The protein C pathway in tissue inflammation and injury: pathogenic role and therapeutic implications

Abstract

Inflammation and coagulation are closely linked interdependent processes. Under physiologic conditions, the tissue microcirculation functions in anticoagulant and anti-inflammatory fashions. However, when inflammation occurs, coagulation is also set in motion and actively participates in enhancing inflammation. Recently, novel and unexpected roles of hemostasis in the humoral and cellular components of innate immunity have been described. In particular, the protein C system, besides its well-recognized role in anticoagulation, plays a crucial role in inflammation. Indeed, the protein C system is now emerging as a novel participant in the pathogenesis of acute and chronic inflammatory diseases, such as sepsis, asthma, inflammatory bowel disease, atherosclerosis, and lung and heart inflammation, and may emerge as unexpected therapeutic targets for intervention. (Blood.

Unexpected role of anticoagulant protein C in controlling epithelial barrier integrity and intestinal inflammation

“…Unexpected roles of hemostasis in the humoral and cellular mechanisms of innate immunity have been reported recently (2). One of the major systems that forms a bridge between inflammation and coagulation is the protein C (PC) pathway (3). This pathway is composed of thrombomodulin (TM), endothelial cell PC receptor (EPCR), PC, and protease-activated receptor-1 (PAR-1).…”

“…Indeed, PC is now emerging as a participant in the pathogenesis of acute and chronic inflammatory diseases, such as sepsis, asthma, inflammatory bowel disease (IBD), atherosclerosis, and lung and heart inflammation, and might represent a previously unexpected therapeutic target for intervention (3,5).…”

“…This pathway is composed of thrombomodulin (TM), endothelial cell PC receptor (EPCR), PC, and protease-activated receptor-1 (PAR-1). TM and EPCR are expressed mainly by vascular endothelial cells and form a complex on the surface of these cells that converts circulating PC into its active form (3).…”

“…Although the function of the PC pathway is classically considered anticoagulative, mounting evidence indicates that this pathway also plays a dominant role in inflammation, with each component of the pathway displaying remarkably potent antiinflammatory activity (2)(3)(4). Indeed, PC is now emerging as a participant in the pathogenesis of acute and chronic inflammatory diseases, such as sepsis, asthma, inflammatory bowel disease (IBD), atherosclerosis, and lung and heart inflammation, and might represent a previously unexpected therapeutic target for intervention (3,5).…”

Differential Effects of Activated Protein C on Synovial Fibroblasts in Response to Hypoxia and Normoxia

“…Activated protein C (APC) results from conversion of protein C and has cytoprotective anti-inflammatory, anti-apoptotic, and anticoagulant activities (Danese et al 2010;McKelvey et al 2014;Minhas et al 2010). APC is triggered by the thrombin-thrombomodulin complex and appears on the endothelial cell surface Xue & Jackson 2015).…”