.A. .et al Serum apolipoprotein A-I and large high-density lipoprotein particles are positively correlated with FEV1 in atopic asthma. Am J Respir Crit Care Med. 2015;191:990-1000 [PubMed]journal. [CrossRef] [PubMed]
 
Rosenson R.S. .Brewer H.B. Jr..Chapman M.J. .et al HDL measures, particle heterogeneity, proposed nomenclature, and relation to atherosclerotic cardiovascular events. Clin Chem. 2011;57:392-410 [PubMed]journal. [CrossRef] [PubMed]
 
Mora S. .Otvos J.D. .Rifai N. .Rosenson R.S. .Buring J.E. .Ridker P.M. . Lipoprotein particle profiles by nuclear magnetic resonance compared with standard lipids and apolipoproteins in predicting incident cardiovascular disease in women. Circulation. 2009;119:931-939 [PubMed]journal. [CrossRef] [PubMed]
 
Getz G.S. .Wool G.D. .Reardon C.A. . Apoprotein A-I mimetic peptides and their potential anti-atherogenic mechanisms of action. Curr Opin Lipidol. 2009;20:171-175 [PubMed]journal. [CrossRef] [PubMed]
 
Segrest J.P. .Jones M.K. .De Loof H. .Brouillette C.G. .Venkatachalapathi Y.V. .Anantharamaiah G.M. . The amphipathic helix in the exchangeable apolipoproteins: a review of secondary structure and function. J Lipid Res. 1992;33:141-166 [PubMed]journal. [PubMed]
 
Leman L.J. .Maryanoff B.E. .Ghadiri M.R. . Molecules that mimic apolipoprotein A-I: potential agents for treating atherosclerosis. J Med Chem. 2014;57:2169-2196 [PubMed]journal. [CrossRef] [PubMed]
 
Reddy S.T. .Navab M. .Anantharamaiah G.M. .Fogelman A.M. . Apolipoprotein A-I mimetics. Curr Opin Lipidol. 2014;25:304-308 [PubMed]journal. [CrossRef] [PubMed]
 
Navab M. .Anantharamaiah G.M. .Hama S. .et al Oral administration of an apo A-I mimetic peptide synthesized from D-amino acids dramatically reduces atherosclerosis in mice independent of plasma cholesterol. Circulation. 2002;105:290-292 [PubMed]journal. [CrossRef] [PubMed]
 
Sethi A.A. .Stonik J.A. .Thomas F. .et al Asymmetry in the lipid affinity of bihelical amphipathic peptides. A structural determinant for the specificity of ABCA1-dependent cholesterol efflux by peptides. J Biol Chem. 2008;283:32273-32282 [PubMed]journal. [CrossRef] [PubMed]
 
Bloedon L.T. .Dunbar R. .Duffy D. .et al Safety, pharmacokinetics, and pharmacodynamics of oral apoA-I mimetic peptide D-4F in high-risk cardiovascular patients. J Lipid Res. 2008;49:1344-1352 [PubMed]journal. [CrossRef] [PubMed]
 
Dunbar R.L. .Bloedon L.T. .Duffy D. .et al Daily oral administration of the apolipoprotein A-I mimetic peptide D-4F in patients with heart disease or equivalent risk improves high-density lipoprotein anti-inflammatory function [abstract]. J Am Coll Cardiol. 2007;49:366A- [PubMed]journal
 

Figures

Figure Jump LinkFigure 1 Administration of apolipoprotein A-I mimetic peptides or human apolipoprotein A-I to murine models of experimental asthma attenuates both neutrophilic and eosinophilic airway inflammation, as well as airway hyperresponsiveness and airway remodeling. G-CSF = granulocyte-colony stimulating factor; IFN = interferon; IL = interleukin; TNF = tumor necrosis factor; TSLP = thymic stromal lymphopoietin; VCAM-1 = vascular cell adhesion molecule 1; ZO-1 = zonula occludens-1.Grahic Jump Location

Tables

References

National Current Asthma Prevalence (2014). Centers for Disease Control and Prevention website.http://www.cdc.gov/asthma/most_recent_data.htm. Accessed June 28, 2016.
 
