Heterogeneity of allergic airway responses in sheep: differences in signal transduction?

In preliminary studies we have observed that inhaled heparin blocks antigen-induced airway responses in sheep that develop only acute responses to inhaled antigen (acute responders), but not in sheep that develop both acute and later responses (dual responders). Because heparin is an antagonist of inositol triphosphate (IP3) (one of the pathways involved in stimulus-secretion-coupling in mast cells), the differential effect of inhaled heparin in acute responders and dual responders might indicate the involvement of different signaling pathways during IgE-mediated mast cell reactions. Therefore, in this study we compared the effects of heparin on antigen-induced bronchconstriction, allergic cutaneous reaction, and histamine release into bronchoalveolar lavage fluid (BAL) in sheep that develop only acute responses or dual responses to inhaled Ascaris suum antigen. Specific lung resistance (SRL) was measured in 21 sheep (eight acute responders; 13 dual responders) before and after inhalation challenge with antigen, without and after pretreatment with inhaled heparin (1,000 units/kg). Histamine in BAL was measured by RIA before and after segmental antigen challenge, without and after pretreatment with inhaled heparin (eight acute responders; eight dual responders). In acute responders, mean +/- SE SRL increased by 197 +/- 21% with antigen; this was prevented by inhaled heparin (deltaSRL = 15 +/- 7%; p < 0.05). In dual responders, inhaled heparin had no effect on antigen-induced early (deltaSRL = 328 +/- 51% versus 305 +/- 76%) or late (deltaSRL = 201 +/- 33% versus 163 +/- 15%) responses. After segmental antigen challenge, BAL mean +/- SE histamine increased from 2.09 +/- 0.8 nM to 75.4 +/- 21.1 nM in acute responders and 1.58 +/- 0.7 nM to 66.8 +/- 27.3 nM in dual responders (p < 0.01). Inhaled heparin inhibited the increase in BAL histamine by 81% in acute responders (p < 0.05) and by only 19% in dual responders (p = NS). As was seen in the airways, heparin attenuated the allergic cutaneous reaction in acute responders by 46% (p < 0.05), but it was ineffective in dual responders. In contrast, H-7, a nonspecific protein kinase C inhibitor, attenuated the cutaneous reaction in dual responders by 28% (p < 0.05), but it was ineffective in acute responders. These data suggest that heterogeneity of allergic airway response is related to difference in mast cell signal transduction; IP3 is the predominant second messenger in acute responders, whereas non-IP3 pathways may be involved in dual responders.