title: Role of protease-activated receptors in human skin fibrosis and scleroderma.
abstract: Proteases and their receptors have poorly understood roles in skin fibrosis and systemic scleroderma (SSc). We examined the role of protease-activated receptors (PAR(1) and PAR(2) ) in the pathophysiology of human SSc and skin fibrosis. Immunohistochemistry showed that PAR(1) immunoreactivity was positive in fibroblasts of SSc skin and healthy skin. PAR(2) immunoreactivity was positive in SSc skin, but negative in endothelial cells and fibroblasts of healthy skin. Double immunofluorescence using an antibody against smooth muscle actin (α-SMA) as a marker for myofibroblasts verified a certain percentage of myofibroblasts positive for PAR(1) and PAR(2) in SSc skin. In human dermal cultured fibroblasts (HDF), PAR(1) stimulation with or without bleomycin pretreatment mobilized intracellular calcium, indicating that the expressed PARs are functional and have effects on downstream signalling by calcium release. PAR(2) -induced intracellular calcium mobilization was only measurable in HDF after bleomycin pretreatment. Thus, PAR(1) - and PAR(2) -positive fibroblasts are increased in SSc, indicating a regulatory role. Intriguingly, bleomycin activated PAR(2) in HDF indicating that fibrosis-promoting factors have a direct effect on PAR(2) expression and functionality.
authors.forename: Ferda
authors.initials: F
authors.lastname: Cevikbas
authors.forename: Stephan
authors.initials: S
authors.lastname: Seeliger
authors.forename: Michaela
authors.initials: M
authors.lastname: Fastrich
authors.forename: Heike
authors.initials: H
authors.lastname: Hinte
authors.forename: Dieter
authors.initials: D
authors.lastname: Metze
authors.forename: Cordula
authors.initials: C
authors.lastname: Kempkes
authors.forename: Bernhard
authors.initials: B
authors.lastname: Homey
authors.forename: Martin
authors.initials: M
authors.lastname: Steinhoff
mesh_terms: D000328:Adult; D000368:Aged; D020013:Calcium Signaling; D016022:Case-Control Studies; D005355:Fibrosis; D006801:Humans; D007150:Immunohistochemistry; D008875:Middle Aged; D058628:Myofibroblasts / Q000378:metabolism / Q000473:pathology; D044463:Receptor, PAR-1; D044464:Receptor, PAR-2 / Q000378:metabolism; D044462:Receptors, Proteinase-Activated / Q000378:metabolism*; D045743:Scleroderma, Diffuse / Q000378:metabolism* / Q000473:pathology; D012867:Skin / Q000378:metabolism* / Q000473:pathology*
chemical_list: D044463:Receptor, PAR-1; D044464:Receptor, PAR-2; D044462:Receptors, Proteinase-Activated