- Title
- The coagulant factor Xa induces protease-activated receptor-1 and annexin A2-dependent airway smooth muscle cytokine production and cell proliferation
- Creator
- Schuliga, Michael; Royce, Simon G.; Langenbach, Shenna; Berhan, Asres; Harris, Trudi; Keenan, Christine R.; Stewart, Alastair G.
- Relation
- NHMRC.1022048
- Relation
- American Journal of Respiratory Cell and Molecular Biology Vol. 54, Issue 2, p. 200-209
- Publisher Link
- http://dx.doi.org/10.1165/rcmb.2014-0419OC
- Publisher
- American Thoracic Society
- Resource Type
- journal article
- Date
- 2016
- Description
- During asthma exacerbation, plasma circulating coagulant factor X (FX) enters the inflamed airways and is activated (FXa). FXa may have an important role in asthma, being involved in thrombin activation and an agonist of protease-activated receptor-1 (PAR-1). Extracellular annexin A2 and integrins are also implicated in PAR-1 signaling. In this study, the potential role of PAR-1 in mediating the effects of FXa on human airway smooth muscle (ASM) cell cytokine production and proliferation was investigated. FXa (5-50 nM), but not FX, stimulated increases in ASM IL-6 production and cell number after 24- and 48-hour incubation, respectively (P < 0.05; n = 5). FXa (15 nM) also stimulated increases in the levels of mRNA for cytokines (IL-6), cell cycle-related protein (cyclin D1), and proremodeling proteins (FGF-2, PDGF-B, CTGF, SM22, and P AI-1) after 3-hour incubation (P < 0.05; n = 4). The actions of FXa were insensitive to inhibition by hirudin (1 U/ml), a selective thrombin inhibitor, but were attenuated by SCH79797 (100 nM), a PAR-1 antagonist, or Cpd 22 (1 µM), an inhibitor of integrin-linked kinase. The selective targeting of PAR-1, annexin A2, or β 1-integrin by small interfering RNA and/or by functional blocking antibodies also attenuated FXa-evoked responses. In contrast, the targeting of annexin A2 did not inhibit thrombin-stimulated ASM function. In airway biopsies of patients with asthma, FXa and annexin A2 were detected in the ASM bundle by immunohistochemistry. These findings establish FXa as a potentially important asthma mediator, stimulating ASM function through actions requiring PAR-1 and annexin A2 and involving integrin coactivation.
- Subject
- airway wall remodeling; annexin A2 hetero-tetramer; asthma; intergin; thrombin
- Identifier
- http://hdl.handle.net/1959.13/1329196
- Identifier
- uon:26091
- Identifier
- ISSN:1044-1549
- Language
- eng
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