Gauthier M. .Ray A. .Wenzel S.E. . Evolving concepts of asthma. Am J Respir Crit Care Med. 2015;192:660-668 [PubMed]journal. [CrossRef] [PubMed]
 
Woodruff P.G. .Modrek B. .Choy D.F. .et al T-helper type 2-driven inflammation defines major subphenotypes of asthma. Am J Respir Crit Care Med. 2009;180:388-395 [PubMed]journal. [CrossRef] [PubMed]
 
Kingwell B.A. .Chapman M.J. .Kontush A. .Miller N.E. . HDL-targeted therapies: progress, failures and future. Nat Rev Drug Discov. 2014;13:445-464 [PubMed]journal. [CrossRef] [PubMed]
 
Rosenson R.S. .Brewer H.B. Jr..Davidson W.S. .et al Cholesterol efflux and atheroprotection: advancing the concept of reverse cholesterol transport. Circulation. 2012;125:1905-1919 [PubMed]journal. [CrossRef] [PubMed]
 
Catapano A.L. .Pirillo A. .Bonacina F. .Norata G.D. . HDL in innate and adaptive immunity. Cardiovasc Res. 2014;103:372-383 [PubMed]journal. [CrossRef] [PubMed]
 
Navab M. .Reddy S.T. .Van Lenten B.J. .Fogelman A.M. . HDL and cardiovascular disease: atherogenic and atheroprotective mechanisms. Nat Rev Cardiol. 2011;8:222-232 [PubMed]journal. [CrossRef] [PubMed]
 
Osei-Hwedieh D.O. .Amar M. .Sviridov D. .Remaley A.T. . Apolipoprotein mimetic peptides: mechanisms of action as anti-atherogenic agents. Pharmacol Ther. 2011;130:83-91 [PubMed]journal. [CrossRef] [PubMed]
 
Dai C. .Yao X. .Keeran K.J. .et al Apolipoprotein A-I attenuates ovalbumin-induced neutrophilic airway inflammation via a granulocyte colony-stimulating factor-dependent mechanism. Am J Respir Cell Mol Biol. 2012;47:186-195 [PubMed]journal. [CrossRef] [PubMed]
 
Kim T.H. .Lee Y.H. .Kim K.H. .et al Role of lung apolipoprotein A-I in idiopathic pulmonary fibrosis: antiinflammatory and antifibrotic effect on experimental lung injury and fibrosis. Am J Respir Crit Care Med. 2010;182:633-642 [PubMed]journal. [CrossRef] [PubMed]
 
Dai C. .Yao X. .Vaisman B. .et al ATP-binding cassette transporter 1 attenuates ovalbumin-induced neutrophilic airway inflammation. Am J Respir Cell Mol Biol. 2014;51:626-636 [PubMed]journal. [CrossRef] [PubMed]
 
Bates S.R. .Tao J.Q. .Yu K.J. .et al Expression and biological activity of ABCA1 in alveolar epithelial cells. Am J Respir Cell Mol Biol. 2008;38:283-292 [PubMed]journal. [CrossRef] [PubMed]
 
Bortnick A.E. .Favari E. .Tao J.Q. .et al Identification and characterization of rodent ABCA1 in isolated type II pneumocytes. Am J Physiol Lung Cell Mol Physiol. 2003;285:L869-L878 [PubMed]journal. [CrossRef] [PubMed]
 
Delvecchio C.J. .Bilan P. .Nair P. .Capone J.P. . LXR-induced reverse cholesterol transport in human airway smooth muscle is mediated exclusively by ABCA1. Am J Physiol Lung Cell Mol Physiol. 2008;295:L949-L957 [PubMed]journal. [CrossRef] [PubMed]
 
Wang W. .Xu H. .Shi Y. .et al Genetic deletion of apolipoprotein A-I increases airway hyperresponsiveness, inflammation, and collagen deposition in the lung. J Lipid Res. 2010;51:2560-2570 [PubMed]journal. [CrossRef] [PubMed]
 
Nightingale J.A. .Rogers D.F. .Hart L.A. .Kharitonov S.A. .Chung K.F. .Barnes P.J. . Effect of inhaled endotoxin on induced sputum in normal, atopic, and atopic asthmatic subjects. Thorax. 1998;53:563-571 [PubMed]journal. [CrossRef] [PubMed]
 
Thorne P.S. .Kulhankova K. .Yin M. .Cohn R. .Arbes S.J. Jr..Zeldin D.C. . Endotoxin exposure is a risk factor for asthma: the national survey of endotoxin in United States housing. Am J Respir Crit Care Med. 2005;172:1371-1377 [PubMed]journal. [CrossRef] [PubMed]
 
Thorne P.S. .Mendy A. .Metwali N. .et al Endotoxin exposure: predictors and prevalence of associated asthma outcomes in the United States. Am J Respir Crit Care Med. 2015;192:1287-1297 [PubMed]journal. [CrossRef] [PubMed]
 
Eisenbarth S.C. .Piggott D.A. .Huleatt J.W. .Visintin I. .Herrick C.A. .Bottomly K. . Lipopolysaccharide-enhanced, Toll-like receptor 4-dependent T helper cell type 2 responses to inhaled antigen. J Exp Med. 2002;196:1645-1651 [PubMed]journal. [CrossRef] [PubMed]
 
