Vliagoftis H, Schwingshackl A, Milne C D, Duszyk M, Hollenberg M D, Wallace J L, Befus A D, Moqbel R
Pulmonary Research Group, the Departments Medicine University of Calgary, Calgary, Alberta, Canada.
J Allergy Clin Immunol. 2000 Sep;106(3):537-45. doi: 10.1067/mai.2000.109058.
Matrix metalloproteinases (MMPs) digest extracellular matrix components and might be important mediators of tissue remodeling. Proteinase activated receptor-2 (PAR-2) is expressed in a variety of cell types including epithelial cells. PAR-2 receptors are activated by serine proteases such as trypsin and mast cell tryptase and have been implicated in inflammation.
To study the effects of PAR-2-mediated airway epithelial cell activation on the production of MMP-9.
A specific PAR-2-activating peptide and trypsin were used to activate the human airway epithelial cell line A549 as well as primary cultures of small airway epithelial cells (SAEC). MMP-2 and MMP-9 messenger RNA and enzymatic activity were evaluated by RT-PCR and gelatin zymography, respectively.
PAR-2-activating peptides upregulated MMP-9 mRNA expression and release of MMP-9 enzymatic activity from airway epithelial cells but had no effect on MMP-2 production. Dexamethasone and budesonide (10(-6) to 10(-10) mmol) inhibited PAR-2-mediated MMP-9 release. Pretreatment with indomethacin indicated that MMP-9 release was not prostaglandin dependent. Inhibitors of the MAP kinase MEK- 1, and NFkappaB showed that both pathways are important for PAR-2-mediated MMP-9 release. Trypsin, a physiologic PAR-2 activator, upregulated MMP-9 but also MMP-2 release from airway epithelial cells.
PAR-2 receptors appear to play an important role in the regulation of MMP-9 release from airway epithelial cells. As such, these receptors may be critical elements in tissue remodeling in asthma and other inflammatory conditions in the airways.
基质金属蛋白酶（MMPs）可消化细胞外基质成分，可能是组织重塑的重要介质。蛋白酶激活受体-2（PAR-2）在包括上皮细胞在内的多种细胞类型中表达。PAR-2受体可被诸如胰蛋白酶和肥大细胞类胰蛋白酶等丝氨酸蛋白酶激活，并与炎症有关。
研究PAR-2介导的气道上皮细胞活化对MMP-9产生的影响。
使用特异性PAR-2激活肽和胰蛋白酶激活人气道上皮细胞系A549以及小气道上皮细胞（SAEC）原代培养物。分别通过逆转录聚合酶链反应（RT-PCR）和明胶酶谱法评估MMP-2和MMP-9信使核糖核酸（mRNA）及酶活性。
PAR-2激活肽上调气道上皮细胞中MMP-9 mRNA表达及MMP-9酶活性的释放，但对MMP-2的产生无影响。地塞米松和布地奈德（10⁻⁶至10⁻¹⁰ mmol）抑制PAR-2介导的MMP-9释放。用吲哚美辛预处理表明MMP-9释放不依赖前列腺素。丝裂原活化蛋白激酶（MAP）激酶MEK-1和核因子κB（NFκB）的抑制剂表明这两条途径对PAR-2介导的MMP-9释放均很重要。胰蛋白酶作为一种生理性PAR-2激活剂，上调气道上皮细胞中MMP-9的表达，但也上调MMP-2的释放。
PAR-2受体似乎在调节气道上皮细胞MMP-9释放中起重要作用。因此，这些受体可能是哮喘和气道其他炎症性疾病中组织重塑的关键因素。
