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

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

Research output: Contribution to journalArticle

8 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)96-104
Number of pages9
JournalAmerican Journal of Respiratory Cell and Molecular Biology
Volume53
Issue number1
DOIs
Publication statusPublished - 1 Jul 2015
Externally publishedYes

Fingerprint

Lymphangioleiomyomatosis
Pulmonary Surfactant-Associated Protein D
Surface-Active Agents
Pneumonia
Lung
Chemokine CCL2
Chemotactic Factors
Interleukin-6
Chemokine CXCL1
Genes
Bronchoalveolar Lavage Fluid
Pulmonary Surfactant-Associated Protein A
Growth
Keratinocytes
Matrix Metalloproteinase 3
Pulmonary diseases
Fluids
Transforming Growth Factors
Nitric Oxide Synthase
Surface tension

Keywords

  • Animal models
  • Interstitial lung disease
  • Nitric oxide
  • Surfactant protein-D
  • Tuberous sclerosis complex 2

ASJC Scopus subject areas

  • Cell Biology
  • Pulmonary and Respiratory Medicine
  • Molecular Biology
  • Clinical Biochemistry

Cite this

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

In: American Journal of Respiratory Cell and Molecular Biology, Vol. 53, No. 1, 01.07.2015, p. 96-104.

Research output: Contribution to journalArticle

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. / Surfactant dysfunction and lung inflammation in the female mouse model of lymphangioleiomyomatosis. In: American Journal of Respiratory Cell and Molecular Biology. 2015 ; Vol. 53, No. 1. pp. 96-104.
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