The A's Have It: Developing Apolipoprotein A-I Mimetic Peptides Into a Novel Treatment for Asthma.
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.
Laboratory 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.
Xianglan
X
Yao
Laboratory 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.
Elizabeth M
EM
Gordon
Laboratory 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.
Amisha V
AV
Barochia
Lipoprotein Metabolism Section, Cardiovascular and Pulmonary Branch, Division of Intramural Research, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD.
Alan T
AT
Remaley
Laboratory 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. Electronic address: levines@nhlbi.nih.gov.
Stewart J
SJ
Levine
D064286:ATP Binding Cassette Transporter 1 / Q000276:immunology* / Q000378:metabolism; D000280:Administration, Inhalation; D016632:Apolipoprotein A-I / Q000276:immunology* / Q000378:metabolism; D001249:Asthma / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism; D001692:Biological Transport; D016535:Bronchial Hyperreactivity / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism; D055808:Drug Discovery; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism; D008075:Lipoproteins, HDL / Q000378:metabolism; D053858:Metabolic Networks and Pathways; D058990:Molecular Targeted Therapy; D010455:Peptides
D064286:ATP Binding Cassette Transporter 1; D016632:Apolipoprotein A-I; D008075:Lipoproteins, HDL; D010455:Peptides; D002784:Cholesterol
airway hyperresponsiveness; airway inflammation; asthma; lipids