Coagulation factor XII regulates inflammatory responses in human lungsFinancial support: This study was funded by the German Research Foundation (SFB/TR84 Project A2 to M. W. and K. T.P), the Else Kröner-Fresenius-Foundation (to M. W. and P. M.), the Oskar Helene Heim Foundation (to P. M.), the German Center for Lung Research (to M. W.) and the University Medical Center Giessen and Marburg (UKGM to M. W. and P. M.).
01 December 2016
Accepted after major revision: 23 June 2017
08 November 2017 (online)
Increased procoagulant activity in the alveolar compartment and uncontrolled inflammation are hallmarks of the acute respiratory distress syndrome (ARDS). Here, we investigated whether the contact phase system of coagulation is activated and may regulate inflammatory responses in human lungs. Components of the contact phase system were characterized in bronchoalveolar lavage fluids (BALF) from 54 ARDS patients and 43 controls, and their impact on cytokine/chemokine expression in human precision cut lung slices (PCLS) was assessed by a PCR array. Activation of the contact system, associated with high levels of coagulation factor XIIa (Hageman factor, FXIIa), plasma kallikrein and bradykinin, occurred rapidly in ARDS lungs after the onset of the disease and virtually normalized within one week from time of diagnosis. FXII levels in BALF were higher in ARDS nonsurvivors than survivors and were positively correlated with tumor necrosis factor (TNF)-α concentration. FXII induced the production and release of interleukin (IL)-8, IL-1β, IL-6, leukemia inhibitory factor (LIF), CXCL5 and TNF-α in human PCLS in a kallikrein-kinin-independent manner. In conclusion, accumulation of FXII in ARDS lungs may contribute to the release of pro-inflammatory mediators and is associated with clinical outcome. FXII inhibition may thus offer a novel and promising therapeutic approach to antagonize overwhelming inflammatory responses in ARDS lungs without interfering with vital haemostasis.
Supplementary Material to this article is available online at www.thrombosis-online.com.
† Member of the German Center for Lung Research.
- 1 Johnson ER, Matthay MA. Acute lung injury: epidemiology, pathogenesis, and treatment. J Aerosol Med Pulm Drug Deliv 2010; 23: 243-252.
- 2 Reiss LK, Uhlig U, Uhlig S. Models and mechanisms of acute lung injury caused by direct insults. Eur J Cell Biol 2012; 91: 590-601.
- 3 Baron RM, Levy BD. Recent advances in understanding and treating ARDS. F1000Res. 2016 05..
- 4 Blondonnet R, Constantin JM, Sapin V. et al. A Pathophysiologic Approach to Biomarkers in Acute Respiratory Distress Syndrome. Dis Markers 2016; 2016: 3501373.
- 5 Toossi Z, Sedor JR, Mettler MA. et al. Induction of expression of monocyte interleukin 1 by Hageman factor (factor XII). Proc Natl Acad Sci USA 1992; 89: 11969-11972.
- 6 Wachtfogel YT, Pixley RA, Kucich U. et al. Purified plasma factor XIIa aggregates human neutrophils and causes degranulation. Blood 1986; 67: 1731-1737.
- 7 Khan MM, Bradford HN, Isordia-Salas I. et al. High-molecular-weight kininogen fragments stimulate the secretion of cytokines and chemokines through uPAR, Mac-1, and gC1qR in monocytes. Arterioscler Thromb Vasc Biol 2006; 26: 2260-2266.
- 8 Velasco F, Torres A, Guerrero A. et al. Behaviour of the contact phase of blood coagulation in the adult respiratory distress syndrome (ARDS). Thromb Haemost 1986; 55: 357-360.
- 9 Herrera C, Velasco F, Guerrero A. et al. Contact phase of blood coagulation in cardiogenic pulmonary oedema (CPO) and adult respiratory distress syndrome (ARDS). Intensive Care Med 1989; 15: 99-104.
- 10 Carvalho AC, DeMarinis S, Scott CF. et al. Activation of the contact system of plasma proteolysis in the adult respiratory distress syndrome. J Lab Clin Med 1988; 112: 270-277.
- 11 de Oliveira GG, Antonio MP. Adult respiratory distress syndrome (ARDS): the pathophysiologic role of catecholamine-kinin interactions. J Trauma 1988; 28: 246-253.
- 12 Coppola R, Cristilli P, Cugno M. et al. Measurement of activated factor XII in health and disease. Blood Coagul Fibrinolysis 1996; 07: 530-535.
- 13 Persson K, Morgelin M, Lindbom L. et al. Severe lung lesions caused by Salmonella are prevented by inhibition of the contact system. J Exp Med 2000; 192: 1415-1424.
- 14 Tucker EI, Verbout NG, Leung PY. et al. Inhibition of factor XI activation attenuates inflammation and coagulopathy while improving the survival of mouse polymicrobial sepsis. Blood 2012; 119: 4762-4768.
- 15 Ranieri VM, Rubenfeld GD, Thompson BT. et al. Acute respiratory distress syndrome: the Berlin Definition. JAMA 2012; 307: 2526-2533.
