Department of Respiratory Medicine, Tongji Hospital, Tongii University School of Medicine, Shanghai 200065, China.
Johns Hopkins Asthma and Allergy Center, 5501 Hopkins Bayview Circle, Baltimore, MD 21224, USA.
Eur J Pharmacol. 2018 Mar 5;822:108-118. doi: 10.1016/j.ejphar.2017.11.017. Epub 2017 Nov 20.
Mast cells play an essential role in immediate type hypersensitivity reactions and in chronic allergic diseases of the airways, including asthma. Mast cell mediator release can be modulated by locally released autacoids and circulating hormones, but surprisingly little is known about the autocrine effects of mediators released upon mast cell activation. We thus set out to characterize the autocrine and paracrine effects of mast cell mediators on mast cell activation in the guinea pig airways. By direct measures of histamine, cysteinyl-leukotriene and thromboxane release and with studies of allergen-evoked contractions of airway smooth muscle, we describe a complex interplay amongst these autacoids. Notably, we observed an autocrine effect of the cysteinyl-leukotrienes acting through cysLT receptors on mast cell leukotriene release. We confirmed the results of previous studies demonstrating a marked enhancement of mast cell mediator release following cyclooxygenase inhibition, but we have extended these results by showing that COX-2 derived eicosanoids inhibit cysteinyl-leukotriene release and yet are without effect on histamine release. Given the prominent role of COX-1 inhibition in aspirin-sensitive asthma, these data implicate preformed mediators stored in granules as the initial drivers of these adverse reactions. Finally, we describe the paracrine signaling cascade leading to thromboxane synthesis in the guinea pig airways following allergen challenge, which occurs indirectly, secondary to cysLT receptor activation on structural cells and/ or leukocytes within the airway wall, and a COX-2 dependent synthesis of the eicosanoid. The results highlight the importance of cell-cell and autocrine interactions in regulating allergic responses in the airways.
肥大细胞在速发型超敏反应和气道慢性过敏性疾病（包括哮喘）中发挥着重要作用。肥大细胞介质的释放可以被局部释放的自分泌物质和循环激素所调节，但令人惊讶的是，对于肥大细胞激活时释放的介质的自分泌作用知之甚少。因此，我们着手研究肥大细胞介质对豚鼠气道中肥大细胞激活的自分泌和旁分泌作用。通过直接测量组胺、半胱氨酰白三烯和血栓素的释放，并研究过敏原诱导的气道平滑肌收缩，我们描述了这些自分泌物质之间复杂的相互作用。值得注意的是，我们观察到半胱氨酰白三烯通过 cysLT 受体对肥大细胞白三烯释放的自分泌作用。我们证实了先前研究的结果，即在环氧化酶抑制后，肥大细胞介质的释放明显增强，但我们的研究结果进一步表明，COX-2 衍生的类花生酸抑制半胱氨酰白三烯的释放，但对组胺的释放没有影响。鉴于 COX-1 抑制在阿司匹林敏感型哮喘中的重要作用，这些数据表明预先形成的储存在颗粒中的介质是这些不良反应的最初驱动因素。最后，我们描述了在过敏原刺激后豚鼠气道中血栓素合成的旁分泌信号级联反应，该反应间接发生，继发于气道壁内结构细胞和/或白细胞上的 cysLT 受体激活，以及 COX-2 依赖性的类花生酸合成。这些结果强调了细胞-细胞和自分泌相互作用在调节气道过敏反应中的重要性。
