The interaction of alpha(1)-proteinase inhibitor and tissue kallikrein in controlling allergic ovine airway hyperresponsiveness

We reported previously that the development of airway hyperresponsiveness (AHR) 24 h after antigen challenge in allergic sheep was associated with increased tissue kallikrein activity (TK) and decreased alpha-1-proteinase inhibitor (alpha(1)-PI) activity in bronchoalveolar fluid (BAL). The inverse correlation between TK and alpha(1)-PI in these experiments suggested that administration of alpha(1)-PI might reduce TK activity and block AHR. To test this hypothesis, airway responsiveness, as determined by calculating the cumulative carbachol breath units (BU) that increased specific lung resistance by 400% (PC400), was measured before and 24 h after aerosol challenge with Ascaris suum antigen in seven sheep hypersensitive to this antigen. On the next day, 30 min before the 24 h PC400 measurement, the sheep were treated with either aerosol alpha(1)-PI (Prolastin, 10 mg/5 ml) or denatured (DN) Prolastin (10 mg/5 ml), which had only 10% of its original activity. BAL was also performed before and 24 h after challenge for the measurement of TK and alpha(1)-PI activity. Treatment with DN-Prolastin at 24 h after antigen challenge did not block antigen-induced AHR: PC400 fell from a baseline (mean +/- SE) of 26.0 +/- 3.2 BU to 11.2 +/- 1.5 BU after challenge (p < 0.05). This AHR was associated with increased TK (363%, p < 0.05) and decreased alpha(1)-PI activity (65%, p < 0.05). Prolastin treatment at 24 h blocked the AHR: PC400 was 21.0 +/- 2.8 before and 23.2 +/- 3.7 after challenge (p < 0.05 versus DN-Prolastin) and the changes in BAL TK (28% increase) and alpha(1)-PI activities (15% increase) were not different from baseline (both p < 0.05 versus DN-Prolastin). There was a significant inverse correlation between alpha(1)-PI activity and TK activity in BAL, as well as the changes between baseline and 24 h in alpha(1)-PI activity and TK activity in BAL. Pretreatment (30 min before antigen challenge) with Prolastin also protected against the antigen-induced AHR. The effect of Prolastin was also seen against aerosol challenge with high-molecular-weight kininogen (HMWK), a substrate of TK. HMWK caused bronchoconstriction which was blocked by Prolastin (p < 0.05), and the bradykinin B-2 antagonist, NPC-567 (indicating that kinins were generated), but not DN-Prolastin or the elastase inhibitor, ICI 200,355. Although the negative association between alpha(1)-PI activity and TK activity identified in this study does not prove cause and effect, our findings do raise the possibility that in vivo alpha(1)-PI may regulate TK activity and allergen-induced AHR.