Pulmonary Fibrosis Is Increased in Mice Carrying the Factor V Leiden Mutation following Bleomycin Injury

Summary

Increased fibrin deposition following inflammatory lung injury has been proposed to facilitate the development of pulmonary fibrosis. Therefore, factors predisposing to thrombosis may affect the fibrotic response to injury. Activated protein C (aPC) resistance due to the factor V Leiden mutation (FνL) is a common genetic risk factor for vascular thrombosis. To examine the relationship between aPC resistance and the development of pulmonary fibrosis, lung inflammation was induced by bleomycin in mice carrying the FvL mutation. Three weeks following the instillation of 0.0375 U of bleomycin, the lungs of mice homozygous and heterozygous for FvL contained significantly more hydroxyproline (35 ± 4 and 36 ± 7 ug hydroxyproline/ mg total protein, respectively) than wild-type mice (26 ± 6 ug/mg protein, p <0.01 for both comparisons). These data demonstrate a strong relationship between aPC resistance and the pulmonary fibrosis that occurs following inflammatory lung injury.

Keywords

Pulmonary fibrosis - thrombosis - bleomycin - factor V Leiden - fibrin

• References

• 1 Eitzman DT, McCoy RD, Zheng X, Fay WP, Shen T, Ginsburg D, Simon RH. Bleomycin-induced pulmonary fibrosis in transgenic mice that either lack or overexpress the murine plasminogen activator inhibitor-1 gene. J Clin Invest 1996; 97: 232-7.
• 2 Olman MA, Mackman N, Gladson CL, Moser KM, Loskutoff DJ. Changes in procoagulant and fibrinolytic gene expression during bleomycin-induced lung injury in the mouse. J Clin Invest 1995; 96: 1621-30.
• 3 Idell S, James KK, Levin EG, Schwartz BS, Manchanda N, Maunder RJ, Martin TR, McLarty J, Fair DS. Local abnormalities in coagulation and fibrinolytic pathways predispose to alveolar fibrin deposition in the adult respiratory distress syndrome. J Clin Invest 1989; 84: 695-705.
• 4 Bertozzi P, Astedt B, Zensius L, Lynch K, LeMaire F, Zapol W, Chapman H. Depressed bronchoalveolar urokinase activity in patients with adult respiratory distress syndrome. N Engl J Med 1990; 322: 890-7.
• 5 Suzuki K, Nishioka J, Hashimoto S. Protein C, inhibitor. Purification from human plasma and characterization. J Biol Chem 1983; 258: 163-8.
• 6 Luckow EA, Lyons DA, Ridgeway TM, Esmon CT, Laue TM. Interaction of clotting factor V heavy chain with prothrombin and prethrombin 1 and role of activated protein C in regulating this interaction. Analysis by analytical ultra-centrifugation. Biochemistry 1989; 28: 2348-54.
• 7 Bertina RM, Koeleman BP, Koster T, Rosendaal FR, Dirven RJ, de Ronde H, van der Velden PA, Reitsma PH. Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature 1994; 369: 64-7.
• 8 Svensson PJ. Resistance to activated protein C as a basis for venous thrombosis. N Engl J Med 1994; 330: 517-22.
• 9 Griffin JH, Evatt B, Wideman C, and Fernandez JA. Anticoagulation protein C pathway defective in majority of thrombophilic patients. Blood 1993; 82: 1989-93.
• 10 Koster T, Rosendaal FR, de Ronde H, Briet E, Vandenbroucke JP. Venous thrombosis due to poor anticoagulant response to activated protein C. Lancet 1993; 342: 1503-6.
• 11 Cui J, Eitzman DT, Westrick RJ, Christie PD, Xu Z, Yang A, Purkayastha A, Yang TL, Metz AL, Gallagher KP, Tyson J, Rosenberg RD, Ginsburg D. Spontaneous thrombosis in mice carrying the factor V Leiden mutation. Blood 2000; 96: 4222-6.
• 12 Idell S, Peters J, James KK, Fair DS, Coalson JJ. Local abnormalities of coagulation and fibrinolytic pathways that promote alveolar fibrin deposition in the lungs of baboons with diffuse alveolar damage. J Clin Invest 1989; 84: 181-93.
• 13 Swaisgood C, French E, Noga C, Simon R, Ploplis V. The development of bleomycin-induced pulmonary fibrosis in mice deficient for components of the fibrinolytic system. Am J Pathol 2000; 157: 177-87.
• 14 Sisson TH, Hattori N, Xu Y, Simon RH. Treatment of bleomycin-induced pulmonary fibrosis by transfer of urokinase-type plasminogen activator genes. Human Gene Therapy 1999; 10: 2315-23.
• 15 Kobayashi H, Gabazza E, Taguchi O, Wada H, Takeya H, Nishioka J, Yasui H, Kobayashi T, Hataji O, Suzuki K, Adachi Y. Protein C, anticoagulant system in patients with interstitial lung disease. Am J Respir Crit Care Med 1998; 157: 1850-4.
• 16 Zoller B, Dahlback B. Linkage between inherited resistance to activated protein C and factor V gene mutation in venous thrombosis. Lancet 1994; 343: 1536-8.
• 17 Voorberg J, Roelse J, Koopman R, Buller H, Berends F, ten Cate J, Mertens K, van Mourik J. Association of idiopathic venous thromboembolism with single point-mutation at Arg⁵⁰⁶ of factor V. Lancet 1994; 343: 1535-6.
• 18 Adamson IY, Bowden DH. The pathogenesis of bleomycin-induced pulmonary fibrosis in mice. Am J Pathol 1974; 77: 185-97.
• 19 Idell S, Gonzalez KK, MacArthur CK, Gillies C, Walsh PN, McLarty J, Thrall RS. Bronchoalveolar lavage procoagulant activity in bleomycin-induced lung injury in marmosets. Characterization and relationship to fibrin deposition and fibrosis. Am Rev Respir Dis 1987; 136: 124-33.
• 20 Ploplis V, Wilberding J, McLennan L, Zhong L, Cornelissen I, DeFord M, Rosen E, Casgtellino F. A total fibrinogen deficiency is compatible with the development of pulmonary fibrosis in mice. Am J Pathol 2000; 157: 703-8.
• 21 Hattori N, Degen J, Sisson T, Liu H, Moore B, Pandragi R, Simon R, Drew A. Bleomycin-induced pulmonary fibrosis in fibrinogen-null mice. J Clin Invest 2000; 106: 1341-50.
• 22 Peterson J, Rayburn H, Lager D, Raife T, Kealey G, Rosenberg R, Lentz S. Expression of thrombomodulin and consequences of thrombomodulin deficiency during healing of cutaneous wounds. Am J Pathol 1999; 155: 1569-75.