Proteinase-activated receptors in fibroproliferative lung disease

José, Ricardo J.; Williams, Andrew E.; Chambers, Rachel C.

doi:10.1136/thoraxjnl-2013-204367

Cited by 87 publications

(83 citation statements)

References 13 publications

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“…PAR1 or PAR2 activation enhanced the production of inflammatory mediators and cytokines and participated in chronic airway diseases, such as asthma, COPD, and IPF (idiopathic pulmonary fibrosis) (15). Virus infection also activated PAR1 and PAR2 to mediate innate immune, airway inflammation, and lung function (16)(17)(18).…”

mentioning

confidence: 99%

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

Zang

Zhuang

Deng

et al. 2016

J Virol

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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...

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mentioning

confidence: 99%

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

Zang

Zhuang

Deng

et al. 2016

J Virol

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“…It is often suggested as an uncontrolled wound healing response, in which multiple effectors are tightly involved. PAR-2, as a critical receptor that orchestrates a diverse range of signaling pathways, is suggested to play an important role in mediating profibrotic effects in fibroblasts and in preclinical experimental animal models (7,19,20,21,(34)(35)(36). Importantly however, the relevance of PAR-2 in pulmonary fibrosis has recently been debated, and the actual role of PAR-2 in pulmonary fibrosis is controversial.…”

Section: Discussionmentioning

confidence: 99%

“…Studies exploring the mechanisms that are crucially involved in the development of IPF identified several possible targets for therapeutic interventions. Among those, protease-activated receptors (PARs) are key candidates, as these receptors mediate the cellular effects of coagulation factors and play central roles in influencing inflammatory and fibrotic responses (5)(6)(7).…”

Section: Introductionmentioning

confidence: 99%

Pharmacological Targeting of Protease-Activated Receptor 2 Affords Protection from Bleomycin-Induced Pulmonary Fibrosis

Lin

Thüsen

Daalhuisen

et al. 2015

Mol Med

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“…This process, mediated by the Tissue Factor (TF)-dependent generation of thrombin, results in the conversion of fibrinogen to a provisional matrix of cross-linked fibrin and facilitates the formation of a clot and the repair of the injured blood vessels. More recently it has been established that the coagulation cascade has a role in regulating both inflammatory and fibro-proliferative responses during wound healing with the provisional fibrin matrix serving as a reservoir for growth factors and pro-inflammatory mediators [156,157]. These mediators are able to facilitate leucocyte migration and the activation and proliferation of mesenchymal cells but in addition, thrombin also appears to mediate direct cellular effects independent of fibrin deposition.…”

Section: Coagulation Pathwaysmentioning

confidence: 97%

“…The role of coagulation in the development of fibrosis has been examined in a number of different organ systems but it is perhaps best described within the lungs both in the context of acute lung injury and in IPF [156,157]. Patients with IPF have recently been shown to be more likely to have a prothrombotic state than the general population and the presence of this prothrombotic state has an adverse effect on survival [159].…”

Section: Coagulation Pathwaysmentioning

confidence: 98%