Transforming growth factor-β1 and extracellular matrix-associated fibronectin expression in pulmonary lymphangioleiomyomatosis

Study objectives: Lymphangioleiomyomatosis (LAM) is a rare disorder of unknown etiology, affecting almost exclusively women of childbearing age, that is associated with the proliferation of spindle cells and cystic changes in the affected lung. The underlying processes that contribute to this disease are poorly understood. Transforming growth factor (TGF)-1 is a potent cytokine that promotes mesenchymal cell proliferation and regulates the synthesis of extracellular matrix (ECM) components, particularly fibronectins. Herein, we evaluate the expression of TGF1 and matrix-associated fibronectin in lung specimens demonstrating LAM. Design: Lung biopsy specimens that were confirmed to contain pathologic LAM cells were obtained from 13 patients. The specimens were submitted to immunohistochemical evaluation for TGF1 and fibronectin, as well as the typical markers of LAM cells. Healthy lung parenchyma surrounding resected neoplasms was studied in a parallel fashion as control tissues. Measurements and results: In all 13 LAM cases and in healthy lung parenchyma, we demonstrated that TGF1 localized consistently to airway epithelial cells. However, in LAM tissues, matrix-associated TGF1 was also consistently found in regions containing pathologic LAM cells. Notably, more abundant TGF1 was observed in highly cellular areas compared to the walls of chronic cystic regions in LAM tissues. Fibronectin, a matrix component that is strongly expressed in response to active TGF1 was found to consistently colocalize with this protein in these highly cellular regions, supporting TGF1 activity in these regions. The markers of proliferating LAM cells, including proliferating cell nuclear antigen, were also markedly present in these highly cellular LAM regions. Conclusion: These studies suggest that the proliferation of aberrant LAM cells may be associated with altered regional expression of TGF1 and related ECM proteins. (CHEST 2004; 125:1063–1070)