Hammad H. .Chieppa M. .Perros F. .Willart M.A. .Germain R.N. .Lambrecht B.N. . House dust mite allergen induces asthma via Toll-like receptor 4 triggering of airway structural cells. Nat Med. 2009;15:410-416 [PubMed]journal. [CrossRef] [PubMed]
 
McAlees J.W. .Whitehead G.S. .Harley I.T. .et al Distinct Tlr4-expressing cell compartments control neutrophilic and eosinophilic airway inflammation. Mucosal Immunol. 2015;8:863-873 [PubMed]journal. [CrossRef] [PubMed]
 
Madenspacher J.H. .Azzam K.M. .Gong W. .et al Apolipoproteins and apolipoprotein mimetic peptides modulate phagocyte trafficking through chemotactic activity. J Biol Chem. 2012;287:43730-43740 [PubMed]journal. [CrossRef] [PubMed]
 
Emancipator K. .Csako G. .Elin R.J. . In vitro inactivation of bacterial endotoxin by human lipoproteins and apolipoproteins. Infect Immun. 1992;60:596-601 [PubMed]journal. [PubMed]
 
Henning M.F. .Herlax V. .Bakas L. . Contribution of the C-terminal end of apolipoprotein AI to neutralization of lipopolysaccharide endotoxic effect. Innate immunity. 2011;17:327-337 [PubMed]journal. [CrossRef] [PubMed]
 
Wurfel M.M. .Kunitake S.T. .Lichenstein H. .Kane J.P. .Wright S.D. . Lipopolysaccharide (LPS)-binding protein is carried on lipoproteins and acts as a cofactor in the neutralization of LPS. J Exp Med. 1994;180:1025-1035 [PubMed]journal. [CrossRef] [PubMed]
 
Liao X.L. .Lou B. .Ma J. .Wu M.P. . Neutrophils activation can be diminished by apolipoprotein A-I. Life Sci. 2005;77:325-335 [PubMed]journal. [CrossRef] [PubMed]
 
Blackburn W.D. Jr..Dohlman J.G. .Venkatachalapathi Y.V. .et al Apolipoprotein A-I decreases neutrophil degranulation and superoxide production. J Lipid Res. 1991;32:1911-1918 [PubMed]journal. [PubMed]
 
Yao X. .Dai C. .Fredriksson K. .et al 5A, an apolipoprotein A-I mimetic peptide, attenuates the induction of house dust mite-induced asthma. J Immunol. 2011;186:576-583 [PubMed]journal. [CrossRef] [PubMed]
 
Nandedkar S.D. .Weihrauch D. .Xu H. .et al D-4F, an apoA-1 mimetic, decreases airway hyperresponsiveness, inflammation, and oxidative stress in a murine model of asthma. J Lipid Res. 2011;52:499-508 [PubMed]journal. [CrossRef] [PubMed]
 
Park S.W. .Lee E.H. .Lee E.J. .et al Apolipoprotein A1 potentiates lipoxin A4 synthesis and recovery of allergen-induced disrupted tight junctions in the airway epithelium. Clin Exp Allergy. 2013;43:914-927 [PubMed]journal. [CrossRef] [PubMed]
 
Hansson G.K. .Bjorkholm M. . Tackling two diseases with HDL. Science. 2010;328:1641-1642 [PubMed]journal. [CrossRef] [PubMed]
 
Yvan-Charvet L. .Pagler T. .Gautier E.L. .et al ATP-binding cassette transporters and HDL suppress hematopoietic stem cell proliferation. Science. 2010;328:1689-1693 [PubMed]journal. [CrossRef] [PubMed]
 
Wang S.H. .Yuan S.G. .Peng D.Q. .Zhao S.P. . HDL and ApoA-I inhibit antigen presentation-mediated T cell activation by disrupting lipid rafts in antigen presenting cells. Atherosclerosis. 2012;225:105-114 [PubMed]journal. [CrossRef] [PubMed]
 
Tiniakou I. .Drakos E. .Sinatkas V. .et al High-density lipoprotein attenuates Th1 and th17 autoimmune responses by modulating dendritic cell maturation and function. J Immunol. 2015;194:4676-4687 [PubMed]journal. [CrossRef] [PubMed]
 
Kim K.D. .Lim H.Y. .Lee H.G. .et al Apolipoprotein A-I induces IL-10 and PGE2 production in human monocytes and inhibits dendritic cell differentiation and maturation. Biochem Biophys Res Commun. 2005;338:1126-1136 [PubMed]journal. [CrossRef] [PubMed]
 
