The effect of direct coagulation factor Xa inhibitor on acute lung injury progression induced by endotoxin in mice_Chinese Journal of Respiratory and Critical Care Medicine

Authors：

SHI Meng , HUANG Jiechun , SUN Xiaotian , WANG Fangrui , CHU Xianglin , JIANG Rongrong , WANG Yiqing ,  PANG Liewen

Department of Cardiothoracic Surgery, Huashan Hospital, Fudan University, Shanghai 200040, P. R. China;

Corresponding?author：

PANG Liewen, Email: huashan_heart@sina.cn

Keywords：

Coagulation factor Xa; Rivaroxaban; Acute lung injury; Protease-activated receptor 2; Nuclear factor kappa B

DOI：

10.7507/1671-6205.201810048

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Objective To investigate whether treatment of rivaroxaban, an approved oral direct coagulation factor Xa inhibitor, attenuates functional changes in LPS -induced acute lung injury (ALI) mouse.Methods C57BL/6 mice were randomly divided into PBS group, N-LPS group, L-LPS group, and H-LPS group. In the C57BL/6 mice being fed chow containing 0.2 mg/g or 0.4 mg/g rivaroxaban for 10 days (L-LPS group and H-LPS group), plasma concentration and coagulation indices were measured. Next, the role of rivaroxaban in ALI by using mice fed by rivaroxaban was studied in a murine ALI model induced by direct intratracheal injection lipopolysaccharides (LPS). Lung injury by histopathological scoring, micro computed tomography, pulmonary edema, inflammatory cell recruitment and activity of inflammatory cytokines in lung tissue or bronchoalveolar lavage fluid (BALF) were assessed. Western blot and immunohistochemistry were performed to examine expression of multiple proteins, including myeloperoxidase, protease-activatedreceptor 2 (PAR-2) and nuclear factor kappa B (NF-κB).Results The increased plasma concentration of rivaroxaban and the prolonged prothrombin time were displayed in the mice with rivaroxaban treatment. Rivaroxaban treatment groups showed significant reductions in neutrophil sequestration and preservation of the lung tissue architecture compared to the LPS positive control (P<0.05). Tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β) and interleukin-6 (IL-6) levels, in addition to total protein and Evans blue concentration were all significantly reduced in BALF from the mice treated with the chow containing rivaroxaban. Administration of rivaroxaban ameliorated ALI with concomitant reductions in the expression of PAR-2 and proinflammatory cytokines. LPS-induced PAR-2 increase and NF-κB activation were also suppressed by rivaroxaban in lung tissues. Furthermore, rivaroxaban inhibited the phosphorylation levels of P65 in ALI.Conclusions The results demonstrate that rivaroxaban effectively attenuates LPS-induced inflammatory responses by noncoagulative pathway in ALI. The beneficial effects are associated with the decreased phosphorylation of NF-κB pathways and the reduced expression of PAR-2.

Citation： SHI Meng, HUANG Jiechun, SUN Xiaotian, WANG Fangrui, CHU Xianglin, JIANG Rongrong, WANG Yiqing, PANG Liewen. The effect of direct coagulation factor Xa inhibitor on acute lung injury progression induced by endotoxin in mice. Chinese Journal of Respiratory and Critical Care Medicine, 2019, 18(4): 369-376. doi: 10.7507/1671-6205.201810048 Copy

