5A, an apolipoprotein A-I mimetic peptide, attenuates the induction of house dust mite-induced asthma.
New treatment approaches are needed for patients with asthma. Apolipoprotein A-I (apoA-I), the major structural protein of high-density lipoproteins, mediates reverse cholesterol transport and has atheroprotective and anti-inflammatory effects. In this study, we hypothesized that an apoA-I mimetic peptide might be effective at inhibiting asthmatic airway inflammation. A 5A peptide, which is a synthetic, bihelical apoA-I mimetic, was administered to wild-type A/J mice via osmotic mini-pump prior to the induction of house dust mite (HDM)-induced asthma. HDM-challenged mice that received the 5A apoA-I mimetic peptide had significant reductions in the number of bronchoalveolar lavage fluid eosinophils, lymphocytes, and neutrophils, as well as in histopathological evidence of airway inflammation. The reduction in airway inflammation was mediated by a reduction in the expression of Th2- and Th17-type cytokines, as well as in chemokines that promote T cell and eosinophil chemotaxis, including CCL7, CCL17, CCL11, and CCL24. Furthermore, the 5A apoA-I mimetic peptide inhibited the alternative activation of pulmonary macrophages in the lungs of HDM-challenged mice. It also abrogated the development of airway hyperresponsiveness and reduced several key features of airway remodeling, including goblet cell hyperplasia and the expression of collagen genes (Col1a1 and Col3a1). Our results demonstrate that the 5A apoA-I mimetic peptide attenuates the development of airway inflammation and airway hyperresponsiveness in an experimental murine model of HDM-induced asthma. These data support the conclusion that strategies using apoA-I mimetic peptides, such as 5A, might be developed further as a possible new treatment approach for asthma.
Pulmonary and Vascular Medicine Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Xianglan
X
Yao
Cuilian
C
Dai
Karin
K
Fredriksson
Pradeep K
PK
Dagur
J Philip
JP
McCoy
Xuan
X
Qu
Zu-Xi
ZX
Yu
Karen J
KJ
Keeran
Gayle J
GJ
Zywicke
Marcelo J A
MJ
Amar
Alan T
AT
Remaley
Stewart J
SJ
Levine
D000280:Administration, Inhalation; D000818:Animals; D018927:Anti-Asthmatic Agents / Q000008:administration & dosage / Q000627:therapeutic use; D016632:Apolipoprotein A-I / Q000008:administration & dosage* / Q000627:therapeutic use; D001249:Asthma / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control*; D016535:Bronchial Hyperreactivity / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors / Q000378:metabolism; D008262:Macrophage Activation / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008805:Mice, Inbred A; D018716:Molecular Mimicry / Q000276:immunology*; D010446:Peptide Fragments / Q000008:administration & dosage* / Q000627:therapeutic use; D039981:Pyroglyphidae / Q000276:immunology*
C505693:APOA1 protein, human; D018927:Anti-Asthmatic Agents; D016632:Apolipoprotein A-I; D016207:Cytokines; D018836:Inflammation Mediators; D010446:Peptide Fragments