Nagase T, Dallaire M J, Ludwig M S
Meakins-Christie Laboratories and Royal Victoria Hospital, McGill University, Montreal, Quebec, Canada.
J Appl Physiol (1985). 1996 Feb;80(2):583-90. doi: 10.1152/jappl.1996.80.2.583.
We have recently demonstrated that tissue resistance increases during the early response (ER) to antigen challenge in sensitized Brown-Norway rats. The purpose of the present study was to investigate the role of the potential ER mediators 5-hydroxytryptamine (5-HT) and leukotriene D4 (LTD4) in the airway and tissue response. We sensitized the rats with ovalbumin (OA) and performed experiments on anesthetized, open-chested, mechanically ventilated [breathing frequency = 1 Hz, tidal volume = 12 ml/kg, positive end-expiratory pressure (PEEP) = 3 cmH2O] animals. We affixed alveolar capsules to the lungs to measure alveolar pressure and calculated the resistance of lung (RL), tissue (Rti), and airway (Raw). To assess the effects of LTD4 and 5-HT, we administered the antagonists methysergide (5-HT antagonist) and MK-571 (LTD4 antagonist) before challenge. To assess lung morphometry during the ER, the lungs of four animals from each group were frozen with liquid nitrogen (PEEP = 3 cmH2O). Airway constriction was assessed by measuring the ratio of the airway lumen to the ideally relaxed airway (Abm/Abm). Tissue distortion was assessed by measuring the mean linear intercept between alveolar walls (Lm), an atelectasis index (ATI) derived by calculating the ratio of tissue to air space, and SD of the two (SD-Lm and SD-ATI). In all animals receiving OA but no antagonists, an ER was seen (RL, Rti, and Raw = 180.7 +/- 6.1, 155.4 +/- 8.2, and 223.1 +/- 14.0% of baseline, respectively). Methysergide significantly inhibited the ER (RL, Rti, and Raw = 117.0 +/- 5.9, 101.2 +/- 1.6, 133.7 +/- 10.2%, respectively), whereas MK-571 partially reduced the ER (RL, Rti, and Raw = 144.2 +/- 5.6, 132.9 +/- 5.7, and 155.5 +/- 9.2%, respectively). Abm/Abm was significantly decreased, and SD-Lm and SD-ATI were significantly increased in animals receiving OA alone and in those receiving MK-571 before OA challenge. These data suggest that alterations in both airways and tissues contribute to the ER and that 5-HT and, to a lesser degree, LTD4 are important mediators of the ER in this rat model of extrinsic asthma.
我们最近证明，在致敏的布朗-挪威大鼠对抗抗原攻击的早期反应（ER）过程中，组织阻力会增加。本研究的目的是调查潜在的ER介质5-羟色胺（5-HT）和白三烯D4（LTD4）在气道和组织反应中的作用。我们用卵清蛋白（OA）致敏大鼠，并在麻醉、开胸、机械通气[呼吸频率 = 1 Hz，潮气量 = 12 ml/kg，呼气末正压（PEEP） = 3 cmH₂O]的动物身上进行实验。我们将肺泡囊固定在肺上以测量肺泡压力，并计算肺阻力（RL）、组织阻力（Rti）和气道阻力（Raw）。为了评估LTD4和5-HT的作用，我们在攻击前给予拮抗剂麦角新碱（5-HT拮抗剂）和MK-571（LTD4拮抗剂）。为了评估ER期间的肺形态计量学，每组的四只动物的肺用液氮冷冻（PEEP = 3 cmH₂O）。通过测量气道管腔与理想松弛气道的比值（Abm/Abm）来评估气道收缩。通过测量肺泡壁之间的平均线性截距（Lm）、通过计算组织与气腔比值得出的肺不张指数（ATI）以及两者的标准差（SD-Lm和SD-ATI）来评估组织变形。在所有接受OA但未接受拮抗剂的动物中，观察到了ER（RL、Rti和Raw分别为基线的180.7±6.1%、155.4±8.2%和223.1±14.0%）。麦角新碱显著抑制了ER（RL、Rti和Raw分别为117.0±5.9%、101.2±1.6%、133.7±10.2%），而MK-571部分降低了ER（RL、Rti和Raw分别为144.2±5.6%、132.9±5.7%和155.5±9.2%）。在单独接受OA的动物以及在OA攻击前接受MK-571的动物中，Abm/Abm显著降低，SD-Lm和SD-ATI显著增加。这些数据表明，气道和组织的改变都有助于ER，并且5-HT以及程度较轻的LTD4是这种外源性哮喘大鼠模型中ER的重要介质。
