基质金属蛋白酶-1活化促进气道平滑肌生长并加重哮喘严重程度
2017/04/28
摘要
引言：基质金属蛋白酶-1（matrix metalloproteinase-1, MMP-1）与肥大细胞存在于哮喘患者气道中。我们假设MMP-1可以被肥大细胞激活并可加重哮喘严重程度。
方法：对稳定期哮喘患者及健康对照者进行肺功能测定、乙酰甲胆碱激发、支气管镜检查，并对他们的气道平滑肌细胞进行培养。另一组哮喘患者及对照者在鼻病毒诱导哮喘急性发作前后均进行症状评分、肺功能测定和支气管肺泡灌洗。从脱细胞的气道平滑肌培养基制备细胞外基质。评估MMP-1蛋白及其活性。
结果：气道平滑肌细胞产生MMP-1前体，而MMP-1前体被肥大细胞类胰蛋白酶蛋白水解激活。采用活化肥大细胞上清液处理的气道平滑肌，其产生的细胞外基质使后续气道平滑肌生长增强了1.5倍（P< 0.05），且这一效应依赖于MMP-1的活化。在哮喘中，气道MMP-1前体水平较健康对照者高5.4倍（P = 0.002）。肥大细胞数与气道平滑肌增殖相关，MMP-1蛋白与支气管高反应性相关。在急性发作过程中，MMP-1活性增加且与FEV1下降和更严重的哮喘症状相关。
结论：MMP-1被肥大细胞类胰蛋白酶激活，产生促增殖的细胞外基质。在哮喘中，肥大细胞与气道平滑肌增殖相关、MMP-1水平与支气管高反应性相关、MMP-1活性与急性发作严重程度具有相关性。我们研究结果提示：气道平滑肌/肥大细胞之间的相互作用通过瞬时增加基质金属蛋白酶活性、气道平滑肌生长及气道反应性，从而加重哮喘严重程度。
关键词：气道重塑；气道平滑肌；哮喘；细胞外基质；肥大细胞
MMP-1 activation contributes to airway smooth muscle growth and asthma severity
Naveed SU, Clements D, Jackson DJ, Philp C, Billington CK, Soomro I, Reynolds C, Harrison TW, Johnston SL, Shaw DE, Johnson SR.
Am J Respir Crit Care Med. 2016 Dec 14. [Epub ahead of print]. DOI:10.1164/rccm.201604-0822OC.
Abstract
Introduction: Matrix metalloproteinase-1 and mast cells are present in the airways of people with asthma. We hypothesised that matrix metalloproteinase-1 could be activated by mast cells and increase asthma severity.
Methods: Patients with stable asthma and healthy controls underwent spirometry, methacholine challenge, bronchoscopy and their airway smooth muscle cells were grown in culture. A second asthma group and controls had symptom scores, spirometry and bronchoalveolar lavage before and after rhinovirus-induced asthma exacerbations. Extracellular matrix was prepared from decellularised airway smooth muscle cultures. Matrix metalloproteinase-1 protein and activity were assessed.
Results: Airway smooth muscle cells generated pro-matrix metalloproteinase-1 which was proteolytically activated by mast cell tryptase. Airway smooth muscle treated with activated mast cell supernatants produced extra-cellular matrix which enhanced subsequent airway smooth muscle growth by 1.5 fold (P< 0.05) which was dependent on matrix metalloproteinase-1 activation. In asthma, airway pro-matrix metalloproteinase-1 was 5.4 fold higher than control subjects (P = 0.002). Mast cell numbers were associated with airway smooth muscle proliferation and matrix metalloproteinase-1 protein associated with bronchial hyper-responsiveness. During exacerbations, matrix metalloproteinase-1 activity increased and was associated with fall in FEV1 and worsening asthma symptoms.
Conclusions: Matrix metalloproteinase-1 is activated by mast cell tryptase resulting in a proproliferative extra-cellular matrix. In asthma, mast cells are associated with airway smooth muscle growth, matrix metalloproteinase-1 levels are associated with bronchial hyperresponsiveness and matrix metalloproteinase-1 activation with exacerbation severity. Our findings suggest that airway smooth muscle/mast cell interactions contribute to asthma severity by transiently increasing matrix metalloproteinase activation, airway smooth muscle growth and airway responsiveness.
