Increased expression of protease nexin-1 in fibroblasts during idiopathic pulmonary fibrosis regulates thrombin activity and fibronectin expression

Abstract

Idiopathic pulmonary fibrosis (IPF) is a chronic diffuse lung disease characterized by an accumulation of excess fibrous material in the lung. Protease nexin-1 (PN-1) is a tissue serpin produced by many cell types, including lung fibroblasts. PN-1 is capable of regulating proteases of both coagulation and fibrinolysis systems, by inhibiting, respectively, thrombin and plasminergic enzymes. PN-1 is thus a good candidate for regulating tissue remodeling occurring during IPF. We demonstrated a significant increase of PN-1 expression in lung tissue extracts, lung fibroblasts and bronchoalveolar lavage fluids of patients with IPF. The increase of PN-1 expression was reproduced after stimulation of control lung fibroblasts by transforming growth factor-b, a major pro-fibrotic cytokine involved in IPF. Another serpin, plasminogen activator inhibitor-1 (PAI-1) is also overexpressed in fibrotic fibroblasts. Unlike PAI-1, cell-bound PN-1 as well as secreted PN-1 from IPF and stimulated fibroblasts were shown to inhibit efficiently thrombin activity, indicating that both serpins should exhibit complementary roles in IPF pathogenesis, via their different preferential antiprotease activities. Moreover, we observed that overexpression of PN-1 induced by transfection of control fibroblasts led to increased fibronectin expression, whereas PN-1 silencing induced in fibrotic fibroblasts led to decreased fibronectin expression. Overexpression of PN-1 lacking either its antiprotease activity or its binding capacity to glycosaminoglycans had no effect on fibronectin expression. These novel findings suggest that modulation of PN-1 expression in lung fibroblasts may also have a role in the development of IPF by directly influencing the expression of extracellular matrix proteins. Our data provide new insights into the role of PN-1 in the poorly understood pathological processes involved in IPF and could therefore give rise to new therapeutic approaches.

Overexpression of SerpinE2/protease nexin-1 Contribute to Pathological Cardiac Fibrosis via increasing Collagen Deposition

“…Secondly, serpinE2 is the phylogenetically closest relative of Plasminogen activator inhibitor type 1 (PAI-1)15 that is implicated in the pathology of fibrosis in multiple organs including the heart, lung, kidney, liver and skin16 SerpinE2 is an inhibitor of uPA and tissue plasminogen activator but has a larger inhibition spectrum than PAI-1, and it may also modulate extracellular matrix degradation in vascular cell10. SerpinE2 is thought to have a pathogenic role in the development of another fibrotic disease, and scleroderma36.…”

The Involvement of Protease Nexin-1 (PN1) in the Pathogenesis of Intervertebral Disc (IVD) Degeneration

“…In the cartilage of OA patients, there is a significant increase in the level of serine protease Htra1 (high temperature factor A-1), which mediates proteolysis of aggrecan and contributes to OA pathology 41 42 . Initially, PN-1 was identified as a serine protease inhibitor in cartilage anlagen during embryogenesis, and interacted with both ECM and intracellular cartilage components 30 43 44 , which is consistent with its role in the binding and inactivation of extracellular proteases followed by internalization 45 . The activity of PN-1 is regulated by several matrix components, such as FN 46 , collagen II, and collagen I 47 .…”

The involvement of the laminin-integrin α7β1 signaling pathway in mechanical ventilation-induced pulmonary fibrosis

“…There has been a general academia consensus in that FN is widely present non-collagen glycoprotein with numerous biological functions. Recent studies have observed considerably enhanced FN formation as well as upregulation of fibroblasts mitosis and proliferation in cases of pulmonary fibrosis (30). E-cadherin (CDH1) belongs to family of cadherin, which is a typical epithelial cell surface marker.…”