transforming-growth-factor-beta and Lymphangioleiomyomatosis

Lymphangioleiomyomatosis (LAM) is associated with abnormal airway smooth muscle that leads to the characteristic pathology of lung nodule formation and destruction of lung tissue. The current authors have previously identified abnormal behaviour of airway smooth muscle cells from patients with asthma. In this study, cells and tissue sections derived from patients with LAM (n=7), asthma (n=8), and nonasthmatic controls (n=9) were compared. The presence of the antigen human melanosome (HM)B-45 was investigated, along with the proliferation and release of extracellular matrix proteins, release of endogenous prostaglandin E2 (PGE2), vascular endothelial growth factor and connective tissue growth factor, and the expression of integrins. Positive HMB-45 staining was found in all LAM patients and no controls. Proliferation of LAM cells was not different from control cells nor was its inhibition by beta-agonists, corticosteroids, rapamycin or PGE2. However, endogenous PGE2 levels were markedly decreased in LAM cells, and this was associated with decreased expression of the inducible form of cyclooxygenase (COX-2). The increased levels of connective tissue growth factor seen in asthma cells were not observed in LAM. Elastin mRNA in response to transforming growth factor-beta stimulation was markedly lower in LAM cells than either asthma or control cells. In conclusion, lymphangioleiomyomatosis cells exhibit abnormal properties in vitro that may contribute to pathophysiology and symptomatology in patients with lymphangioleiomyomatosis.

Topics: Adolescent; Adult; Aged; Antigens, Neoplasm; Asthma; Cells, Cultured; Connective Tissue Growth Factor; Cyclooxygenase 2; Dinoprostone; Extracellular Matrix Proteins; Female; Growth Substances; Humans; Immediate-Early Proteins; Integrins; Intercellular Signaling Peptides and Proteins; Lung; Lymphangioleiomyomatosis; Male; Melanoma-Specific Antigens; Middle Aged; Myocytes, Smooth Muscle; Neoplasm Proteins; Transforming Growth Factor beta; Vascular Endothelial Growth Factor A

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.. 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.. 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.. 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.

Topics: Actins; Adult; Antigens, Neoplasm; Biomarkers; Extracellular Matrix; Female; Fibronectins; Humans; Immunohistochemistry; Lung; Lung Neoplasms; Lymphangioleiomyomatosis; Melanoma-Specific Antigens; Middle Aged; Neoplasm Proteins; Proliferating Cell Nuclear Antigen; Respiratory Mucosa; Transforming Growth Factor beta; Transforming Growth Factor beta1