Skip Navigation
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Your Environment. Your Health.

Publication Detail

Title: Surfactant dysfunction and lung inflammation in the female mouse model of lymphangioleiomyomatosis.

Authors: Atochina-Vasserman, Elena N; Guo, Chang-Jiang; Abramova, Elena; Golden, Thea N; Sims, Michael; James, Melane L; Beers, Michael F; Gow, Andrew J; Krymskaya, Vera P

Published In Am J Respir Cell Mol Biol, (2015 Jul)

Abstract: Pulmonary lymphangioleiomyomatosis (LAM) is a rare lung disease caused by mutations of the tumor suppressor genes, tuberous sclerosis complex (TSC) 1 or TSC2. LAM affects women almost exclusively, and it is characterized by neoplastic growth of atypical smooth muscle-like TSC2-null LAM cells in the pulmonary interstitium, cystic destruction of lung parenchyma, and progressive decline in lung function. In this study, we hypothesized that TSC2-null lesions promote a proinflammatory environment, which contributes to lung parenchyma destruction. Using a TSC2-null female murine LAM model, we demonstrate that TSC2-null lesions promote alveolar macrophage accumulation, recruitment of immature multinucleated cells, an increased induction of proinflammatory genes, nitric oxide (NO) synthase 2, IL-6, chemokine (C-C motif) ligand 2 (CCL2)/monocyte chemotactic protein 1 (MCP1), chemokine (C-X-C motif) ligand 1 (CXCL1)/keratinocyte chemoattractant (KC), and up-regulation of IL-6, KC, MCP-1, and transforming growth factor-β1 levels in bronchoalveolar lavage fluid. Bronchoalveolar lavage fluid also contained an increased level of surfactant protein (SP)-D, but not SP-A, significant reduction of SP-B levels, and a resultant increase in alveolar surface tension. Consistent with the growth of TSC2-null lesions, NO levels were also increased and, in turn, modified SP-D through S-nitrosylation, forming S-nitrosylated SP-D, a known consequence of lung inflammation. Progressive growth of TSC2-null lesions was accompanied by elevated levels of matrix metalloproteinase-3 and -9. This report demonstrates a link between growth of TSC2-null lesions and inflammation-induced surfactant dysfunction that might contribute to lung destruction in LAM.

PubMed ID: 25474372 Exiting the NIEHS site

MeSH Terms: Animals; Bronchoalveolar Lavage; Cytokines/genetics; Cytokines/metabolism; Disease Models, Animal; Female; Inflammation/genetics; Inflammation/metabolism; Inflammation/pathology; Lymphangioleiomyomatosis/genetics; Lymphangioleiomyomatosis/metabolism*; Lymphangioleiomyomatosis/pathology*; Matrix Metalloproteinase 3/genetics; Matrix Metalloproteinase 3/metabolism; Matrix Metalloproteinase 9/genetics; Matrix Metalloproteinase 9/metabolism; Mice; Mice, Mutant Strains; Nitric Oxide Synthase Type II/genetics; Nitric Oxide Synthase Type II/metabolism; Nitric Oxide/genetics; Nitric Oxide/metabolism; Pulmonary Alveoli/metabolism*; Pulmonary Alveoli/pathology*; Pulmonary Surfactant-Associated Protein A/genetics; Pulmonary Surfactant-Associated Protein A/metabolism; Pulmonary Surfactant-Associated Protein D/genetics; Pulmonary Surfactant-Associated Protein D/metabolism; Tumor Suppressor Proteins/deficiency; Tumor Suppressor Proteins/genetics; Tumor Suppressor Proteins/metabolism

Back
to Top