Prevention of alveolar destruction and airspace enlargement in a mouse model of pulmonary lymphangioleiomyomatosis (LAM)

Elena A. Goncharova, Dmitry A. Goncharov, Melane Fehrenbach, Irene Khavin, Blerina Ducka, Okio Hino, Thomas V. Colby, Mervyn J. Merrilees, Angela Haczku, Steven M. Albelda, Vera P. Krymskaya

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Abstract

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 nudemice, we have developed a mousemodel 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. Themice show enlargement of alveolar airspaces that is associatedwith 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 proapoptoticmechanism). 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.

Original languageEnglish (US)
Article number154ra134
JournalScience translational medicine
Volume4
Issue number154
DOIs
StatePublished - Oct 3 2012

ASJC Scopus subject areas

  • Medicine(all)

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    Goncharova, E. A., Goncharov, D. A., Fehrenbach, M., Khavin, I., Ducka, B., Hino, O., Colby, T. V., Merrilees, M. J., Haczku, A., Albelda, S. M., & Krymskaya, V. P. (2012). Prevention of alveolar destruction and airspace enlargement in a mouse model of pulmonary lymphangioleiomyomatosis (LAM). Science translational medicine, 4(154), [154ra134]. https://doi.org/10.1126/scitranslmed.3003840