α1-Proteinase inhibitor (α1-PI) is a natural serine protease inhibitor. Although mainly thought to protect the airways from neutrophil elastase, α1-PI may also regulate the development of airway hyperresponsiveness (AHR), as indicated by our previous findings of an inverse relationship between lung α1-PI activity and the severity of antigen-induced AHR. Because allergic stimulation of the airways causes release of elastase, tissue kallikrein, and reactive oxygen species (ROS), all of which can reduce α1-PI activity and contribute to AHR, we hypothesized that administration of exogenous α1-PI should protect against pathophysiological airway responses caused by these agents. In untreated allergic sheep, airway challenge with elastase, xanthine/xanthine oxidase (which generates ROS), high-molecular-weight kininogen, the substrate for tissue kallikrein, and antigen resulted in bronchoconstriction. ROS and antigen also induced AHR to inhaled carbachol. Treatment with 10 mg of recombinant α1-PI (rα1-PI) blocked the bronchoconstriction caused by elastase, high-molecular-weight kininogen, and ROS, and the AHR induced by ROS and antigen. One milligram of rα1-PI was ineffective. These are the first in vivo data demonstrating the effects of rα1-PI. Our results are consistent with and extend findings obtained with human plasma-derived α1-PI and suggest that α1-PI may be important in the regulation of airway responsiveness.
- Oxygen radicals
ASJC Scopus subject areas
- Orthopedics and Sports Medicine
- Physical Therapy, Sports Therapy and Rehabilitation