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

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 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.

SUBMITTER: Goncharova EA

PROVIDER: S-EPMC3684391 | biostudies-literature | 2012 Oct

REPOSITORIES: biostudies-literature

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

Goncharova Elena A EA Goncharov Dmitry A DA Fehrenbach Melane M Khavin Irene I Ducka Blerina B Hino Okio O Colby Thomas V TV Merrilees Mervyn J MJ Haczku Angela A Albelda Steven M SM Krymskaya Vera P VP

Science translational medicine 20121001 154

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 n ...[more]

PMID: 23035046

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Project description:Rationale: Lymphangioleiomyomatosis (LAM) is a rare disease associated with cystic destruction of the pulmonary parenchyma and chronic respiratory failure, and there are trials underway to determine if early intervention can prevent disease progression. An imaging technique that is sensitive to early regional disease would therefore be valuable for patient care and clinical trials.Objectives: We postulated that hyperpolarized 129Xe MRI would be sensitive to ventilation abnormalities and alveolar airspace dilation in patients with mild LAM disease and normal pulmonary function and that 129Xe MRI would reveal important features of cyst ventilation.Methods: 129Xe ventilation and diffusion-weighted MR images were acquired in 22 patients with LAM during two breath-holds of hyperpolarized 129Xe. 129Xe ventilation defect percentage (VDP; percentage of voxels <60% of the mean whole-lung 129Xe MRI signal) and apparent diffusion coefficient (ADC), a measure of alveolar airspace size, were quantified and compared with pulmonary function test parameters with Spearman statistics. Sixteen patients with LAM had a recent, clinical chest computed tomography (CT) scan available, and cyst ventilation was assessed by thresholding cysts on the CT images and registration to the 129Xe ventilation images.Results: Ventilation deficits were observed in all patients with LAM, including those with normal pulmonary function and few cysts, and the mean VDP was 19.2% (95% confidence interval [CI], 14.8-23.5%). 129Xe VDP was strongly correlated with forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC) ratio (r = -0.51, P = 0.02) and diffusing capacity of the lung for carbon monoxide (DlCO) (r = -0.60, P = 0.009) but not with FEV1 (r = -0.33, P = 0.13), likely because of the sensitivity of 129Xe MRI to mild LAM disease in patients with normal FEV1. The mean ADC was 0.048 cm2/s (95% CI, 0.042-0.053 cm2/s). In many cases, ADC was elevated relative to previously reported values in adults, and ADC was correlated with FEV1, FEV1/FVC ratio, and DlCO (P ≤ 0.02 for all). Co-registered 129Xe MRI and CT imaging revealed considerable ventilation heterogeneity within individual patients with LAM and across patients with similarly sized cysts.Conclusions: 129Xe MRI provides a means to assess the complex regional ventilation and alveolar airspace size changes of LAM with high sensitivity and may be a clinically useful future tool for screening, managing patients, and measuring treatment efficacy.

Dataset Information

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

Publications

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

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