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12.	Hara T, Fukuda D, Tanaka K, et al. Rivaroxaban, a novel oral anticoagulant, attenuates atherosclerotic plaque progression and destabilization in ApoE-deficient mice. Atherosclerosis, 2015, 242(2): 639-646.
13.	Esmon CT. Targeting factor Xa and thrombin: impact on coagulation and beyond. Thromb Haemost, 2014, 111(4): 625-633.
14.	Sparkenbaugh EM, Chantrathammachart P, Mickelson J, et al. Differential contribution of FXa and thrombin to vascular inflammation in a mouse model of sickle cell disease. Blood, 2014, 123(11): 1747-1756.
15.	Alberelli MA, De Candia E. Functional role of protease activated receptors in vascular biology. Vascul Pharmacol, 2014, 62(2): 72-81.
16.	李超, 胡晉紅. 以蛋白酶活化受體 2 為靶點的藥物研究進展. 藥學學報, 2016, 51(3): 362-366.
17.	Osuga Y, Hirota Y, Yoshino O, et al. Proteinase-activated receptors in the endometrium and endometriosis. Front Biosci (Schol Ed), 2012, 4: 1201-1212.
18.	Oe Y, Hayashi S, Fushima T, et al. Coagulation factor Xa and protease-activated receptor 2 as novel therapeutic targets for diabetic nephropathy. Arterioscler Thromb Vasc Biol, 2016, 36(8): 1525-1533.
19.	Rohde G. Determination of rivaroxaban--a novel, oral, direct Factor Xa inhibitor--in human plasma by high-performance liquid chromatography-tandem mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci, 2008, 872(1-2): 43-50.
20.	Camici GG, Steffel J, Akhmedov A, et al. Dimethyl sulfoxide inhibits tissue factor expression, thrombus formation, and vascular smooth muscle cell activation: a potential treatment strategy for drug-eluting stents. Circulation, 2006, 114(14): 1512-1521.
21.	Becker PM, Kazi AA, Wadgaonkar R, et al. Pulmonary vascular permeability and ischemic injury in gelsolin-deficient mice. Am J Respir Cell Mol Biol, 2003, 28(4): 478-484.
22.	Duan YL, Learoyd J, Meliton AY, et al. Inhibition of Pyk2 blocks lung inflammation and injury in a mouse model of acute lung injury. Respir Res, 2012, 13: 4.
23.	Peng X, Hassoun PM, Sammani S, et al. Protective effects of sphingosine 1-phosphate in murine endotoxin- induced inflammatory lung injury. Am J Respir Crit Care Med, 2004, 169(11): 1245-1251.
24.	Madoiwa S. Recent advances in disseminated intravascular coagulation: endothelial cells and fibrinolysis in sepsis-induced DIC. J Intensive Care, 2015, 3: 8.
25.	Borissoff JI, Spronk HM, ten Cate H. The hemostatic system as a modulator of atherosclerosis. N Engl J Med, 2011, 364(18): 1746-1760.
26.	Komarova YA, Kruse K, Mehta D, et al. Protein interactions at endothelial junctions and signaling mechanisms regulating endothelial permeability. Circ Res, 2017, 120(1): 179-206.

