Original contributionHigh levels of extracellular matrix metalloproteinase inducer are expressed in lymphangioleiomyomatosis☆
Introduction
Lymphangioleiomyomatosis (LAM) is a rare multisystem disease characterized by recurrent spontaneous pneumothorax, chylothorax, chylous ascites, and angiomyolipomas that primarily affects women of childbearing age [1]. Abnormally proliferative smooth muscle-like LAM cells underlie the formation of characteristic LAM nodules in the lungs and of angiomyolipomas in the kidney [2]. Although the characteristics of LAM cells are not yet fully understood, immunopathologic studies have found that high levels of matrix metalloproteinase (MMP)–2, MMP-9, and membrane type 1–MMP are expressed in LAM cells, implying their involvement in the destructive cystic formation and/or metastasis associated with pulmonary LAM [3], [4]. We recently reported that levels of MMP-9 are higher in serum from patients with LAM than from healthy controls [5]. However, the regulatory mechanism of MMP induction in LAM remains largely unknown.
Several studies of MMP-inducing factors in tumor cells have led to the identification of the highly glycosylated transmembrane protein extracellular matrix metalloproteinase inducer (EMMPRIN)/CD147/basigin [6], [7]. Levels of EMMPRIN expression are high in fetal lung epithelium [8], suggesting a physiologic role in development. Although essentially minimal in healthy adult lung and other tissues, EMMPRIN is up-regulated in diverse pathologic processes, such as failing myocardium [9], hepatitis C virus–associated cirrhotic liver [10], chronic smoker's lung [11], and interstitial pneumonia [12]. In particular, EMMPRIN has been identified on the surface of cancer cells [13], [14], where it induces several MMPs including MMP-1, -2, -3, and -9 and membrane type 1–MMP in neighboring stromal cells or cancer cells themselves, resulting in invasion or metastasis.
Until recently, LAM cells have been considered histologically benign not only in sporadic LAM, but also in tuberous sclerosis complex (TSC)–related LAM. However, compelling evidence such as LAM recurrence after lung transplantation and the presence of LAM cells with the same mutations in the lungs, lymph nodes, and kidneys suggests that LAM cells can spread among lesions [15], [16]. Thus, metastasis seems to be one mechanism through which LAM cells are disseminated [15], [17].
We therefore postulated that LAM cells produce EMMPRIN that is involved in the induction of MMPs. The present study immunohistochemically localizes EMMPRIN in association with MMP-2 and MMP-9 in LAM nodules; examines the expression of LAM-driven EMMPRIN at the messenger RNA (mRNA) level; and quantifies levels of EMMPRIN, MMP-2, and MMP-9 in bronchoalveolar lavage (BAL) fluids.
Section snippets
Patients
We enrolled 10 female patients with LAM, 6 of whom had been pathologically diagnosed with pulmonary LAM by video-assisted thoracoscopy-guided lung biopsy; the other 4 were diagnosed by clinical and radiographic findings as previously described [18]. Among 10 patients with LAM enrolled in this study, 2 were current smokers. Paraffin-embedded and frozen tissues were obtained from 4 of the 6 pathologically diagnosed patients, and only paraffin-embedded tissues were obtained from 2 of them. All
Characteristics of the participants
Table 1 summarizes the clinical characteristics of each of the enrolled patients with LAM. None of them received hormonal therapy during this study. Airflow limitation was frequent but mild in the patients, most of whom were asymptomatic. Table 2 summarizes the findings of participants who were enrolled in the BAL study. The total number of cells and the total protein in BAL fluid were significantly elevated in the patients compared with healthy controls (19.0 ± 6.2 versus 5.3 ± 0.5 × 104/mL, P
Discussion
Here, we discovered that EMMPRIN is prominently expressed at the mRNA and protein levels in LAM cells. We also found that EMMPRIN colocalized with αSMA, MMP-2, and MMP-9 in LAM cells, suggesting that EMMPRIN in LAM cells could induce MMP-2 and MMP-9 in an autocrine fashion.
EMMPRIN is up-regulated exclusively in epithelial-driven cells, such as aberrant regenerated epithelial cells in fibrotic lung injuries in mice [24] and humans [12], in the bronchiolar epithelium of smokers' lungs [11], and
Acknowledgments
We thank Ms Yoko Suzuki for excellent technical assistance with LCM.
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