It is disclosed herein that blockade of inter-alpha-trypsin inhibitor (IaI) prevents the development of airway hyperresponsiveness in animal models of asthma and chronic obstructive pulmonary disease. Provided herein are methods of treating an airway disease or disorder in a subject by administering to the subject a therapeutically effective amount of an inhibitor of IaI. Also provided is a method of preventing or reducing airway hyperresponsiveness in a subject by administering to the subject a therapeutically effective amount of an inhibitor of IaI. The IaI inhibitor can be any compound that inhibits the expression or activity of IaI or a gene encoding an IaI polypeptide. In some embodiments, the IaI inhibitor is administered locally to the airway of the subject in need of treatment. For example, the inhibitor can be administered by aerosol delivery, such as by using an inhaler or nebulizer.