Journal of Applied Physiology
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J Appl Physiol 93: 1900-1906, 2002; doi:10.1152/japplphysiol.00400.2002
8750-7587/02 $5.00
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Vol. 93, Issue 6, 1900-1906, December 2002

Recombinant alpha 1-proteinase inhibitor blocks antigen- and mediator-induced airway responses in sheep

Mario Scuri, Yelena Botvinnikova, Isabel T. Lauredo, and William M. Abraham

Division of Pulmonary and Critical Care Medicine, University of Miami at Mount Sinai Medical Center, Miami Beach, Florida 33140

alpha 1-Proteinase inhibitor (alpha 1-PI) is a natural serine protease inhibitor. Although mainly thought to protect the airways from neutrophil elastase, alpha 1-PI may also regulate the development of airway hyperresponsiveness (AHR), as indicated by our previous findings of an inverse relationship between lung alpha 1-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 alpha 1-PI activity and contribute to AHR, we hypothesized that administration of exogenous alpha 1-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 alpha 1-PI (ralpha 1-PI) blocked the bronchoconstriction caused by elastase, high-molecular-weight kininogen, and ROS, and the AHR induced by ROS and antigen. One milligram of ralpha 1-PI was ineffective. These are the first in vivo data demonstrating the effects of ralpha 1-PI. Our results are consistent with and extend findings obtained with human plasma-derived alpha 1-PI and suggest that alpha 1-PI may be important in the regulation of airway responsiveness.

proteases; oxygen radicals


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