title: Surfactant dysfunction and lung inflammation in the female mouse model of lymphangioleiomyomatosis.
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.
authors.affiliation: 1 Airway Biology Initiative and.|2 Pulmonary, Allergy, and Critical Care Division, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania; and.
authors.forename: Elena N
authors.initials: EN
authors.lastname: Atochina-Vasserman
authors.affiliation: 3 Department of Pharmacology and Toxicology, Rutgers University, Piscataway, New Jersey.
authors.forename: Chang-Jiang
authors.initials: CJ
authors.lastname: Guo
authors.affiliation: 3 Department of Pharmacology and Toxicology, Rutgers University, Piscataway, New Jersey.
authors.forename: Elena
authors.initials: E
authors.lastname: Abramova
authors.affiliation: 3 Department of Pharmacology and Toxicology, Rutgers University, Piscataway, New Jersey.
authors.forename: Thea N
authors.initials: TN
authors.lastname: Golden
authors.affiliation: 2 Pulmonary, Allergy, and Critical Care Division, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania; and.
authors.forename: Michael
authors.initials: M
authors.lastname: Sims
authors.affiliation: 1 Airway Biology Initiative and.|2 Pulmonary, Allergy, and Critical Care Division, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania; and.
authors.forename: Melane L
authors.initials: ML
authors.lastname: James
authors.affiliation: 2 Pulmonary, Allergy, and Critical Care Division, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania; and.
authors.forename: Michael F
authors.initials: MF
authors.lastname: Beers
authors.affiliation: 3 Department of Pharmacology and Toxicology, Rutgers University, Piscataway, New Jersey.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Gow
authors.affiliation: 1 Airway Biology Initiative and.|2 Pulmonary, Allergy, and Critical Care Division, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania; and.
authors.forename: Vera P
authors.initials: VP
authors.lastname: Krymskaya
mesh_terms: D000818:Animals; D018893:Bronchoalveolar Lavage; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018192:Lymphangioleiomyomatosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D019278:Matrix Metalloproteinase 3 / Q000235:genetics / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D009569:Nitric Oxide / Q000235:genetics / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D011650:Pulmonary Alveoli / Q000378:metabolism* / Q000473:pathology*; D037662:Pulmonary Surfactant-Associated Protein A / Q000235:genetics / Q000378:metabolism; D037663:Pulmonary Surfactant-Associated Protein D / Q000235:genetics / Q000378:metabolism; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism
chemical_list: D016207:Cytokines; D037662:Pulmonary Surfactant-Associated Protein A; D037663:Pulmonary Surfactant-Associated Protein D; C000624654:Tsc2 protein, mouse; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D019278:Matrix Metalloproteinase 3; C511769:Mmp3 protein, mouse; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse
keywords: animal models; interstitial lung disease; nitric oxide; surfactant protein-D; tuberous sclerosis complex 2