Scleroderma bronchoalveolar lavage fluid contains thrombin, a mediator of human lung fibroblast proliferation via induction of platelet-derived growth factor alpha-receptor.
In addition to its procoagulant properties, the serine protease thrombin increases endothelial permeability, stimulates granulocyte adherence, and serves as a fibroblast mitogen. We demonstrate that thrombin is mitogenic for human lung fibroblasts in vitro. The mitogenic effect of thrombin is associated with an increase in the expression of the ligand PDGF-AA and up-regulation of PDGF alpha-receptor. Since scleroderma (systemic sclerosis; SSc) is characterized by widespread microvascular injury and is frequently complicated by pulmonary fibrosis, we sought to determine the level of thrombin activity in bronchoalveolar lavage (BAL) fluid from SSc patients and normal controls. We report a significantly higher level of thrombin activity in BAL fluid from SSc patients compared with normal controls (P < 0.001). Taken together, the high levels of thrombin in BAL fluid and its demonstrated mitogenicity for lung fibroblasts suggest an important role for thrombin in the pathogenesis of SSc and perhaps other fibrotic lung diseases.
Ohba
T
T
Department of Medicine, Medical University of South Carolina, Charleston.
McDonald
J K
JK
Silver
R M
RM
Strange
C
C
LeRoy
E C
EC
Ludwicka
A
A
D000328:Adult; D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000906:Antibodies; D000991:Antithrombins / Q000494:pharmacology; D000077214:Becaplermin; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry*; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D004247:DNA / Q000096:biosynthesis; D005347:Fibroblasts; D006801:Humans; D008168:Lung / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010982:Platelet-Derived Growth Factor / Q000032:analysis / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D020574:Proto-Oncogene Proteins c-sis; D012313:RNA / Q000032:analysis / Q000096:biosynthesis; D017479:Receptors, Platelet-Derived Growth Factor / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D011994:Recombinant Proteins / Q000032:analysis; D012595:Scleroderma, Systemic / Q000209:etiology / Q000378:metabolism*; D013917:Thrombin / Q000032:analysis / Q000378:metabolism* / Q000494:pharmacology; D015854:Up-Regulation
D000590:Amino Acid Chloromethyl Ketones; D000906:Antibodies; D000991:Antithrombins; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D011994:Recombinant Proteins; C075278:platelet-derived growth factor A; D000077214:Becaplermin; D012313:RNA; D004247:DNA; D017479:Receptors, Platelet-Derived Growth Factor; D013917:Thrombin; C040308:phenylalanyl-prolyl-arginine-chloromethyl ketone