肥大细胞类糜蛋白酶影响原代人气道成纤维细胞的功能特性：对哮喘的影响
2021/08/24
摘要
背景：肥大细胞对过敏性哮喘具有深远影响。在这种情况下，肥大细胞发生脱粒，导致异常大量的肥大细胞限制性蛋白酶释放。然而，这些蛋白酶在哮喘中的作用只是部分了解。
目的：我们假设肥大细胞蛋白酶可以影响人肺成纤维细胞的功能。
方法：采用肥大细胞类糜酶或类胰蛋白酶处理原代人肺成纤维细胞(HLFs)，随后评估与成纤维细胞功能相关的参数。
结果：HLFs对类糜蛋白酶发生反应，发生明显的形态学改变，表现出细胞收缩的迹象，但对类胰蛋白酶不敏感。然而，类糜蛋白酶对HLFs的活力或增殖无明显影响。类糜蛋白酶，而非类胰蛋白酶，对HLFs细胞外基质相关化合物的产生具有重要影响，包括纤维连接蛋白和胶原-1的降解和前基质金属蛋白酶-2的激活。此外，类糜蛋白酶诱导HLFs释放多种趋化因子。与此相一致的是，经类糜蛋白酶处理的HLFs的条件培培养基对中性粒细胞显示出趋化活性。转录组分析显示，类糜蛋白酶诱导HLFs的促炎基因转录谱，而类胰蛋白酶的作用很小。
结论：我们的研究结果显示，类糜蛋白酶，而非类胰蛋白酶，通过改变其细胞外基质成分的产生和诱导促炎表型，对原代气道成纤维细胞的表型产生重要影响。
Mast cell chymase affects the functional properties of primary human airway fibroblasts: implications for asthma
Xinran O Zhao, Maria Lampinen, Ola Rollman, Christian P Sommerhoff, Aida Paivandy, Gunnar Pejler
Abstract
BACKGROUND: Mast cells have a profound impact on allergic asthma. Under such conditions, mast cells undergo degranulation, resulting in the release of exceptionally large amounts of mast cell-restricted proteases. However, the role of these proteases in asthma is only partially understood.
OBJECTIVES: Here we hypothesized that the mast cell proteases can influence the functionality of human lung fibroblasts.
METHODS: Primary human lung fibroblasts (HLFs) were treated with mast cell chymase or tryptase, followed by assessment of parameters related to fibroblast function.
RESULTS: HLFs underwent major morphological 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 pro-inflammatory gene transcription profile in HLFs, whereas tryptase had minimal effects.
CONCLUSION: Our findings reveal that 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 pro-inflammatory phenotype.
背景：肥大细胞对过敏性哮喘具有深远影响。在这种情况下，肥大细胞发生脱粒，导致异常大量的肥大细胞限制性蛋白酶释放。然而，这些蛋白酶在哮喘中的作用只是部分了解。
目的：我们假设肥大细胞蛋白酶可以影响人肺成纤维细胞的功能。
方法：采用肥大细胞类糜酶或类胰蛋白酶处理原代人肺成纤维细胞(HLFs)，随后评估与成纤维细胞功能相关的参数。
结果：HLFs对类糜蛋白酶发生反应，发生明显的形态学改变，表现出细胞收缩的迹象，但对类胰蛋白酶不敏感。然而，类糜蛋白酶对HLFs的活力或增殖无明显影响。类糜蛋白酶，而非类胰蛋白酶，对HLFs细胞外基质相关化合物的产生具有重要影响，包括纤维连接蛋白和胶原-1的降解和前基质金属蛋白酶-2的激活。此外，类糜蛋白酶诱导HLFs释放多种趋化因子。与此相一致的是，经类糜蛋白酶处理的HLFs的条件培培养基对中性粒细胞显示出趋化活性。转录组分析显示，类糜蛋白酶诱导HLFs的促炎基因转录谱，而类胰蛋白酶的作用很小。
结论：我们的研究结果显示，类糜蛋白酶，而非类胰蛋白酶，通过改变其细胞外基质成分的产生和诱导促炎表型，对原代气道成纤维细胞的表型产生重要影响。
(中日友好医院呼吸与危重症医学科 王静茹 摘译 林江涛 审校)
(J Allergy Clin Immunol. 2021 Jul 28; S0091-6749(21)01140-4. doi: 10.1016/j.jaci.2021.07.020.)
(J Allergy Clin Immunol. 2021 Jul 28; S0091-6749(21)01140-4. doi: 10.1016/j.jaci.2021.07.020.)
Mast cell chymase affects the functional properties of primary human airway fibroblasts: implications for asthma
Xinran O Zhao, Maria Lampinen, Ola Rollman, Christian P Sommerhoff, Aida Paivandy, Gunnar Pejler
Abstract
BACKGROUND: Mast cells have a profound impact on allergic asthma. Under such conditions, mast cells undergo degranulation, resulting in the release of exceptionally large amounts of mast cell-restricted proteases. However, the role of these proteases in asthma is only partially understood.
OBJECTIVES: Here we hypothesized that the mast cell proteases can influence the functionality of human lung fibroblasts.
METHODS: Primary human lung fibroblasts (HLFs) were treated with mast cell chymase or tryptase, followed by assessment of parameters related to fibroblast function.
RESULTS: HLFs underwent major morphological 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 pro-inflammatory gene transcription profile in HLFs, whereas tryptase had minimal effects.
CONCLUSION: Our findings reveal that 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 pro-inflammatory phenotype.
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塑料微粒暴露对正常和哮喘肺生理的有害影响
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聚-L-精氨酸通过激活 mTORC1-STAT3 通路诱导气道上皮细胞中的 FGFBP1 促进哮喘血管生成
