Recombinant alpha1-proteinase inhibitor blocks antigen- and mediator-induced airway responses in sheep

• Published in: Journal of applied physiology (1985) 2002-12, Vol.93 (6), p.1900
• Main Authors: Scuri, Mario, Botvinnikova, Yelena, Lauredo, Isabel T, Abraham, William M
• Format: Article
• Language: English
• Subjects: Oxygen; Respiratory system; Sheep
• ISSN: 8750-7587; 1522-1601

Alpha1-Proteinase inhibitor (alpha1-PI) is a natural serine protease inhibitor. Although mainly thought to protect the airways from neutrophil elastase, alpha1-PI may also regulate the development of airway hyperresponsiveness (AHR), as indicated by our previous findings of an inverse relationship between lung alpha1-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 alpha1-PI activity and contribute to AHR, we hypothesized that administration of exogenous alpha1-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 alpha1-PI (ralpha1-PI) blocked the bronchoconstriction caused by elastase, high-molecular-weight kininogen, and ROS, and the AHR induced by ROS and antigen. One milligram of ralpha1-PI was ineffective. These are the first in vivo data demonstrating the effects of ralpha1-PI. Our results are consistent with and extend findings obtained with human plasma-derived alpha1-PI and suggest that alpha1-PI may be important in the regulation of airway responsiveness.