Document Detail


Prevention of alveolar destruction and airspace enlargement in a mouse model of pulmonary lymphangioleiomyomatosis (LAM).
MedLine Citation:
PMID:  23035046     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
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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Publication Detail:
Type:  In Vitro; Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Science translational medicine     Volume:  4     ISSN:  1946-6242     ISO Abbreviation:  Sci Transl Med     Publication Date:  2012 Oct 
Date Detail:
Created Date:  2012-10-04     Completed Date:  2013-02-13     Revised Date:  2013-07-11    
Medline Journal Info:
Nlm Unique ID:  101505086     Medline TA:  Sci Transl Med     Country:  United States    
Other Details:
Languages:  eng     Pagination:  154ra134     Citation Subset:  IM    
Affiliation:
Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Antineoplastic Combined Chemotherapy Protocols / therapeutic use
Female
Humans
Lung Neoplasms / drug therapy*
Lymphangioleiomyomatosis / drug therapy*
Matrix Metalloproteinase 2 / metabolism
Matrix Metalloproteinase 3 / metabolism
Matrix Metalloproteinase 9 / metabolism
Mice
Mice, Nude
Simvastatin / therapeutic use
Sirolimus / therapeutic use
Tumor Suppressor Proteins / genetics,  metabolism
Vascular Endothelial Growth Factor D / genetics,  metabolism
Grant Support
ID/Acronym/Agency:
2R01HL71106/HL/NHLBI NIH HHS; P130-CA-016520-34/CA/NCI NIH HHS; P30ES013508/ES/NIEHS NIH HHS; R01 AI072197/AI/NIAID NIH HHS; R01 HL071106/HL/NHLBI NIH HHS; R01 HL090829/HL/NHLBI NIH HHS; R01 HL114085/HL/NHLBI NIH HHS; R01AI072197/AI/NIAID NIH HHS; R01HL090829/HL/NHLBI NIH HHS; R01HL114085/HL/NHLBI NIH HHS; RC1 ES018505/ES/NIEHS NIH HHS; RC1ES018505/ES/NIEHS NIH HHS
Chemical
Reg. No./Substance:
0/Tumor Suppressor Proteins; 0/Vascular Endothelial Growth Factor D; 0/tuberous sclerosis complex 1 protein; 4JG2LF96VF/tuberous sclerosis complex 2 protein; 53123-88-9/Sirolimus; 79902-63-9/Simvastatin; EC 3.4.24.17/Matrix Metalloproteinase 3; EC 3.4.24.24/Matrix Metalloproteinase 2; EC 3.4.24.35/Matrix Metalloproteinase 9
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