High endogenous activated protein C levels attenuates bleomycin-induced pulmonary fibrosis.
Coagulation activation accompanied by reduced anticoagulant activity is a key characteristic of patients with idiopathic pulmonary fibrosis (IPF). Although the importance of coagulation activation in IPF is well studied, the potential relevance of endogenous anticoagulant activity in IPF progression remains elusive. We assess the importance of the endogenous anticoagulant protein C pathway on disease progression during bleomycin-induced pulmonary fibrosis. Wild-type mice and mice with high endogenous activated protein C APC levels (APChigh) were subjected to bleomycin-induced pulmonary fibrosis. Fibrosis was assesses by hydroxyproline and histochemical analysis. Macrophage recruitment was assessed immunohistochemically. In vitro, macrophage migration was analysed by transwell migration assays. Fourteen days after bleomycin instillation, APChighmice developed pulmonary fibrosis to a similar degree as wild-type mice. Interestingly, Aschcroft scores as well as lung hydroxyproline levels were significantly lower in APChighmice than in wild-type mice on day 28. The reduction in fibrosis in APChighmice was accompanied by reduced macrophage numbers in their lungs and subsequent in vitro experiments showed that APC inhibits thrombin-dependent macrophage migration. Our data suggest that high endogenous APC levels inhibit the progression of bleomycin-induced pulmonary fibrosis and that APC modifies pulmonary fibrosis by limiting thrombin-dependent macrophage recruitment.
Center for Experimental and Molecular Medicine, Academic Medical Center, Amsterdam, The Netherlands.
Cong
C
Lin
Department of Pathology, Erasmus Medical Center, Rotterdam, The Netherlands.
Jan
J
von der Thüsen
Medizinische Fakultät, Otto-von-Guericke-Universität Magdeburg, Magdeburg, Germany.
Berend
B
Isermann
Department of Physiology, BloodCenter of Wisconsin, Milwaukee, WI, USA.
Hartmut
H
Weiler
Center for Experimental and Molecular Medicine, Academic Medical Center, Amsterdam, The Netherlands.
Tom
T
van der Poll
Center for Experimental and Molecular Medicine, Academic Medical Center, Amsterdam, The Netherlands.|Inserm UMR1152, Medical School Xavier Bichat, Paris, France.|Département Hospitalo-universtaire FIRE (Fibrosis Inflammation and Remodeling) and LabEx Inflamex, Paris, France.
Keren
K
Borensztajn
Center for Experimental and Molecular Medicine, Academic Medical Center, Amsterdam, The Netherlands. c.a.spek@amc.uva.nl.
Chris A
CA
Spek
D000818:Animals; D001761:Bleomycin; D018450:Disease Progression; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000473:pathology; D041681:NIH 3T3 Cells; D011486:Protein C / Q000378:metabolism*; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology*; D000067996:RAW 264.7 Cells; D013917:Thrombin / Q000494:pharmacology
D011486:Protein C; D001761:Bleomycin; D013917:Thrombin
activated protein C; bleomycin and macrophages; idiopathic pulmonary fibrosis