Role for activation of matrix metalloproteinases in the pathogenesis of pulmonary lymphangioleiomyomatosis.
BACKGROUND
Matrix metalloproteinases (MMPs) have been shown to be involved in the pathogenesis of the destructive pulmonary lesions in patients with lymphangioleiomyomatosis (LAM); in the present report, the activation of these enzymes is examined.


OBJECTIVE
To evaluate the role of MMPs and their activating enzymes, immunohistochemical and confocalmicroscopic techniques were used to localize alpha-smooth muscle actin (alpha-SMA), HMB-45, proliferating cell nuclear antigen (PCNA), MMP-2, membrane-type 1 MMP (MT1-MMP), MT2-MMP, and MT3-MMP in lung tissues from 10 women with LAM. Tissue samples were obtained from 5 patients before treatment and in 5 patients after hormone treatment (progesterone and/or tamoxifen citrate).


RESULTS
Staining for alpha-SMA and MMP-2 was present in all the abnormal smooth muscle cells (LAM cells) in both groups. The percentages of PCNA-, MMP-2-, or MT1-MMP-positive LAM cells were much higher in the untreated group than in the treated group, whereas the percentages of HMB-45-reactive LAM cells were similar in both groups. The reactions for MT1-MMP and PCNA were preferentially localized in small spindle-shaped LAM cells; the reaction for HMB-45 was found in large epithelioid LAM cells. Many of the PCNA-positive cells were also positive for MT1-MMP. Staining for MT2-MMP and MT3-MMP was negative.


CONCLUSIONS
This study demonstrates an association between cellular proliferation and the presence of MT1-MMP in LAM cells. The activation of MMP-2 by MT1-MMP may play an important role in the destruction of lung tissue in this disorder.
Matsui
K
K
Pathology Section, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
Takeda
K
K
Yu
Z X
ZX
Travis
W D
WD
Moss
J
J
Ferrans
V J
VJ
D000199:Actins / Q000378:metabolism; D000328:Adult; D000951:Antigens, Neoplasm; D004789:Enzyme Activation; D005260:Female; D019084:Fluorescent Antibody Technique, Indirect; D006801:Humans; D007124:Immunoenzyme Techniques; D008175:Lung Neoplasms / Q000201:enzymology* / Q000473:pathology; D018192:Lymphangioleiomyomatosis / Q000201:enzymology* / Q000473:pathology; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D058950:Melanoma-Specific Antigens; D018613:Microscopy, Confocal; D008875:Middle Aged; D009130:Muscle, Smooth / Q000201:enzymology; D009363:Neoplasm Proteins / Q000378:metabolism; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism
D000199:Actins; D000951:Antigens, Neoplasm; D058950:Melanoma-Specific Antigens; D009363:Neoplasm Proteins; D018809:Proliferating Cell Nuclear Antigen; D020782:Matrix Metalloproteinases