An alpha4beta1 integrin antagonist decreases airway inflammation in ovalbumin-exposed mice.
Inhibition of the alpha4 subunit of both the alpha4beta1 and alpha4beta7 integrins has shown promise in decreasing airway inflammation and airway hyperresponsiveness in various animal models. We hypothesized that a novel, high-affinity alpha4beta1 antagonist (LLP2A) would decrease the migration of eosinophils to the lung and ameliorate the airway hyperresponsiveness in a mouse model of ovalbumin-induced airway inflammation. To test this hypothesis, we administered LLP2A, or scrambled LLP2A (a negative control), prior to exposure of sensitized BALB/c mice to ovalbumin aerosol. We can partially prevent, or reverse, the airway inflammatory response, but not airways hyperresponsiveness, by treatment of mice with LLP2A, a synthetic peptidomimetic alpha4beta1 antagonist. Specifically engineered, PEGylated (PEG) formulations of this antagonist further reduce the airway inflammatory response to ovalbumin, presumably by improving the circulating half-life of the drug.
Kenyon
Nicholas J
NJ
Pulmonary and Critical Care Medicine, Genome and Biomedical Sciences Facility, Davis, CA 95616, United States. njkenyon@ucdavis.edu
Liu
Ruiwu
R
O'Roark
Erin M
EM
Huang
Wenzhe
W
Peng
Li
L
Lam
Kit S
KS
D000818:Animals; D001682:Biological Availability; D015415:Biomarkers / Q000378:metabolism; D018893:Bronchoalveolar Lavage; D004151:Dipeptides / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D045853:Exhalation; D020397:Goblet Cells / Q000187:drug effects / Q000378:metabolism; D007249:Inflammation / Q000139:chemically induced* / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D039041:Integrin alpha4beta1 / Q000037:antagonists & inhibitors*; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008170:Lung Compliance / Q000187:drug effects; D008297:Male; D051379:Mice; D009566:Nitrates / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D009573:Nitrites / Q000378:metabolism; D010047:Ovalbumin / Q000633:toxicity*; D018384:Oxidative Stress; D010671:Phenylurea Compounds / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D011092:Polyethylene Glycols / Q000737:chemistry; D012137:Respiratory System / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology
D015415:Biomarkers; D004151:Dipeptides; D039041:Integrin alpha4beta1; C512274:LLP2A compound; D009566:Nitrates; D009573:Nitrites; D010671:Phenylurea Compounds; D009569:Nitric Oxide; D011092:Polyethylene Glycols; D010047:Ovalbumin