Lung Epithelial Cell–Specific Expression of Human Lysosomal Acid Lipase Ameliorates Lung Inflammation and Tumor Metastasis in Lipa−/− Mice

Ting Zhao, Xinchun Ding, Hong Du, Cong Yan

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Lysosomal acid lipase (LAL), a key enzyme in the metabolic pathway of neutral lipids, has a close connection with inflammation and tumor progression. One major manifestation in LAL-deficient (Lipa−/−) mice is an increase of tumor growth and metastasis associated with expansion of myeloid-derived suppressor cells. In the lung, LAL is highly expressed in alveolar type II epithelial cells. To assess how LAL in lung epithelial cells plays a role in this inflammation-related pathogenic process, lung alveolar type II epithelial cell–specific expression of human LAL (hLAL) in Lipa−/− mice was established by crossbreeding of CCSP-driven rtTA transgene and (TetO)7-CMV-hLAL transgene into Lipa−/− mice (CCSP-Tg/KO). hLAL expression in lung epithelial cells not only reduced tumor-promoting myeloid-derived suppressor cells in the lung, but also down-regulated the synthesis and secretion of tumor-promoting cytokines and chemokines into the bronchoalveolar lavage fluid of Lipa−/− mice. hLAL expression reduced the immunosuppressive functions of bronchoalveolar lavage fluid cells, inhibited bone marrow cell transendothelial migration, and inhibited endothelial cell proliferation and migration in Lipa−/− mice. As a result, hLAL expression in CCSP-Tg/KO mice corrected pulmonary damage, and inhibited tumor cell proliferation and migration in vitro, and tumor metastasis to the lung in vivo. These results support a concept that LAL is a critical metabolic enzyme in lung epithelial cells that regulates lung homeostasis, immune response, and tumor metastasis.

Original languageEnglish (US)
Pages (from-to)2183-2192
Number of pages10
JournalAmerican Journal of Pathology
Volume186
Issue number8
DOIs
StatePublished - Aug 1 2016

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Pneumonia
Sterol Esterase
Neoplasm Metastasis
Lung
Neoplasms
Cell Movement
Epithelial Cells
Bronchoalveolar Lavage Fluid
Transgenes
Cell Proliferation
Genetic Hybridization
Inflammation
Transendothelial and Transepithelial Migration
Alveolar Epithelial Cells
human LIPA protein
Alveolar Process
Enzymes
Immunosuppressive Agents
Metabolic Networks and Pathways
Chemokines

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Lung Epithelial Cell–Specific Expression of Human Lysosomal Acid Lipase Ameliorates Lung Inflammation and Tumor Metastasis in Lipa−/− Mice. / Zhao, Ting; Ding, Xinchun; Du, Hong; Yan, Cong.

In: American Journal of Pathology, Vol. 186, No. 8, 01.08.2016, p. 2183-2192.

Research output: Contribution to journalArticle

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