Role of intrinsic coagulation pathway in the pathogenesis of idiopathic pulmonary fibrosis
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Idiopathic pulmonary fibrosis (IPF) is a rare, chronic, progressive interstitial lungdisease characterized by abnormal and excessive deposition of fibrotic tissue in thepulmonary interstitium. Elevated procoagulant and decreased fibrinolytic activities havebeen observed in bronchoalveolar lavage (BAL) fluid from IPF patients. Alterations ofalveolar haemostatic balance, mainly due to increased expression of tissue factor (TF),factor VII (FVII) and plasminogen activator inhibitor 1 (PAI-1), and decreased synthesisof urokinase (u-PA) promote fibrin deposition in the alveolar compartment. Moreover,cellular activities of coagulation factors also potentiate fibrotic responses in the lungsthrough stimulation of fibroblast proliferation and differentiation, production ofprofibrotic cytokines and increased deposition of extracellular matrix components.Coagulation factor XII (FXII) is a key component of the intrinsic blood coagulationpathway involved in coagulation, fibrinolysis and inflammation. Active FXII (FXIIa)converts factor XI (FXI) into activated FXI (FXIa) and prekallikrein (PK) into kallikrein(KLK). Consequently, FXI activation culminates in a series of proteolytic reactionsresulting in thrombin generation and the release of the proinflammatory and vasodilatorybradykinin (BK).The implication of the extrinsic coagulation pathway in the pathogenesis ofpulmonary fibrosis has been well described, however the potential role of intrinsiccoagulation factors, namely FXII, FXI and high molecular weight kininogen (HMWK),has never been reported in the pathomechanisms of chronic fibroproliferative lungdiseases. The present study was undertaken to evaluate the contribution of the intrinsiccoagulation pathway in the pathogenesis of IPF.Increased expression of FXII, FXI and HMWK and elevated activity of FXIIa weredetected in the lungs of bleomycin-treated mice as well as of IPF patients. The strongestimmunoreactivity of FXII was observed in fibroblasts and on the surface of alveolarepithelial type II cells (ATII). In vitro experiments identified FXIIa as a potent mitogenfor primary murine lung fibroblasts. FXIIa mitogenic activity was mediated by the a51-integrin and the u-PA receptor (uPAR), since a blockade of these molecules abolishedFXIIa-induced cell proliferation. Moreover, FXII-dependent induction of lung fibroblastproliferation was attenuated by the pharmacological blockade of the extracellular signal-regulated kinase (ERK) 1/2 pathway. In line with in vitro data, FXII knockout mice werefound to be protected against bleomycin-induced fibrosis and intratracheal application ofFXIIa inhibitor strongly reduced a fibrotic response after bleomycin administration. Thelack in reduction of fibrotic responses in bradykinin receptor 1/2 deficient mice indicatedthat BK did not mediate FXII profibrotic properties.Although regulation of FXII expression by estrogen in hepatocytes is welldescribed, no data are available about regulation of FXII synthesis in cells other thanhepatocytes. Interestingly, human lung fibroblasts (HLF) were found to express FXII in aregulated manner. Treatment of HLF with Transforming growth factor-ß1 (TGF-ß1)induced FXII production in a time-dependent manner. The intracellular mechanism bywhich TGF-1 stimulates FXII expression was investigated and the respective FXIIpromoter region necessary for TGF-1 mediated FXII production was characterized.In conclusion, these findings identified FXII/FXIIa, apart from its possible role ascoagulation factor in the alveolar compartment, as a novel profibrotic factor that maycontribute to the development of lung fibrosis by potentiating proliferation of lungfibroblasts. Therefore, FXII and its downstream signaling pathway in lung fibroblastsshould be considered as a novel target for therapeutic intervention in pulmonary fibrosis.Verknüpfung zu Publikationen oder weiteren Datensätzen
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Giessen : VVB Laufersweiler