Keywords: airway remodeling; airway smooth muscle; asthma; extracellular matrix; mast cells
引言：基质金属蛋白酶-1（matrix metalloproteinase-1, MMP-1）与肥大细胞存在于哮喘患者气道中。我们假设MMP-1可以被肥大细胞激活并可加重哮喘严重程度。
方法：对稳定期哮喘患者及健康对照者进行肺功能测定、乙酰甲胆碱激发、支气管镜检查，并对他们的气道平滑肌细胞进行培养。另一组哮喘患者及对照者在鼻病毒诱导哮喘急性发作前后均进行症状评分、肺功能测定和支气管肺泡灌洗。从脱细胞的气道平滑肌培养基制备细胞外基质。评估MMP-1蛋白及其活性。
结果：气道平滑肌细胞产生MMP-1前体，而MMP-1前体被肥大细胞类胰蛋白酶蛋白水解激活。采用活化肥大细胞上清液处理的气道平滑肌，其产生的细胞外基质使后续气道平滑肌生长增强了1.5倍（P< 0.05），且这一效应依赖于MMP-1的活化。在哮喘中，气道MMP-1前体水平较健康对照者高5.4倍（P = 0.002）。肥大细胞数与气道平滑肌增殖相关，MMP-1蛋白与支气管高反应性相关。在急性发作过程中，MMP-1活性增加且与FEV1下降和更严重的哮喘症状相关。
结论：MMP-1被肥大细胞类胰蛋白酶激活，产生促增殖的细胞外基质。在哮喘中，肥大细胞与气道平滑肌增殖相关、MMP-1水平与支气管高反应性相关、MMP-1活性与急性发作严重程度具有相关性。我们研究结果提示：气道平滑肌/肥大细胞之间的相互作用通过瞬时增加基质金属蛋白酶活性、气道平滑肌生长及气道反应性，从而加重哮喘严重程度。
关键词：气道重塑；气道平滑肌；哮喘；细胞外基质；肥大细胞
(张丽1 张红萍1 王刚 四川大学华西医院中西医结合科呼吸病组 610041 摘译)
（AmJRespirCritCareMed.2016Dec14.[Epubaheadofprint].DOI:10.1164/rccm.201604-0822OC.）
（AmJRespirCritCareMed.2016Dec14.[Epubaheadofprint].DOI:10.1164/rccm.201604-0822OC.）
MMP-1 activation contributes to airway smooth muscle growth and asthma severity
Naveed SU, Clements D, Jackson DJ, Philp C, Billington CK, Soomro I, Reynolds C, Harrison TW, Johnston SL, Shaw DE, Johnson SR.
Am J Respir Crit Care Med. 2016 Dec 14. [Epub ahead of print]. DOI:10.1164/rccm.201604-0822OC.
Abstract
Introduction: Matrix metalloproteinase-1 and mast cells are present in the airways of people with asthma. We hypothesised that matrix metalloproteinase-1 could be activated by mast cells and increase asthma severity.
Methods: Patients with stable asthma and healthy controls underwent spirometry, methacholine challenge, bronchoscopy and their airway smooth muscle cells were grown in culture. A second asthma group and controls had symptom scores, spirometry and bronchoalveolar lavage before and after rhinovirus-induced asthma exacerbations. Extracellular matrix was prepared from decellularised airway smooth muscle cultures. Matrix metalloproteinase-1 protein and activity were assessed.
Results: Airway smooth muscle cells generated pro-matrix metalloproteinase-1 which was proteolytically activated by mast cell tryptase. Airway smooth muscle treated with activated mast cell supernatants produced extra-cellular matrix which enhanced subsequent airway smooth muscle growth by 1.5 fold (P< 0.05) which was dependent on matrix metalloproteinase-1 activation. In asthma, airway pro-matrix metalloproteinase-1 was 5.4 fold higher than control subjects (P = 0.002). Mast cell numbers were associated with airway smooth muscle proliferation and matrix metalloproteinase-1 protein associated with bronchial hyper-responsiveness. During exacerbations, matrix metalloproteinase-1 activity increased and was associated with fall in FEV1 and worsening asthma symptoms.
Conclusions: Matrix metalloproteinase-1 is activated by mast cell tryptase resulting in a proproliferative extra-cellular matrix. In asthma, mast cells are associated with airway smooth muscle growth, matrix metalloproteinase-1 levels are associated with bronchial hyperresponsiveness and matrix metalloproteinase-1 activation with exacerbation severity. Our findings suggest that airway smooth muscle/mast cell interactions contribute to asthma severity by transiently increasing matrix metalloproteinase activation, airway smooth muscle growth and airway responsiveness.
Keywords: airway remodeling; airway smooth muscle; asthma; extracellular matrix; mast cells
上一篇：
肥胖与哮喘共同决定了一个独特的呼吸系统代谢表型
下一篇：
钙蛋白酶活化的mTORC2 / Akt通路介导哮喘气道平滑肌重塑
