Potential novel targets: Protease-activated receptors in idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is the most devastating diffuse fibrosing lung disease of unknown etiology. IPF patients suffer from severe breathlessness caused by decreasing lung compliance eventually leading to respiratory failure and death. The prognosis of IPF is devastating: there is only a 20-30% survival rate of 3-5 year after diagnosis of pulmonary fibrosis. Unfortunately, IPF remains refractory to current pharmacological therapies and novel treatment options are eagerly awaited for. With the research performed in this thesis, we assess the potential clinical relevance of targeting protease activated receptors (PARs) in pulmonary fibrosis and identify potential effectors and mechanisms which contribute to the pathogenesis of IPF. Pharmacological inhibition of PAR-1 and PAR-2, even starting after the onset of fibrosis, affords protection against bleomycin-induced pulmonary fibrosis. As current treatment options for IPF are limited, these findings may be particularly interesting for future medical interventions in IPF patients. Based on the notion that PAR-1 seems to drive pulmonary fibrosis in a PAR-2 dependent manner, it is tempting to speculate that blocking PAR-2 may be a better treatment strategy for IPF. Although blood coagulation seems to contribute to IPF progression, warfarin lacks effect in treating IPF, which may due to the fact that warfarin inhibits the activity of all vitamin K dependent coagulation factors including APC. The endogenous anticoagulant protein C has potential importance in limiting IPF progression. Therefore, increasing APC levels, either by the administration of APC or zymogen PC, may thus also be an alternative strategy for treating IPF.