Activated Protein C Inhibits the Expression of Platelet-derived Growth Factor in the Lung

Abstract

The natural anticoagulant-activated protein C may inhibit inflammation and fibrosis in the lung. Platelet-derived growth factor is involved in the pathogenesis of lung fibrosis. This study assessed the effect of activated protein C on platelet-derived growth factor expression in human cell lines and in an in vivo model of lung fibrosis. Activated protein C significantly inhibited the secretion and expression of platelet-derived growth factor in human lung cell lines, primary bronchial epithelial cells, and macrophages. In vitro studies also showed that the endothelial activated protein C receptor is expressed by lung epithelial cells and macrophages, and that this receptor and the proteolytic activity of activated protein are implicated in the inhibition of platelet-derived growth factor expression. In the in vivo model of lung fibrosis, intratracheal administration of activated protein C decreased the expression of platelet-derived growth factor and suppressed the development of lung fibrosis. Concomitant intratracheal administration of activated protein C and anti-endothelial activated protein C receptor or anti-platelet-derived growth factor suppressed the inhibitory activity of activated protein C in vivo. In brief, this study describes a novel biological function of activated protein C that may further explain its inhibitory activity on lung inflammation and fibrosis.

The bleomycin animal model: A useful tool to investigate treatment options for idiopathic pulmonary fibrosis?

“…), Angiotensin receptor blockers (Losartan (Fang, Zhu, Hu, & Liu, 2002;Marshall et al, 2004;Yao, Zhu, Zhao, & Lu, 2006), Candesartan (Otsuka, Takahashi, Shiratori, Chiba, & Abe, 2004), Valsartan (F. Liu, Xu, & Ye, 2005;Mancini & Khalil, 2005) etc. ), Anticoagulants (TFPI = tissue factor pathway inhibitor (Kijiyama et al, 2006), Urokinase (Hart, Whidden, Green, Henkin, & Woods, 1994;Hattori et al, 2004;Howell et al, 2001;Howell, Laurent, & Chambers, 2002;Ikeda, Hirose, Koto, Hirano, & Shigematsu, 1989), Heparin (Gunther et al, 2003;Piguet, Van, & Guo, 1996), APC = anticoagulant protein C (S. Shimizu et al, 2003;H. Yasui et al, 2001), Thromboxane synthetase inhibitor (Sato et al, 2004) etc.…”

Thrombin-Activatable Fibrinolysis Inhibitor Deficiency Attenuates Bleomycin-Induced Lung Fibrosis

“…Platelet-derived growth factor (PDGF) was measured using anti-PDGF (Genzyme, Boston, MA) and biotin-labeled anti-PDGF antibodies. 10 The total number of cells in BALF was measured using a nucleocounter from ChemoMetec (Allerød, Denmark). For differential cell counting BALF was centrifuged using a cytospin and the cells were stained with May-Grunwald-Giemsa (Merck, Darmstadt, Germany).…”

“…6 Similar findings have been reported in animal models of lung injury induced by bleomycin or lipopolysaccharides. 9,10 In addition, patients with systemic disorders including diabetes mellitus and arterial hypertension with glomerulosclerosis also have decreased fibrinolytic activity because of an increased circulating level of PAI-1.…”

Neuroprotective Efficacy of Activated Protein C in An Experimental Spinal Cord Injury Model in Rats

“…APC; endotel, monosit, nötrofil, eosinofil ve solunum epitel hücrelerindeki reseptörü-ne bağlanarak direkt antiinflamatuvar ve antiapoptotik etki gösterebilir. (26) Daha önceki çalışmalarda APC iv olarak 100 µg kg -1 ve 25 IU kg -1 dozlarında uygulanmıştır. (12,27) Bu çalışmada uyguladığımız APC dozları pubmed'de ulaşabildiğimiz literatürle uyumlu olarak 100 µg kg -1 aktive Drotrekogin alfa (XIGRIS®) iv şeklinde olmuştur.…”

“…APC'nin antiinflamatuvar ve antiapoptotik etkisinden (26) dolayı nöron kaybını azalttığını düşünüyoruz. Benzer şekilde Taoka ve ark.…”