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. IMPORTANCEThe 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. R espiratory syncytial virus (RSV) remains the leading cause of viral bronchiolitis and pneumonia in infants and young children throughout the world. Among the 1% to 3% of infants hospitalized with RSV bronchiolitis, up to 90% of children have experience 2 or more wheezing episodes, and almost 50% will be given a diagnosis of asthma by the age of 6 years (1, 2). Several studies, including epidemiology studies and animal model studies, have shown that RSV persistence in the lung of the host after RSV infection was related to long-term airway hyperresponsiveness (AHR) and inflammation (3-5). However, the mechanisms of these sequelae are poorly understood.We have reported that enhanced NGF (nerve growth factor) was partially involved in long-term airway inflammation and AHR after RSV infection (6), suggesting that neurogenic factors participate in long-term airway diseases. Eleva...

Assessment of Respiratory Function in Conscious Mice by Double-chamber Plethysmography

“…Conveniently, it allows one to concomitantly measure the acute effects of these exposures. In fact, one of the common uses of the DCP is to assess the degree of responsiveness to aerosolized methacholine in different models of respiratory diseases 20 21 22 23 24 25 .…”

Aspergillus fumigatus Increased PAR-2 Expression and Elevated Proinflammatory Cytokines Expression Through the Pathway of PAR-2/ERK1/2 in Cornea

“…11 Moreover, PAR-2 plays a crucial role in different animal models of intestinal diseases, focal segmental glomerulosclerosis, skin inflammatory diseases, myocarditis, and airway inflammation. [12][13][14][15][16][17][18][19] Recent studies have shown that human corneal epithelial cells express PAR-2. In human corneal epithelial cells, inhibition of PAR-2 by a specific antagonist prevents proinflammatory cytokine production and reduces inflammation induced by Acanthamoeba plasminogen activator, a serine protease secreted by Acanthamoeba trophozoites, that is involved in the pathogenesis of Acanthamoeba keratitis, indicating that disruption of PAR-2 activity might have a major impact on preventing inflammatory responses in Acanthamoeba keratitis.…”

Roles of Bronchopulmonary C-fibers in airway Hyperresponsiveness and airway remodeling induced by house dust mite

“…While the HDM-induced asthma possesses the asthmatic characteristics (AHR, airway inflammation and remodeling) similar to those induced by OVA, ozone, and virus; however, the pathological processing to cause these characteristics is likely not the same. For example, ozone and respiratory syncytial virus either fails or only affects some types of inflammatory cells [ 12 , 17 ], but HDM increases all or more types of inflammatory cells in our pilot and previously reported studies [ 9 , 17 , 18 ]. Moreover, HDM induces chronic airway inflammation and remodeling with a multifaceted immune responses initiated in the lungs, but the classical OVA model is more related to acute airway inflammation with the Th2 skewing adjuvant aluminum hydroxide and sensitization originated in the periphery [ 8 ].…”

“…After the final exposure, AHR was measured in conscious mice by means of specific airway resistance (sRaw). In brief, the mice were individually placed in the double-chamber to assess sRaw [ 12 ]. The mice were exposed to aerosolized saline (0 mg/ml) and methacholine solutions in a dose-increasing manner (3.125, 6.25, 12.5, 25, and 50 mg/ml; Sigma).…”

“…Previous studies showed that PCF degeneration by neonatal capsaicin (CAP) pretreatment decreased the allergic airway inflammation [ 10 ] and the pulmonary remodeling characterized by collagen and elastic fiber deposition in airways [ 11 ] in ovalbumin-induced asthma model. PCF degeneration also eliminated the AHR induced by respiratory syncytial viral infection [ 12 ]. These PCF effects are thought to be achieved by the PCF-released neuropeptides, especially the substance P (SP) that is responsible for neurogenic inflammation, potentiation of airway constriction, epithelial cells proliferation, and mucus hypersecretion in asthma [ 13 – 16 ].…”