Transforming growth factor-beta 1 and extracellular matrix-associated fibronectin expression in pulmonary lymphangioleiomyomatosis.
OBJECTIVE
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)-beta(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 TGF beta(1) and matrix-associated fibronectin in lung specimens demonstrating LAM.


METHODS
Lung biopsy specimens that were confirmed to contain pathologic LAM cells were obtained from 13 patients. The specimens were submitted to immunohistochemical evaluation for TGF beta(1) 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.


RESULTS
In all 13 LAM cases and in healthy lung parenchyma, we demonstrated that TGF beta(1) localized consistently to airway epithelial cells. However, in LAM tissues, matrix-associated TGF beta(1) was also consistently found in regions containing pathologic LAM cells. Notably, more abundant TGF beta(1) 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 TGF beta(1) was found to consistently colocalize with this protein in these highly cellular regions, supporting TGF beta(1) 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.


CONCLUSIONS
These studies suggest that the proliferation of aberrant LAM cells may be associated with altered regional expression of TGF beta(1) and related ECM proteins.
Evans
Scott E
SE
Thoracic Diseases Research Unit, Division of Pulmonary & Critical Care, Department of Internal Medicine, Mayo Clinic and Foundation, Rochester, MN 55905, USA.
Colby
Thomas V
TV
Ryu
Jay H
JH
Limper
Andrew H
AH
D000199:Actins / Q000032:analysis; D000328:Adult; D000951:Antigens, Neoplasm; D015415:Biomarkers / Q000032:analysis; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D005353:Fibronectins / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D008168:Lung / Q000378:metabolism*; D008175:Lung Neoplasms / Q000175:diagnosis / Q000378:metabolism* / Q000473:pathology; D018192:Lymphangioleiomyomatosis / Q000175:diagnosis / Q000378:metabolism* / Q000473:pathology; D058950:Melanoma-Specific Antigens; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000032:analysis; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis; D020545:Respiratory Mucosa / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D053773:Transforming Growth Factor beta1
D000199:Actins; D000951:Antigens, Neoplasm; D015415:Biomarkers; D005353:Fibronectins; D058950:Melanoma-Specific Antigens; D009363:Neoplasm Proteins; D018809:Proliferating Cell Nuclear Antigen; C508960:TGFB1 protein, human; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1