PMID- 25474372 OWN - NLM STAT- MEDLINE DCOM- 20150916 LR - 20181203 IS - 1535-4989 (Electronic) IS - 1044-1549 (Print) IS - 1044-1549 (Linking) VI - 53 IP - 1 DP - 2015 Jul TI - Surfactant dysfunction and lung inflammation in the female mouse model of lymphangioleiomyomatosis. PG - 96-104 LID - 10.1165/rcmb.2014-0224OC [doi] AB - 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-beta1 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. FAU - Atochina-Vasserman, Elena N AU - Atochina-Vasserman EN AD - 1 Airway Biology Initiative and. AD - 2 Pulmonary, Allergy, and Critical Care Division, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania; and. FAU - Guo, Chang-Jiang AU - Guo CJ AD - 3 Department of Pharmacology and Toxicology, Rutgers University, Piscataway, New Jersey. FAU - Abramova, Elena AU - Abramova E AD - 3 Department of Pharmacology and Toxicology, Rutgers University, Piscataway, New Jersey. FAU - Golden, Thea N AU - Golden TN AD - 3 Department of Pharmacology and Toxicology, Rutgers University, Piscataway, New Jersey. FAU - Sims, Michael AU - Sims M AD - 2 Pulmonary, Allergy, and Critical Care Division, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania; and. FAU - James, Melane L AU - James ML AD - 1 Airway Biology Initiative and. AD - 2 Pulmonary, Allergy, and Critical Care Division, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania; and. FAU - Beers, Michael F AU - Beers MF AD - 2 Pulmonary, Allergy, and Critical Care Division, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania; and. FAU - Gow, Andrew J AU - Gow AJ AD - 3 Department of Pharmacology and Toxicology, Rutgers University, Piscataway, New Jersey. FAU - Krymskaya, Vera P AU - Krymskaya VP AD - 1 Airway Biology Initiative and. AD - 2 Pulmonary, Allergy, and Critical Care Division, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania; and. LA - eng GR - R01 HL119436/HL/NHLBI NIH HHS/United States GR - R01 HL090829/HL/NHLBI NIH HHS/United States GR - R01 HL086621/HL/NHLBI NIH HHS/United States GR - T32 ES007148/ES/NIEHS NIH HHS/United States GR - HL86621/HL/NHLBI NIH HHS/United States GR - P30 ES013508/ES/NIEHS NIH HHS/United States GR - R01 HL114085/HL/NHLBI NIH HHS/United States GR - R01 HL110551/HL/NHLBI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PL - United States TA - Am J Respir Cell Mol Biol JT - American journal of respiratory cell and molecular biology JID - 8917225 RN - 0 (Cytokines) RN - 0 (Pulmonary Surfactant-Associated Protein A) RN - 0 (Pulmonary Surfactant-Associated Protein D) RN - 0 (Tsc2 protein, mouse) RN - 0 (Tuberous Sclerosis Complex 1 Protein) RN - 0 (Tuberous Sclerosis Complex 2 Protein) RN - 0 (Tumor Suppressor Proteins) RN - 31C4KY9ESH (Nitric Oxide) RN - EC 1.14.13.39 (Nitric Oxide Synthase Type II) RN - EC 1.14.13.39 (Nos2 protein, mouse) RN - EC 3.4.24.17 (Matrix Metalloproteinase 3) RN - EC 3.4.24.17 (Mmp3 protein, mouse) RN - EC 3.4.24.35 (Matrix Metalloproteinase 9) RN - EC 3.4.24.35 (Mmp9 protein, mouse) SB - IM MH - Animals MH - Bronchoalveolar Lavage MH - Cytokines/genetics/metabolism MH - Disease Models, Animal MH - Female MH - Inflammation/genetics/metabolism/pathology MH - Lymphangioleiomyomatosis/genetics/*metabolism/*pathology MH - Matrix Metalloproteinase 3/genetics/metabolism MH - Matrix Metalloproteinase 9/genetics/metabolism MH - Mice MH - Mice, Mutant Strains MH - Nitric Oxide/genetics/metabolism MH - Nitric Oxide Synthase Type II/genetics/metabolism MH - Pulmonary Alveoli/*metabolism/*pathology MH - Pulmonary Surfactant-Associated Protein A/genetics/metabolism MH - Pulmonary Surfactant-Associated Protein D/genetics/metabolism MH - Tuberous Sclerosis Complex 1 Protein MH - Tuberous Sclerosis Complex 2 Protein MH - Tumor Suppressor Proteins/deficiency/genetics/metabolism PMC - PMC4566108 OTO - NOTNLM OT - animal models OT - interstitial lung disease OT - nitric oxide OT - surfactant protein-D OT - tuberous sclerosis complex 2 EDAT- 2014/12/05 06:00 MHDA- 2015/09/17 06:00 PMCR- 2016/07/01 CRDT- 2014/12/05 06:00 PHST- 2014/12/05 06:00 [entrez] PHST- 2014/12/05 06:00 [pubmed] PHST- 2015/09/17 06:00 [medline] PHST- 2016/07/01 00:00 [pmc-release] AID - 10.1165/rcmb.2014-0224OC [doi] PST - ppublish SO - Am J Respir Cell Mol Biol. 2015 Jul;53(1):96-104. doi: 10.1165/rcmb.2014-0224OC.