Pulmonary C Fibers Modulate MMP-12 Production via PAR2 and Are Involved in the Long-Term Airway Inflammation and Airway Hyperresponsiveness Induced by Respiratory Syncytial Virus Infection
Pulmonary C Fibers Modulate MMP-12 Production via PAR2 and Are Involved in the Long-Term Airway Inflammation and Airway Hyperresponsiveness Induced by Respiratory Syncytial Virus Infection
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DOI：
10.1128/jvi.02534-15
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发表时间：
2015-12
影响因子：
5.4
通讯作者：
N. Zang;Jianguo Zhuang;Yu Deng;Zhimei Yang;Zhixu Ye;Xiao-hong Xie;L. Ren;Z. Fu;Z. Luo;
中科院分区：
文献类型：
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作者：
N. Zang;Jianguo Zhuang;Yu Deng;Zhimei Yang;Zhixu Ye;Xiao-hong Xie;L. Ren;Z. Fu;Z. Luo;
摘要急性呼吸道合胞病毒(RSV)感染的儿童常出现持续性呼吸道炎症和喘息的后遗症。肺C纤维(PCF)参与了呼吸道炎症和抵抗的发生；然而，它们在RSV后持续性呼吸道疾病中的作用尚不清楚。在这里，我们阐明了PCF激活在RSV诱导的持续性呼吸道疾病中的发病机制。本研究使用的是PCF变性小鼠和完整小鼠。观察两组患者的气道炎症和气道阻力。MMP408和FSLLRY-NH2分别作为MMP12和PAR2的选择性拮抗剂，探讨MMP12和PAR2在PCFS介导呼吸道疾病中的作用。因此，PCF的变性显著降低了对RSV感染的下列反应：炎症细胞，特别是巨噬细胞，肺组织中炎症细胞的增加和炎症细胞的渗透；对乙酰甲胆碱的特异性呼吸道阻力(SRAW)反应；以及上调MMP12和PAR2的表达。此外，MMP12的抑制减少了BALF中细胞和巨噬细胞的总数，并减少了炎症细胞的渗入，降低了SRAW对乙酰胆碱的反应。此外，在RSV感染的后期，PAR2表达上调。下调PAR2可改善呼吸道合胞病毒感染后的气道炎症和阻力，并抑制基质金属蛋白酶-12的水平。综上所述，这些结果提示PCF参与了长期的气道炎症和气道高反应性，至少部分是通过调节MMP12来实现的，而PAR2的激活可能与PCF调节MMP12的产生有关。我们的初步发现表明，抑制PCF活性将作为治疗病毒感染引起的长期呼吸道疾病的靶点。重要性目前的研究对于理解PCF通过PAR2介导基质金属蛋白酶-12的产生而参与RSV感染后的长期呼吸道炎症和呼吸道抵抗至关重要，表明抑制PCF活性可以靶向治疗病毒感染引起的长期呼吸道疾病。
ABSTRACT Children with acute respiratory syncytial virus (RSV) infection often develop sequelae of persistent airway inflammation and wheezing. Pulmonary C fibers (PCFs) are involved in the generation of airway inflammation and resistance; however, their role in persistent airway diseases after RSV is unexplored. Here, we elucidated the pathogenesis of PCF activation in RSV-induced persistent airway disorders. PCF-degenerated and intact mice were used in the current study. Airway inflammation and airway resistance were evaluated. MMP408 and FSLLRY-NH2 were the selective antagonists for MMP-12 and PAR2, respectively, to investigate the roles of MMP-12 and PAR2 in PCFs mediating airway diseases. As a result, PCF degeneration significantly reduced the following responses to RSV infection: augmenting of inflammatory cells, especially macrophages, and infiltrating of inflammatory cells in lung tissues; specific airway resistance (sRaw) response to methacholine; and upregulation of MMP-12 and PAR2 expression. Moreover, the inhibition of MMP-12 reduced the total number of cells and macrophages in bronchiolar lavage fluid (BALF), as well infiltrating inflammatory cells, and decreased the sRaw response to methacholine. In addition, PAR2 was upregulated especially at the later stage of RSV infection. Downregulation of PAR2 ameliorated airway inflammation and resistance following RSV infection and suppressed the level of MMP-12. In all, the results suggest that PCF involvement in long-term airway inflammation and airway hyperresponsiveness occurred at least partially via modulating MMP-12, and the activation of PAR2 might be related to PCF-modulated MMP-12 production. Our initial findings indicated that the inhibition of PCF activity would be targeted therapeutically for virus infection-induced long-term airway disorders. IMPORTANCE The current study is critical to understanding that PCFs are involved in long-term airway inflammation and airway resistance after RSV infection through mediating MMP-12 production via PAR2, indicating that the inhibition of PCF activity can be targeted therapeutically for virus infection-induced long-term airway disorders.