title: Temsirolimus induces surfactant lipid accumulation and lung inflammation in mice.
abstract: Interstitial lung disease (ILD) is a well-known adverse effect of mammalian target of rapamycin (mTOR) inhibitors. However, it remains unknown how lung toxicities are induced by mTOR inhibitors. Here, we constructed a mouse model of mTOR inhibitor-induced ILD using temsirolimus and examined the pathogenesis of the disease. Male ICR mice were treated with an intraperitoneal injection of different doses of temsirolimus (3 or 30 mg·kg(-1)·wk(-1)) or vehicle. Temsirolimus treatment increased capillary-alveolar permeability and induced neutrophil infiltration and fibrinous exudate into the alveolar space, indicating alveolar epithelial and/or endothelial injury. It also induced macrophage depletion and the accumulation of excessive surfactant phospholipids and cholesterols. Alveolar macrophage depletion is thought to cause surfactant lipid accumulation. To further examine whether temsirolimus has cytotoxic and/or cytostatic effects on alveolar macrophages and alveolar epithelial cells, we performed in vitro experiments. Temsirolimus inhibited cell proliferation and viability in both alveolar macrophage and alveolar epithelial cells. Temsirolimus treatment caused some signs of pulmonary inflammation, including upregulated expression of several proinflammatory cytokines in both bronchoalveolar lavage cells and lung homogenates, and an increase in lymphocytes in the bronchoalveolar lavage fluid. These findings indicate that temsirolimus has the potential to induce alveolar epithelial injury and to deplete alveolar macrophages followed by surfactant lipid accumulation, resulting in pulmonary inflammation. This is the first study to focus on the pathogenesis of mTOR inhibitor-induced ILD using an animal model.
authors.affiliation: Department of Urology, Jichi Medical University, Tochigi, Japan;
authors.forename: Satoshi
authors.initials: S
authors.lastname: Washino
authors.affiliation: Department of Clinical Pharmacology, Jichi Medical University, Tochigi, Japan;
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Ando
authors.affiliation: Department of Clinical Pharmacology, Jichi Medical University, Tochigi, Japan;
authors.forename: Kentarou
authors.initials: K
authors.lastname: Ushijima
authors.affiliation: Department of Clinical Pharmacology, Jichi Medical University, Tochigi, Japan;
authors.forename: Keiko
authors.initials: K
authors.lastname: Hosohata
authors.affiliation: Department of Clinical Pharmacology, Jichi Medical University, Tochigi, Japan;
authors.forename: Masafumi
authors.initials: M
authors.lastname: Kumazaki
authors.affiliation: Department of Pulmonary Medicine, Jichi Medical University, Tochigi, Japan; and.
authors.forename: Naoko
authors.initials: N
authors.lastname: Mato
authors.affiliation: Department of Pulmonary Medicine, Jichi Medical University, Tochigi, Japan; and.
authors.forename: Yukihiko
authors.initials: Y
authors.lastname: Sugiyama
authors.affiliation: Department of Urology, Jichi Saitama Medical Center, Saitama, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Kobayashi
authors.affiliation: Department of Clinical Pharmacology, Jichi Medical University, Tochigi, Japan; akiofuji@jichi.ac.jp.
authors.forename: Akio
authors.initials: A
authors.lastname: Fujimura
authors.affiliation: Department of Urology, Jichi Medical University, Tochigi, Japan;
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Morita
mesh_terms: D000818:Animals; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D050356:Lipid Metabolism / Q000187:drug effects*; D016676:Macrophages, Alveolar / Q000378:metabolism*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D010743:Phospholipids / Q000378:metabolism; D011014:Pneumonia / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D011650:Pulmonary Alveoli / Q000378:metabolism / Q000473:pathology; D011663:Pulmonary Surfactants / Q000378:metabolism*; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D016207:Cytokines; D010743:Phospholipids; D011663:Pulmonary Surfactants; C401859:temsirolimus; D020123:Sirolimus
keywords: inflammation; interstitial lung disease; mammalian target of rapamycin inhibitor; surfactant lipids; temsirolimus