Factor Xa Stimulates Proinflammatory and Profibrotic Responses in Fibroblasts via Protease-Activated Receptor-2 Activation

Borensztajn, Keren; Stiekema, J.; Nijmeijer, S. W. R.; Reitsma, Pieter H.; Peppelenbosch, Maikel P.; Spek, C. Arnold

doi:10.2353/ajpath.2008.070347

Cited by 116 publications

(113 citation statements)

References 58 publications

(64 reference statements)

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“…17). Thus, some coagulation cascade serine proteinases have noncoagulant functions in the joint that can modulate various cellular processes such as cell proliferation and survival, gene transcription, and protein translation (18).…”

Section: Coagulation Cascadementioning

confidence: 99%

Emerging roles of serine proteinases in tissue turnover in arthritis

Milner

Patel

Rowan

2008

Arthritis & Rheumatism

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Section: Coagulation Cascadementioning

confidence: 99%

Emerging roles of serine proteinases in tissue turnover in arthritis

Milner

Patel

Rowan

2008

Arthritis & Rheumatism

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“…Cell viability was determined at the indicated intervals using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium (MTT) assay, as described before. 13 Tick anticoagulant peptide (TAP) and hirudin (Calbiochem, San Diego, CA) were used at a concentration of 200 nmol/L (TAP) and 100 nmol/L (hirudin).…”

Section: Viability Assaymentioning

confidence: 99%

“…Recent data suggest that protease-activated receptor 2 (PAR-2), a cellular receptor activated by (among others) coagulation factor (F)Xa, is an important player in fibrotic disease. PAR-2 triggers fibroproliferative responses in vitro [11][12][13] and is highly expressed in fibrotic disorders. 12 This study explores the role of blood coagulation factor driven PAR-2 activation in pulmonary fibrosis.…”

mentioning

confidence: 99%

Protease-Activated Receptor-2 Induces Myofibroblast Differentiation and Tissue Factor Up-Regulation during Bleomycin-Induced Lung Injury

Borensztajn

Bresser

Loos

et al. 2010

The American Journal of Pathology

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Idiopathic pulmonary fibrosis constitutes the most devastating form of fibrotic lung disorders and remains refractory to current therapies. The coagulation cascade is frequently activated during pulmonary fibrosis, but this observation has so far resisted a mechanistic explanation. Recent data suggest that protease-activated receptor (PAR)-2, a receptor activated by (among others) coagulation factor (F)Xa, plays a key role in fibrotic disease; consequently, we assessed the role of PAR-2 in the development of pulmonary fibrosis in this study. We show that PAR-2 is up-regulated in the lungs of patients with idiopathic pulmonary fibrosis and that bronchoalveolar lavage fluid from these patients displays increased procoagulant activity that triggers fibroblast survival. Using a bleomycin model of pulmonary fibrosis, we show that bleomycin induces PAR-2 expression, as well as both myofibroblast differentiation and collagen synthesis. In PAR-2؊/؊ mice, both the extent and severity of fibrotic lesions are reduced, whereas myofibroblast differentiation is diminished and collagen expression is decreased. Moreover, fibrin deposition in the lungs of fibrotic PAR-2؊/؊ mice is reduced compared with wild-type mice due to differential tissue factor expression in response to bleomycin. Taken together , these results suggest an important role for PAR-2 in the development of pulmonary fibrosis , and the inhibition of the PAR-2-coagulation axis may provide a novel therapeutic approach to treat this devastating disease.

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“…The in vitro wound-healing ability was measured using the method of Borensztajn et al (2008) with some modifications. Gastric cancer cells were cultured in six-well plates.…”

Section: Wound-healing Assaysmentioning

confidence: 99%

Establishment and characterization of a new hypoxia-resistant cancer cell line, OCUM-12/Hypo, derived from a scirrhous gastric carcinoma

et al. 2010

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BACKGROUND: Many kinds of solid tumour have heterogeneously a hypoxic environment. Tumour hypoxia reported to be associated with more aggressive tumour phenotypes such as high metastatic ability and resistance to various anti-cancer therapies which may lead to a poorer prognosis. However, the mechanisms by which hypoxia affects the aggressive phenotypes remain unclear. METHODS: We established a scirrhous gastric carcinoma cell line (OCUM-12) from ascites associated with scirrhous gastric carcinoma, and a hypoxia-resistant cancer cell line (OCUM-12/Hypo) was cloned from OCUM-12 cells by continuous exposure to 1% oxygen. RESULTS: Histologic findings from orthotopic tumours derived from parent OCUM-12 cells and daughter OCUM-12/Hypo cells revealed poorly differentiated adenocarcinoma with extensive fibrosis that resembled human scirrhous gastric cancer. Necrotic lesions were frequently detected in the OCUM-12 tumours but were rarely found in the OCUM-12/Hypo tumours, although both types had multiple hypoxic loci. Apoptosis rate of OCUM-12 cells was increased to 24.7% at 1% O 2 , whereas that of OCUM-12/ Hypo was 5.6%. The OCUM-12/Hypo orthotopic models developed multiple metastases to the peritoneum and lymph nodes, but the OCUM-12 models did not. OCUM-12/Hypo cells showed epithelial-to-mesenchymal transition and high migratory and invasive activities in comparison with OCUM-12 cells. The mRNA expression levels of both E-cadherin and zonula occludens ZO-1 and ZO-2 decreased in OCUM-12/Hypo cells, and that of vimentin, Snail-1, Slug/Snail-2, Twist, ZEB-1, ZEB-2, matrix metalloproteinase-1 (MMP-1), and MMP-2 were increased in OCUM-12/Hypo cells. CONCLUSION: OCUM-12 and OCUM-12/Hypo may be useful for the elucidation of disease progression associated with scirrhous gastric cancer in the setting of chronic hypoxia.

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Factor Xa Stimulates Proinflammatory and Profibrotic Responses in Fibroblasts via Protease-Activated Receptor-2 Activation

Cited by 116 publications

References 58 publications

Emerging roles of serine proteinases in tissue turnover in arthritis

Emerging roles of serine proteinases in tissue turnover in arthritis

Protease-Activated Receptor-2 Induces Myofibroblast Differentiation and Tissue Factor Up-Regulation during Bleomycin-Induced Lung Injury

Establishment and characterization of a new hypoxia-resistant cancer cell line, OCUM-12/Hypo, derived from a scirrhous gastric carcinoma

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