Absence of Proteinase-Activated Receptor-1 Signaling in Mice Confers Protection from fMLP-Induced Goblet Cell Metaplasia
Absence of Proteinase-Activated Receptor-1 Signaling in Mice Confers Protection from fMLP-Induced Goblet Cell Metaplasia
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DOI：
10.1165/rcmb.2007-0386oc
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发表时间：
2009-12-01
影响因子：
6.4
通讯作者：
Lungarella, Giuseppe
中科院分区：
文献类型：
--
作者：
Atzori, Luigi;Lucattelli, Monica;Lungarella, Giuseppe
男性慢性阻塞性肺疾病的形态学特征包括肺气肿和慢性支气管炎伴粘液高分泌。这些变化可以通过单次气管内滴注N-甲酰基-L-甲硫氨酰基-L-亮氨酰基-L-苯丙氨酸（fMLP）（中性粒细胞的化学引诱剂和脱粒剂）在小鼠中诱导。慢性阻塞性肺疾病中粘液产生过多，特别是杯状细胞增生/化生的机制仍然知之甚少。蛋白酶激活受体（PARs）在炎症过程中的调节特性被广泛认可。在这项研究中，我们通过比较PAR-1缺陷型（PAR-1（-/-））小鼠与野生型（WT）小鼠的反应，研究了帕拉是否有助于fMLP诱导的炎症和肺损伤。在滴注fMLP（200 μ g/50 μ l）后的不同时间点处死小鼠。WT小鼠出现肺气肿和杯状细胞化生。肺部病变的发病之前，在支气管气道和肺泡组织中的凝血酶免疫反应性增加。随后，气道上皮细胞管腔表面的帕拉免疫反应性降低，IL-13免疫染色增加。在PAR-1（-/-）小鼠中，fMLP给药在炎症和肺气肿方面诱导了类似的反应，但这些小鼠被保护免于杯状细胞化生的发展。气道上皮细胞转分化中帕拉的参与通过证明气管内滴注选择性帕拉激动剂（TFLLR）仅在WT小鼠的气道中诱导杯状细胞化生来证实。这些数据表明，肺气肿和杯状细胞化生独立发生，并且通过IL-13刺激的帕拉信号传导可能在诱导杯状细胞化生中起重要作用。
The morphological features of chronic obstructive pulmonary disease in man include emphysema and chronic bronchitis associated with mucus hypersecretion. These alterations can be induced in mice by a single intratracheal instillation of N-formyl-L-methionyl-L-leucyl-L-phenylalanine (fMLP), a chemoattractant and degranulating agent for neutrophils. The mechanisms underlying excessive mucus production and, in particular, goblet cell hyperplasia/metaplasia in chronic obstructive pulmonary disease remain poorly understood. The proteinase-activated receptors (PARs) are widely recognized for their modulatory properties during inflammation. In this study, we examined whether PARA contributes to inflammation and lung damage induced by fMLP by comparing the response of PAR-1-deficient (PAR-1(-/-)) mice with that of wild-type (WT) mice. Mice were killed at various time points after fMLP instillation (200 mu g/50 mu l). WT mice developed emphysema and goblet cell metaplasia. The onset of pulmonary lesions was preceded by an increase in thrombin immunoreactivity in bronchial airways and alveolar tissue. This was followed by a decrease in PARA immunoreactivity, and by an increase in IL-13 immunostaining on the luminal surface of airway epithelial cells. In PAR-1(-/-) mice, fMLP administration induced similar responses in terms of inflammation and emphysema, but these mice were protected from the development of goblet cell metaplasia. The involvement of PARA in airway epithelial cell transdifferentiation was confirmed by demonstrating that intratracheal instillation of the selective PARA agonist (TFLLR) induced goblet cell metaplasia in the airways of WT mice only. These data suggest that emphysema and goblet cell metaplasia occur independently, and that PARA signaling through IL-13 stimulation may play an important role in inducing goblet cell metaplasia.