title: An alpha4beta1 integrin antagonist decreases airway inflammation in ovalbumin-exposed mice.
abstract: 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.
authors.affiliation: Pulmonary and Critical Care Medicine, Genome and Biomedical Sciences Facility, Davis, CA 95616, United States. njkenyon@ucdavis.edu
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Kenyon
authors.forename: Ruiwu
authors.initials: R
authors.lastname: Liu
authors.forename: Erin M
authors.initials: EM
authors.lastname: O'Roark
authors.forename: Wenzhe
authors.initials: W
authors.lastname: Huang
authors.forename: Li
authors.initials: L
authors.lastname: Peng
authors.forename: Kit S
authors.initials: KS
authors.lastname: Lam
mesh_terms: 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
chemical_list: 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