HETEROGENEITY OF ALLERGIC AIRWAY RESPONSES IN SHEEP - DIFFERENCES IN SIGNAL-TRANSDUCTION

In preliminary studies we have observed that inhaled heparin blocks an tigen-induced airway responses in sheep that develop only acute respon ses to inhaled antigen (acute responders), but not in sheep that devel op both acute and later responses (dual responders). Because heparin i s an antagonist of inositol triphosphate (IP3) (one of the pathways in volved in stimulus-secretion-coupling in mast cells), the differential effect of inhaled heparin in acute responders and dual responders mig ht indicate the involvement of different signaling pathways during IgE -mediated mast cell reactions. Therefore, in this study we compared th e effects of hepa rin on antigen-induced bronchconstriction, allergic cutaneous reaction, and histamine release into bronchoalveolar lavage fluid (BAL) in sheep that develop only acute responses or dual respons es to inhaled Ascaris suum antigen. Specific lung resistance (SRL) was measured in 21 sheep (eight acute responders; 13 dual responders) bef ore and after inhalation challenge with antigen, without and after pre treatment 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; e ight dual responders). In acute responders, mean +/- SE SRL increased by 197 +/- 21% with antigen; this was prevented by inhaled heparin (De lta SRL = 15 +/- 7%; p < 0.05). In dual responders, inhaled heparin ha d no effect on antigen-induced early (Delta SRL = 328 +/- 51% versus 3 05 +/- 76%) or late (Delta SRL = 201 +/- 33% versus 163 +/- 15%) respo nses. After segmental antigen challenge, BAL mean +/- SE histamine inc reased from 2.09 +/- 0.8 nM to 75.4 +/- 21.1 nM in acute responders an d 1.58 +/- 0.7 nM to 66.8 +/- 27.3 nM in dual responders (p < 0.01). I nhaled 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 re action in acute responders by 46% (p < 0.05), but it was ineffective i n dual responders. In contrast, H-7, a nonspecific protein kinase C in hibitor, attenuated the cutaneous reaction in dual responders by 28% ( p < 0.05), but it was ineffective in acute responders. These data sugg est that heterogeneity of allergic airway response is related to diffe rence in mast cell signal transduction; IP3 is the predominant second messenger in acute responders, whereas non-IP3 pathways may be involve d in dual responders.