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 journalArticlepeer-review

10 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

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

Fingerprint Dive into the research topics of 'Surfactant dysfunction and lung inflammation in the female mouse model of lymphangioleiomyomatosis'. Together they form a unique fingerprint.

Cite this