title: 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.
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.
  
  
  OBJECTIVE
  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.
authors.affiliation: Ministry of Education Key Laboratory of Child Development and Disorders, Key Laboratory of Pediatrics in Chongqing, Chongqing International Science and Technology Cooperation Center for Child Development and Disorders, Chongqing, China Department of Respiratory Medicine, Children's Hospital of Chongqing Medical University, Chongqing, China Pathophysiology Program, Lovelace Respiratory Research Institute, Albuquerque, New Mexico, USA.
authors.forename: Na
authors.initials: N
authors.lastname: Zang
authors.affiliation: Pathophysiology Program, Lovelace Respiratory Research Institute, Albuquerque, New Mexico, USA.
authors.forename: Jianguo
authors.initials: J
authors.lastname: Zhuang
authors.affiliation: Department of Respiratory Medicine, Children's Hospital of Chongqing Medical University, Chongqing, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Deng
authors.affiliation: Department of Respiratory Medicine, Children's Hospital of Chongqing Medical University, Chongqing, China.
authors.forename: Zhimei
authors.initials: Z
authors.lastname: Yang
authors.affiliation: Ministry of Education Key Laboratory of Child Development and Disorders, Key Laboratory of Pediatrics in Chongqing, Chongqing International Science and Technology Cooperation Center for Child Development and Disorders, Chongqing, China.
authors.forename: Zhixu
authors.initials: Z
authors.lastname: Ye
authors.affiliation: Department of Respiratory Medicine, Children's Hospital of Chongqing Medical University, Chongqing, China.
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Xie
authors.affiliation: Ministry of Education Key Laboratory of Child Development and Disorders, Key Laboratory of Pediatrics in Chongqing, Chongqing International Science and Technology Cooperation Center for Child Development and Disorders, Chongqing, China.
authors.forename: Luo
authors.initials: L
authors.lastname: Ren
authors.affiliation: Department of Respiratory Medicine, Children's Hospital of Chongqing Medical University, Chongqing, China.
authors.forename: Zhou
authors.initials: Z
authors.lastname: Fu
authors.affiliation: Department of Respiratory Medicine, Children's Hospital of Chongqing Medical University, Chongqing, China.
authors.forename: Zhengxiu
authors.initials: Z
authors.lastname: Luo
authors.affiliation: Pathophysiology Program, Lovelace Respiratory Research Institute, Albuquerque, New Mexico, USA.
authors.forename: Fadi
authors.initials: F
authors.lastname: Xu
authors.affiliation: Department of Respiratory Medicine, Children's Hospital of Chongqing Medical University, Chongqing, China emliu186@hotmail.com.
authors.forename: Enmei
authors.initials: E
authors.lastname: Liu
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D007249:Inflammation / Q000473:pathology*; D008168:Lung / Q000473:pathology*; D053508:Matrix Metalloproteinase 12 / Q000378:metabolism*; D008807:Mice, Inbred BALB C; D036421:Nerve Fibers, Unmyelinated / Q000473:pathology*; D044464:Receptor, PAR-2 / Q000378:metabolism; D018357:Respiratory Syncytial Virus Infections / Q000473:pathology*
chemical_list: D044464:Receptor, PAR-2; D053508:Matrix Metalloproteinase 12