Role of Protease-activated Receptor-2 in Idiopathic Pulmonary Fibrosis

Wygrecka, Małgorzata; Kwapiszewska, Grażyna; Jabłońska, Ewa; Gerlach, Susanne von; Henneke, Ingrid; Zakrzewicz, Dariusz; Güenther, Andreas; Preissner, Klaus T.; Markart, Philipp

doi:10.1164/rccm.201009-1479oc

Cited by 81 publications

(79 citation statements)

References 50 publications

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“…As shown in Figure 1B, in control lungs (lanes 1-6), matriptase expression is low, and it increased by 2.25-fold in IPF lungs (lanes 8-12). Additionally, consistent with previous studies (20,21), PAR-2 expression was up-regulated in IPF lung (3.5 6 2-fold) ( Figure 1B). Subsequently, we determined the proteolytic activity of matriptase in control and IPF tissues by monitoring the cleavage of its highly specific fluorogenic peptide substrate t-butyloxycarbonyl BocGln-Ala-Arg-MCA (Boc-QAR-AMC) (7,22).…”

Section: Increased Matriptase Expression and Activity In The Lungs Ofsupporting

confidence: 92%

Membrane-anchored Serine Protease Matriptase Is a Trigger of Pulmonary Fibrogenesis

Bardou

Menou

François

et al. 2016

Am J Respir Crit Care Med

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Rationale: Idiopathic pulmonary fibrosis (IPF) is a devastating disease that remains refractory to current therapies.Objectives: To characterize the expression and activity of the membrane-anchored serine protease matriptase in IPF in humans and unravel its potential role in human and experimental pulmonary fibrogenesis.Methods: Matriptase expression was assessed in tissue specimens from patients with IPF versus control subjects using quantitative reverse transcriptase-polymerase chain reaction, immunohistochemistry, and Western blotting, while matriptase activity was monitored by fluorogenic substrate cleavage. Matriptaseinduced fibroproliferative responses and the receptor involved were characterized in human primary pulmonary fibroblasts by Western blot, viability, and migration assays. In the murine model of bleomycin-induced pulmonary fibrosis, the consequences of matriptase depletion, either by using the pharmacological inhibitor camostat mesilate (CM), or by genetic down-regulation using matriptase hypomorphic mice, were characterized by quantification of secreted collagen and immunostainings.Measurements and Main Results: Matriptase expression and activity were up-regulated in IPF and bleomycin-induced pulmonary fibrosis. In cultured human pulmonary fibroblasts, matriptase expression was significantly induced by transforming growth factor-b. Furthermore, matriptase elicited signaling via protease-activated receptor-2 (PAR-2), and promoted fibroblast activation, proliferation, and migration. In the experimental bleomycin model, matriptase depletion, by the pharmacological inhibitor CM or by genetic downregulation, diminished lung injury, collagen production, and transforming growth factor-b expression and signaling.Conclusions: These results implicate increased matriptase expression and activity in the pathogenesis of pulmonary fibrosis in human IPF and in an experimental mouse model. Overall, targeting matriptase, or treatment by CM, which is already in clinical use for other diseases, may represent potential therapies for IPF.

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Section: Increased Matriptase Expression and Activity In The Lungs Ofsupporting

confidence: 92%

Membrane-anchored Serine Protease Matriptase Is a Trigger of Pulmonary Fibrogenesis

Bardou

Menou

François

et al. 2016

Am J Respir Crit Care Med

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show abstract

“…Protease-activated receptors (PARs) promote the deposition of fibrin in addition to a multitude of other actions (43). A study by Wygrecka and colleagues (43) demonstrate that patients with IPF express increased levels of PAR-2 in type 2 alveolar epithelial cells and fibroblasts, which is further up-regulated by TGF-b. They provide evidence that factor VIIa/tissue factor complexes on the hyperplastic alveolar epithelium activate PAR-2, which then promotes fibroblast proliferation and matrix deposition.…”

Section: Coagulationmentioning

confidence: 99%

Update in Diffuse Parenchymal Lung Disease 2011

Luckhardt¹,

Müller–Quernheim²,

Thannickal³

2012

Am J Respir Crit Care Med

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“…Increased PAR-2 expression has been detected in the lungs of patients with IPF, and a recent study proposed that the PAR-2/tissue factor (TF)/FVIIa axis may contribute to the development and/or progression of IPF (16). This study provided in vitro evidence that FVIIa exerts profibrotic effects in human fibroblasts by specifically activating PAR-2.…”

Section: Pharmacological Targeting Of Protease-activated Receptor 2 Amentioning

confidence: 71%

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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Role of Protease-activated Receptor-2 in Idiopathic Pulmonary Fibrosis

Abstract: The PAR-2/TF/FVIIa axis may contribute to the development of pulmonary fibrosis; thus, interference with this pathway confers novel therapeutic potential for the treatment of IPF.

Cited by 81 publications

References 50 publications

Membrane-anchored Serine Protease Matriptase Is a Trigger of Pulmonary Fibrogenesis

Membrane-anchored Serine Protease Matriptase Is a Trigger of Pulmonary Fibrogenesis

Update in Diffuse Parenchymal Lung Disease 2011

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

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