Wilhelm A.J. .Zabalawi M. .Owen J.S. .et al Apolipoprotein A-I modulates regulatory T cells in autoimmune LDLr-/-, ApoA-I-/- mice. J Biol Chem. 2010;285:36158-36169 [PubMed]journal. [CrossRef] [PubMed]
 
Black L.L. .Srivastava R. .Schoeb T.R. .Moore R.D. .Barnes S. .Kabarowski J.H. . Cholesterol-independent suppression of lymphocyte activation, autoimmunity, and glomerulonephritis by apolipoprotein A-I in normocholesterolemic lupus-prone mice. J Immunol. 2015;195:4685-4698 [PubMed]journal. [CrossRef] [PubMed]
 
Hyka N. .Dayer J.M. .Modoux C. .et al Apolipoprotein A-I inhibits the production of interleukin-1beta and tumor necrosis factor-alpha by blocking contact-mediated activation of monocytes by T lymphocytes. Blood. 2001;97:2381-2389 [PubMed]journal. [CrossRef] [PubMed]
 
Cirillo D.J. .Agrawal Y. .Cassano P.A. . Lipids and pulmonary function in the Third National Health and Nutrition Examination Survey. Am J Epidemiol. 2002;155:842-848 [PubMed]journal. [CrossRef] [PubMed]
 
Barochia A.V. .Kaler M. .Cuento R.A. .et al Serum apolipoprotein A-I and large high-density lipoprotein particles are positively correlated with FEV1 in atopic asthma. Am J Respir Crit Care Med. 2015;191:990-1000 [PubMed]journal. [CrossRef] [PubMed]
 
Rosenson R.S. .Brewer H.B. Jr..Chapman M.J. .et al HDL measures, particle heterogeneity, proposed nomenclature, and relation to atherosclerotic cardiovascular events. Clin Chem. 2011;57:392-410 [PubMed]journal. [CrossRef] [PubMed]
 
Mora S. .Otvos J.D. .Rifai N. .Rosenson R.S. .Buring J.E. .Ridker P.M. . Lipoprotein particle profiles by nuclear magnetic resonance compared with standard lipids and apolipoproteins in predicting incident cardiovascular disease in women. Circulation. 2009;119:931-939 [PubMed]journal. [CrossRef] [PubMed]
 
Getz G.S. .Wool G.D. .Reardon C.A. . Apoprotein A-I mimetic peptides and their potential anti-atherogenic mechanisms of action. Curr Opin Lipidol. 2009;20:171-175 [PubMed]journal. [CrossRef] [PubMed]
 
Segrest J.P. .Jones M.K. .De Loof H. .Brouillette C.G. .Venkatachalapathi Y.V. .Anantharamaiah G.M. . The amphipathic helix in the exchangeable apolipoproteins: a review of secondary structure and function. J Lipid Res. 1992;33:141-166 [PubMed]journal. [PubMed]
 
Leman L.J. .Maryanoff B.E. .Ghadiri M.R. . Molecules that mimic apolipoprotein A-I: potential agents for treating atherosclerosis. J Med Chem. 2014;57:2169-2196 [PubMed]journal. [CrossRef] [PubMed]
 
Reddy S.T. .Navab M. .Anantharamaiah G.M. .Fogelman A.M. . Apolipoprotein A-I mimetics. Curr Opin Lipidol. 2014;25:304-308 [PubMed]journal. [CrossRef] [PubMed]
 
Navab M. .Anantharamaiah G.M. .Hama S. .et al Oral administration of an apo A-I mimetic peptide synthesized from D-amino acids dramatically reduces atherosclerosis in mice independent of plasma cholesterol. Circulation. 2002;105:290-292 [PubMed]journal. [CrossRef] [PubMed]
 
Sethi A.A. .Stonik J.A. .Thomas F. .et al Asymmetry in the lipid affinity of bihelical amphipathic peptides. A structural determinant for the specificity of ABCA1-dependent cholesterol efflux by peptides. J Biol Chem. 2008;283:32273-32282 [PubMed]journal. [CrossRef] [PubMed]
 
Bloedon L.T. .Dunbar R. .Duffy D. .et al Safety, pharmacokinetics, and pharmacodynamics of oral apoA-I mimetic peptide D-4F in high-risk cardiovascular patients. J Lipid Res. 2008;49:1344-1352 [PubMed]journal. [CrossRef] [PubMed]
 
Dunbar R.L. .Bloedon L.T. .Duffy D. .et al Daily oral administration of the apolipoprotein A-I mimetic peptide D-4F in patients with heart disease or equivalent risk improves high-density lipoprotein anti-inflammatory function [abstract]. J Am Coll Cardiol. 2007;49:366A- [PubMed]journal
 
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