Prevention of Alveolar Destruction and Airspace Enlargement in a Mouse Model of Pulmonary Lymphangioleiomyomatosis (LAM)

Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Science translational medicine (Impact Factor: 15.84). 10/2012; 4(154):154ra134. DOI: 10.1126/scitranslmed.3003840
Source: PubMed


Pulmonary lymphangioleiomyomatosis (LAM) is a rare genetic disease characterized by neoplastic growth of atypical smooth muscle-like LAM cells, destruction of lung parenchyma, obstruction of lymphatics, and formation of lung cysts, leading to spontaneous pneumothoraces (lung rupture and collapse) and progressive loss of pulmonary function. The disease is caused by mutational inactivation of the tumor suppressor gene tuberous sclerosis complex 1 (TSC1) or TSC2. By injecting TSC2-null cells into nude mice, we have developed a mouse model of LAM that is characterized by multiple random TSC2-null lung lesions, vascular endothelial growth factor-D expression, lymphangiogenesis, destruction of lung parenchyma, and decreased survival, similar to human LAM. The mice show enlargement of alveolar airspaces that is associated with progressive growth of TSC2-null lesions in the lung, up-regulation of proinflammatory cytokines and matrix metalloproteinases (MMPs) that degrade extracellular matrix, and destruction of elastic fibers. TSC2-null lesions and alveolar destruction were differentially inhibited by the macrolide antibiotic rapamycin (which inhibits TSC2-null lesion growth by a cytostatic mechanism) and a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, simvastatin (which inhibits growth of TSC2-null lesions by a predominantly proapoptotic mechanism). Treatment with simvastatin markedly inhibited MMP-2, MMP-3, and MMP-9 levels in lung and prevented alveolar destruction. The combination of rapamycin and simvastatin prevented both growth of TSC2-null lesions and lung destruction by inhibiting MMP-2, MMP-3, and MMP-9. Our findings demonstrate a mechanistic link between loss of TSC2 and alveolar destruction and suggest that treatment with rapamycin and simvastatin together could benefit patients with LAM by targeting cells with TSC2 dysfunction and preventing airspace enlargement.

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Available from: Vera P Krymskaya
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    • "Lung function was measured on a computerized FlexiVent System (SCIREQ) (Haczku et al., 2002). For morphological analyses, lungs were inflated at constant 25 cm H 2 O pressure with 1:1 optimal cutting temperature/PBS or low-melting agarose in PBS for approximately 8 min (Goncharova et al., 2012). Each experimental group included a minimum of five animals per condition . "

    Full-text · Conference Paper · May 2012
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    ABSTRACT: Pulmonary lymphangioleiomyomatosis (LAM) is a rare disease found almost exclusively in women that is characterized by neoplastic growth of atypical smooth muscle-like cells in the lung, destruction of lung parenchyma, and obstruction of lymphatics. These processes lead to the formation of lung cysts, rupture of which results in spontaneous pneumothorax. Progression of LAM often results in loss of pulmonary function and death. LAM affects predominantly women of childbearing age and is exacerbated by pregnancy. The only proven treatment for LAM is lung transplantation, and even then LAM cells will often return to the transplanted lung. However, methodical and targeted approaches toward understanding LAM pathophysiology have led to the discovery of new potential therapeutic avenues. For example, the mutational inactivation of tumor suppressor complex genes tuberous sclerosis complex 1 or tuberous sclerosis complex 2 has been shown to be present in lung LAM cells. These mutations occur sporadically or in association with inherited hamartoma syndrome tuberous sclerosis (TSC). Since TSC genes function as negative regulators of the mammalian target of rapamycin, a major controller of cell growth, metabolism, and survival, rapamycin analogs have recently been used to treat LAM patients with promising results. Similarly, studies focusing on the importance of estrogen in LAM progression have suggested that anti-estrogen therapy might prove to be an alternative means of treating LAM. This minireview summarizes recent progress in understanding LAM pathophysiology, including the latest preclinical and clinical studies, and insights regarding the role of hormones in LAM.
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    ABSTRACT: Lymphangioleiomyomatosis (LAM) is a rare disease usually diagnosed in women of childbearing age. It is characterized by a rapidly progressive cystic destruction of the lung parenchyma due to an abnormal proliferation of smooth muscle-like cells, and this can be associated with chylous pleural effusion and renal angiomyolipomas. Currently, LAM is treated with various nonspecific approaches such as bronchodilators, oxygen therapy, chylothorax or pharmacological or surgical estrogen blockade, but none of these methods is able to stop lung function decline. In LAM, the abnormal proliferation of the "LAM" cells is caused by a complex pathogenetic mechanism involving various inflammatory mediators. Recently, the mTOR pathway was described for its role in LAM development, and mTOR inhibitors such as sirolimus were investigated for their antiproliferative effects. This review discusses the potential therapeutic role of this compound in LAM based on the existing preclinical and clinical data. Copyright © 2013 Prous Science, S.A.U. or its licensors. All rights reserved.
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