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.
Publication types
-
Research Support, N.I.H., Extramural
MeSH terms
-
Animals
-
Biological Availability
-
Biomarkers / metabolism
-
Bronchoalveolar Lavage
-
Dipeptides / chemistry
-
Dipeptides / pharmacokinetics
-
Dipeptides / pharmacology*
-
Dipeptides / therapeutic use
-
Exhalation
-
Goblet Cells / drug effects
-
Goblet Cells / metabolism
-
Inflammation / chemically induced*
-
Inflammation / drug therapy
-
Inflammation / metabolism
-
Inflammation / pathology
-
Integrin alpha4beta1 / antagonists & inhibitors*
-
Lung / drug effects
-
Lung / metabolism
-
Lung / pathology
-
Lung / physiopathology
-
Lung Compliance / drug effects
-
Male
-
Mice
-
Nitrates / metabolism
-
Nitric Oxide / metabolism
-
Nitrites / metabolism
-
Ovalbumin / toxicity*
-
Oxidative Stress
-
Phenylurea Compounds / chemistry
-
Phenylurea Compounds / pharmacokinetics
-
Phenylurea Compounds / pharmacology*
-
Phenylurea Compounds / therapeutic use
-
Polyethylene Glycols / chemistry
-
Respiratory System / drug effects*
-
Respiratory System / metabolism
-
Respiratory System / pathology
-
Respiratory System / physiopathology
Substances
-
Biomarkers
-
Dipeptides
-
Integrin alpha4beta1
-
LLP2A compound
-
Nitrates
-
Nitrites
-
Phenylurea Compounds
-
Nitric Oxide
-
Polyethylene Glycols
-
Ovalbumin