Imbalanced plasminogen system in lymphangioleiomyomatosis: potential role of serum response factor.
Pulmonary lymphangioleiomyomatosis (LAM) is characterized by abnormal smooth muscle-like cell (LAM cell) proliferation leading to tissue destruction. We previously demonstrated that serum response factor (SRF), a critical smooth muscle transcription factor, is highly expressed in LAM cells. Here we show that a high SRF level alters the plasminogen (Plg) system. Specifically, overexpression of SRF in human lung fibroblasts upregulated urokinase-type plasminogen activator (uPA) and its substrate Plg, whereas it downregulated plasminogen activator inhibitor (PAI)-1. Because uPA cleaves Plg into plasmin, which activates matrix metalloproteinases (MMP), the end result was an increase in MMP activity. To determine whether uPA, Plg, and PAI-1 were abnormally expressed in LAM in vivo, we immunostained 12 LAM cases. In all cases, the LAM lesions showed stronger immunoreaction for uPA and Plg than the surrounding normal lung parenchyma. On the contrary, PAI-1 was absent in LAM lesions, whereas it was ubiquitous in normal lung parenchyma. Microdissection-based reverse transcriptase/polymerase chain reaction further confirmed upregulation of uPA and Plg and downregulation of PAI-1 message in LAM. Altogether, our findings suggest that the high SRF level seen in LAM contributes to extracellular matrix degradation and progressive LAM cell infiltration of the lung.
Zhe
Xiaoning
X
Department of Pathology, Wayne State University, School of Medicine, Detroit, Michigan 48201, USA.
Yang
Yan
Y
Schuger
Lucia
L
D049109:Cell Proliferation; D002478:Cells, Cultured; D005341:Fibrinolysin / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D018192:Lymphangioleiomyomatosis / Q000378:metabolism* / Q000473:pathology; D020782:Matrix Metalloproteinases / Q000378:metabolism; D010958:Plasminogen / Q000378:metabolism; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D026362:Serum Response Factor / Q000235:genetics / Q000378:metabolism*; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism*
D017395:Plasminogen Activator Inhibitor 1; D026362:Serum Response Factor; D010958:Plasminogen; D005341:Fibrinolysin; D014568:Urokinase-Type Plasminogen Activator; D020782:Matrix Metalloproteinases