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 (SM) transcription factor, is highly expressed in LAM cells. Here we show that 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 downregulated plasminogen activator inhibitor (PAI)-1. Since uPA cleaves Plg into plasmin, which in turn activates matrix metalloproteinases (MMPs), 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 of them 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 while it was ubiquitously present in normal lung parenchyma. Microdissection-based RT-PCR 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.