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
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