title: Lung Epithelial Cell-Specific Expression of Human Lysosomal Acid Lipase Ameliorates Lung Inflammation and Tumor Metastasis in Lipa(-/-) Mice.
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.
authors.affiliation: Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Ting
authors.initials: T
authors.lastname: Zhao
authors.affiliation: Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Xinchun
authors.initials: X
authors.lastname: Ding
authors.affiliation: Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana; Indiana University Simon Cancer Center, Indiana University School of Medicine, Indianapolis, Indiana. Electronic address: hongdu@iupui.edu.
authors.forename: Hong
authors.initials: H
authors.lastname: Du
authors.affiliation: Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana; Indiana University Simon Cancer Center, Indiana University School of Medicine, Indianapolis, Indiana. Electronic address: coyan@iupui.edu.
authors.forename: Cong
authors.initials: C
authors.lastname: Yan
mesh_terms: D056809:Alveolar Epithelial Cells / Q000378:metabolism*; D000818:Animals; D002465:Cell Movement / Q000502:physiology; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D018345:Mice, Knockout; D009362:Neoplasm Metastasis / Q000473:pathology*; D011014:Pneumonia / Q000378:metabolism* / Q000473:pathology; D060888:Real-Time Polymerase Chain Reaction; D002787:Sterol Esterase / Q000096:biosynthesis*
chemical_list: C503451:LIPA protein, human; D002787:Sterol Esterase