Background

Mast cells (MCs) have a profound impact on allergic asthma. Under such conditions, MCs undergo degranulation, resulting in the release of exceptionally large amounts of MC-restricted proteases. However, the role of these proteases in asthma is only partially understood.

Objectives

We sought to test our hypothesis that MC proteases can influence the functionality of human lung fibroblasts (HLFs).

Methods

Primary HLFs were treated with MC chymase or tryptase, followed by assessment of parameters related to fibroblast function.

Results

HLFs underwent major morphologic changes in response to chymase, showing signs of cellular contraction, but were refractory to tryptase. However, no effects of chymase on HLF viability or proliferation were seen. Chymase, but not tryptase, had a major impact on the output of extracellular matrix–associated compounds from the HLFs, including degradation of fibronectin and collagen-1, and activation of pro–matrix metalloprotease 2. Further, chymase induced the release of various chemotactic factors from HLFs. In line with this, conditioned medium from chymase-treated HLFs showed chemotactic activity on neutrophils. Transcriptome analysis revealed that chymase induced a proinflammatory gene transcription profile in HLFs, whereas tryptase had minimal effects.

Conclusions

Chymase, but not tryptase, has a major impact on the phenotype of primary airway fibroblasts by modifying their output of extracellular matrix components and by inducing a proinflammatory phenotype.

中文翻译：

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肥大细胞糜酶影响原代人气道成纤维细胞的功能特性：对哮喘的影响

背景

肥大细胞 (MCs) 对过敏性哮喘有着深远的影响。在这种情况下，MC 会发生脱粒，导致释放出异常大量的 MC 限制性蛋白酶。然而，这些蛋白酶在哮喘中的作用只是部分了解。

目标

我们试图验证我们的假设，即 MC 蛋白酶可以影响人肺成纤维细胞 (HLF) 的功能。

方法

初级 HLF 用 MC 糜酶或类胰蛋白酶处理，然后评估与成纤维细胞功能相关的参数。

结果

HLF 在响应糜酶时经历了主要的形态学变化，显示出细胞收缩的迹象，但对类胰蛋白酶不敏感。然而，没有观察到糜酶对 HLF 活力或增殖的影响。糜蛋白酶，但不是类胰蛋白酶，对 HLF 中细胞外基质相关化合物的输出有重大影响，包括纤连蛋白和胶原蛋白 1 的降解，以及前基质金属蛋白酶 2 的激活。此外，糜酶诱导各种趋化性的释放来自 HLF 的因素。与此一致，来自食糜酶处理的 HLF 的条件培养基显示出对中性粒细胞的趋化活性。转录组分析显示糜酶在 HLF 中诱导促炎基因转录谱，而类胰蛋白酶的影响很小。

结论

糜蛋白酶，但不是类胰蛋白酶，通过改变其细胞外基质成分的输出和诱导促炎表型，对初级气道成纤维细胞的表型产生重大影响。