1. 施夢, 祝禾辰, 曹同瓦. 急性肺損傷發病機制研究進展. 中華急診醫學雜志, 2008, 17(4): 443-444.
2. Glas GJ, Van Der Sluijs KF, Schultz MJ, et al. Bronchoalveolar hemostasis in lung injury and acute respiratory distress syndrome. J Thromb Haemost, 2013, 11(1): 17-25.
3. Czikora I, Sridhar S, Gorshkov B, et al. Protective effect of growth hormone-releasing hormone agonist in bacterial toxin-induced pulmonary barrier dysfunction. Front Physiol, 2014, 5: 259.
4. 周玲玲, 夏國際, 羅萍. 促紅細胞生成素對急性肺損傷保護作用機制的研究進展. 中國呼吸與危重監護雜志, 2018, 17(1): 105-108.
5. Fouassier M, Souweine B, Sapin AF, et al. Increase in proinflammatory cytokines in peripheral blood without haemostatic changes after LPS inhalation. Thromb Res, 2009, 124(5): 584-587.
6. Russell JA. Genetics of coagulation factors in acute lung injury. Crit Care Med, 2003, 31(4 Suppl): S243-S247.
7. Anthoni C, Russell J, Wood KC, et al. Tissue factor: a mediator of inflammatory cell recruitment, tissue injury, and thrombus formation in experimental colitis. J Exp Med, 2007, 204(7): 1595-1601.
8. Borensztajn K, Peppelenbosch MP, Spek CA. Factor Xa: at the crossroads between coagulation and signaling in physiology and disease. Trends Mol Med, 2008, 14(10): 429-440.
9. Schwientek P, Ellinghaus P, Steppan S, et al. Global gene expression analysis in nonfailing and failing myocardium pre- and postpulsatile and nonpulsatile ventricular assist device support. Physiol Genomics, 2010, 42(3): 397-405.
10. Scotton CJ, Krupiczojc MA, K?nigshoff M, et al. Increased local expression of coagulation factor X contributes to the fibrotic response in human and murine lung injury. J Clin Invest, 2009, 119(9): 2550-2563.
11. Bukowska A, Zacharias I, Weinert S, et al. Coagulation factor Xa induces an inflammatory signalling by activation of protease-activated receptors in human atrial tissue. Eur J Pharmacol, 2013, 718(1-3): 114-123.
12. Hara T, Fukuda D, Tanaka K, et al. Rivaroxaban, a novel oral anticoagulant, attenuates atherosclerotic plaque progression and destabilization in ApoE-deficient mice. Atherosclerosis, 2015, 242(2): 639-646.
13. Esmon CT. Targeting factor Xa and thrombin: impact on coagulation and beyond. Thromb Haemost, 2014, 111(4): 625-633.
14. Sparkenbaugh EM, Chantrathammachart P, Mickelson J, et al. Differential contribution of FXa and thrombin to vascular inflammation in a mouse model of sickle cell disease. Blood, 2014, 123(11): 1747-1756.
15. Alberelli MA, De Candia E. Functional role of protease activated receptors in vascular biology. Vascul Pharmacol, 2014, 62(2): 72-81.
16. 李超, 胡晉紅. 以蛋白酶活化受體 2 為靶點的藥物研究進展. 藥學學報, 2016, 51(3): 362-366.
17. Osuga Y, Hirota Y, Yoshino O, et al. Proteinase-activated receptors in the endometrium and endometriosis. Front Biosci (Schol Ed), 2012, 4: 1201-1212.
18. Oe Y, Hayashi S, Fushima T, et al. Coagulation factor Xa and protease-activated receptor 2 as novel therapeutic targets for diabetic nephropathy. Arterioscler Thromb Vasc Biol, 2016, 36(8): 1525-1533.
19. Rohde G. Determination of rivaroxaban--a novel, oral, direct Factor Xa inhibitor--in human plasma by high-performance liquid chromatography-tandem mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci, 2008, 872(1-2): 43-50.
20. Camici GG, Steffel J, Akhmedov A, et al. Dimethyl sulfoxide inhibits tissue factor expression, thrombus formation, and vascular smooth muscle cell activation: a potential treatment strategy for drug-eluting stents. Circulation, 2006, 114(14): 1512-1521.
21. Becker PM, Kazi AA, Wadgaonkar R, et al. Pulmonary vascular permeability and ischemic injury in gelsolin-deficient mice. Am J Respir Cell Mol Biol, 2003, 28(4): 478-484.
22. Duan YL, Learoyd J, Meliton AY, et al. Inhibition of Pyk2 blocks lung inflammation and injury in a mouse model of acute lung injury. Respir Res, 2012, 13: 4.
23. Peng X, Hassoun PM, Sammani S, et al. Protective effects of sphingosine 1-phosphate in murine endotoxin- induced inflammatory lung injury. Am J Respir Crit Care Med, 2004, 169(11): 1245-1251.
24. Madoiwa S. Recent advances in disseminated intravascular coagulation: endothelial cells and fibrinolysis in sepsis-induced DIC. J Intensive Care, 2015, 3: 8.
25. Borissoff JI, Spronk HM, ten Cate H. The hemostatic system as a modulator of atherosclerosis. N Engl J Med, 2011, 364(18): 1746-1760.
26. Komarova YA, Kruse K, Mehta D, et al. Protein interactions at endothelial junctions and signaling mechanisms regulating endothelial permeability. Circ Res, 2017, 120(1): 179-206.

Chinese Journal of Respiratory and Critical Care Medicine

The effect of direct coagulation factor Xa inhibitor on acute lung injury progression induced by endotoxin in mice

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