Ahmed T, D'Brot J, Abraham W M, Lucio J, Mendelssohn R, Robinson M J, Shakir S, Sanpedro B
The Division of Pulmonary Disease, University of Miami School of Medicine, Mount Sinai Medical Center, Miami Beach, Florida, USA.
Am J Respir Crit Care Med. 1996 Oct;154(4 Pt 1):843-9. doi: 10.1164/ajrccm.154.4.8887573.
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.
在初步研究中，我们观察到，吸入肝素可阻断仅对吸入抗原产生急性反应的绵羊（急性反应者）中抗原诱导的气道反应，但对同时产生急性和后期反应的绵羊（双重反应者）则无此作用。由于肝素是肌醇三磷酸（IP3）（肥大细胞刺激-分泌偶联所涉及的途径之一）的拮抗剂，吸入肝素在急性反应者和双重反应者中的不同作用可能表明在IgE介导的肥大细胞反应过程中涉及不同的信号通路。因此，在本研究中，我们比较了肝素对仅对吸入猪蛔虫抗原产生急性反应或双重反应的绵羊中抗原诱导的支气管收缩、过敏性皮肤反应以及支气管肺泡灌洗液（BAL）中组胺释放的影响。在21只绵羊（8只急性反应者；13只双重反应者）吸入抗原激发前后，在未用吸入肝素（1000单位/千克）预处理和预处理后，测量了特异性肺阻力（SRL）。在8只急性反应者和8只双重反应者中，在节段性抗原激发前后，在未用吸入肝素预处理和预处理后，通过放射免疫分析法（RIA）测量了BAL中的组胺。在急性反应者中，抗原使平均±标准误SRL增加了197±21%；吸入肝素可预防此增加（SRL变化量=15±7%；p<0.05）。在双重反应者中，吸入肝素对抗原诱导的早期（SRL变化量=328±51%对305±76%）或晚期（SRL变化量=201±33%对163±15%）反应均无作用。节段性抗原激发后，急性反应者BAL中的平均±标准误组胺从2.09±0.8纳摩尔增加至75.4±21.1纳摩尔，双重反应者从1.58±0.7纳摩尔增加至66.8±27.3纳摩尔（p<0.01）。吸入肝素在急性反应者中可使BAL中组胺的增加减少81%（p<0.05），而在双重反应者中仅减少19%（p=无显著性差异）。正如在气道中所见，肝素使急性反应者的过敏性皮肤反应减轻了46%（p<0.05），但对双重反应者无效。相反，非特异性蛋白激酶C抑制剂H-7使双重反应者的皮肤反应减轻了28%（p<0.05），但对急性反应者无效。这些数据表明，过敏性气道反应的异质性与肥大细胞信号转导的差异有关；IP3是急性反应者中的主要第二信使，而双重反应者可能涉及非IP3途径。