- 16 Vorlova S, Koch M, Manthey HD. et al. Coagulation factor XII induces pro-inflammatory cytokine responses in macrophages and promotes atherosclerosis in mice. Thromb Haemost 2017; 117: 176-187.
- 17 Gobel K, Pankratz S, Asaridou CM. et al. Blood coagulation factor XII drives adaptive immunity during neuroinflammation via CD87-mediated modulation of dendritic cells. Nat Commun 2016; 07: 11626.
- 18 LaRusch GA, Mahdi F, Shariat-Madar Z. et al. Factor XII stimulates ERK1/2 and Akt through uPAR, integrins, and the EGFR to initiate angiogenesis. Blood 2010; 115: 5111-5120.
- 19 Shi JX, Su X, Xu J. et al. MK2 posttranscriptionally regulates TNF-alpha-induced expression of ICAM-1 and IL-8 via tristetraprolin in human pulmonary microvascular endothelial cells. Am J Physiol Lung Cell Mol Physiol 2012; 302: L793-L799.
- 20 Pugin J, Ricou B, Steinberg KP. et al. Proinflammatory activity in bronchoalveolar lavage fluids from patients with ARDS, a prominent role for interleukin-1. Am J Respir Crit Care Med 1996; 153: 1850-1856.
- 21 Oikonomopoulou K, Ricklin D, Ward PA. et al. Interactions between coagulation and complement--their role in inflammation. Semin Immunopathol 2012; 34: 151-165.
- 22 Ghebrehiwet B, Silverberg M, Kaplan AP. Activation of the classical pathway of complement by Hageman factor fragment. J Exp Med 1981; 153: 665-676.
- 23 Broadley KJ, Blair AE, Kidd EJ. et al. Bradykinin-induced lung inflammation and bronchoconstriction: role in parainfluenze-3 virus-induced inflammation and airway hyperreactivity. J Pharmacol Exp Ther 2010; 335: 681-692.
- 24 Ridings PC, Blocher CR, Fisher BJ. et al. Beneficial effects of a bradykinin antagonist in a model of gram-negative sepsis. J Trauma 1995; 39: 81-89.
- 25 Koyama S, Sato E, Nomura H. et al. Bradykinin stimulates type II alveolar cells to release neutrophil and monocyte chemotactic activity and inflammatory cytokines. Am J Pathol 1998; 153: 1885-1893.
- 26 Koyama S, Sato E, Numanami H. et al. Bradykinin stimulates lung fibroblasts to release neutrophil and monocyte chemotactic activity. Am J Respir Cell Mol Biol 2000; 22: 75-84.
- 27 Deng X, Wang X, Andersson R. Endothelial barrier resistance in multiple organs after septic and nonseptic challenges in the rat. J Appl Physiol 1995; 78: 2052-2061.
- 28 Meduri GU, Kohler G, Headley S. et al. Inflammatory cytokines in the BAL of patients with ARDS. Persistent elevation over time predicts poor outcome. Chest 1995; 108: 1303-1314.
- 29 Wachtfogel YT, Kucich U, James HL. et al. Human plasma kallikrein releases neutrophil elastase during blood coagulation. J Clin Invest 1983; 72: 1672-1677.
- 30 Itakura A, Verbout NG, Phillips KG. et al. Activated factor XI inhibits chemotaxis of polymorphonuclear leukocytes. J Leukoc Biol 2011; 90: 923-927.
- 31 Bane Jr CE, Ivanov I, Matafonov A. et al. Factor XI Deficiency Alters the Cytokine Response and Activation of Contact Proteases during Polymicrobial Sepsis in Mice. PLoS One 2016; 11: e0152968.
- 32 White-Adams TC, Berny MA, Tucker EI. et al. Identification of coagulation factor XI as a ligand for platelet apolipoprotein E receptor 2 (ApoER2). Arterioscler Thromb Vasc Biol 2009; 29: 1602-1607.
- 33 Pixley RA, De La Cadena R, Page JD. et al. The contact system contributes to hypotension but not disseminated intravascular coagulation in lethal bacteremia. In vivo use of a monoclonal anti-factor XII antibody to block contact activation in baboons. J Clin Invest 1993; 91: 61-68.
- 34 Iwaki T, Cruz-Topete D, Castellino FJ. A complete factor XII deficiency does not affect coagulopathy, inflammatory responses, and lethality, but attenuates early hypotension in endotoxemic mice. J Thromb Haemost 2008; 06: 1993-1995.
- 35 Lener M, Vinci G, Duponchel C. et al. Molecular cloning, gene structure and expression profile of mouse C1 inhibitor. Eur J Biochem 1998; 254: 117-122.
- 36 Schousboe I. Binding of activated Factor XII to endothelial cells affects its inactivation by the C1-esterase inhibitor. Eur J Biochem 2003; 270: 111-118.
- 37 Matthay MA, Zemans RL. The acute respiratory distress syndrome: pathogenesis and treatment. Annu Rev Pathol 2011; 06: 147-163.