Blerina Ducka

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

In a mouse model of the human disease pulmonary lymphangioleiomyomatosis, treatment with rapamycin plus simvastatin prevented alveolar space enlargement and growth of TSC2-null lesions. On the LAM, in Search of Treatments Typically diagnosed in women of childbearing age or in patients with tuberous sclerosis (a genetic disease associated with nonmalignant tumors in the brain and other organs), pulmonary lymphangioleiomyomatosis (LAM) is a rare disease that results in proliferation of smooth muscle–like cells in the lung and destruction of the surrounding normal lung tissue, leading to progressive respiratory problems. LAM can also cause benign tumors in other organs such as the kidneys. Although antiestrogen medications have been used to treat this disorder, these drugs have major side effects and have to be used indefinitely because they do not cure the disease. Now, Goncharova and colleagues have developed a mouse model that recapitulates the key clinical features of LAM and shows promising results after treatment with a combination of medications. Even in patients who do not have tuberous sclerosis, LAM is associated with inactivating mutations in tuberous sclerosis complex (TSC) genes, which encode tumor suppressor proteins. The authors found that injection of kidney tumor cells derived from mice lacking one of these genes, TSC2, into nude mice produced symptoms that are similar to those seen in human LAM disease. These mice developed LAM-like lung lesions, which accumulated around blood vessels and airways, as well as inflammation and destruction of surrounding normal lung tissue. Using this mouse model, the authors demonstrated that simvastatin (a commonly used cholesterol-lowering drug) and rapamycin (an immunosuppressive medication) displayed an additive effect on LAM lesions, inhibiting their growth. In addition, the authors showed that simvastatin decreased the destruction of normal lung tissue, which rapamycin alone did not do. The rapamycin-simvastatin treatment combination did not cure LAM in the mice, and more research is needed to determine whether these promising findings will translate to human patients. However, the two drugs are already approved for use in human subjects for other indications. Thus, the current study brings this treatment regimen one step closer to the clinic—and to a more tolerable long-term therapy for LAM. 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.