title: Effects of the mTOR inhibitor everolimus and the PI3K/mTOR inhibitor NVP-BEZ235 in murine acute lung injury models.
abstract: The mammalian target of rapamycin (mTOR) is a key signaling kinase associated with a variety of cellular functions including the regulation of immunological and inflammatory responses. Classic mTOR inhibitors such as rapamycin or everolimus are commonly used in transplant as well as cancer patients to prevent transplant rejection or cancer progression, respectively. Noninfectious drug-induced pneumonitis is a frequent side effect in mTOR-inhibitor-treated patients. Therefore, we tested the effects of the mTOR inhibitor everolimus and the novel dual PI3K/mTOR inhibitor NVP-BEZ235 in a murine lipopolysaccharide (LPS)-induced acute lung injury model. C57BL/6 mice were treated with either everolimus or NVP-BEZ235 on two consecutive days prior to intratracheal administration of LPS. LPS administration induced a significant increase in total cell, neutrophil and erythrocyte numbers in the bronchoalveolar lavage fluid. Histological examination revealed a serious lung injury as shown by interstitial edema, vascular congestion and mononuclear cell infiltration in these mice after 24h. Everolimus as well as NVP-BEZ235 did not noticeably affect overall histopathology of the lungs in the lung injury model. However, NVP-BEZ235 enhanced IL-6 and TNF-α expression after 24h. In contrast, everolimus did not affect IL-6 and TNF-α levels. Interestingly, both inhibitors reduced inflammatory cytokines in an LPS/oleic acid-induced lung injury model. In conclusion, the mTOR inhibitors did not worsen the overall histopathological severity, but they exerted distinct effects on proinflammatory cytokine expression in the lung depending on the lung injury model applied.
authors.affiliation: Institute of Medical Genetics, Medical University of Vienna, Vienna, Austria.
authors.forename: Sevdican
authors.initials: S
authors.lastname: Üstün
authors.affiliation: Institute of Animal Breeding and Genetics & Biomodels Austria, University of Veterinary Medicine Vienna, Vienna, Austria.
authors.forename: Caroline
authors.initials: C
authors.lastname: Lassnig
authors.affiliation: Institute of Medical Genetics, Medical University of Vienna, Vienna, Austria.
authors.forename: Andrea
authors.initials: A
authors.lastname: Preitschopf
authors.affiliation: Institute of Medical Genetics, Medical University of Vienna, Vienna, Austria.
authors.forename: Mario
authors.initials: M
authors.lastname: Mikula
authors.affiliation: Institute of Animal Breeding and Genetics & Biomodels Austria, University of Veterinary Medicine Vienna, Vienna, Austria.
authors.forename: Mathias
authors.initials: M
authors.lastname: Müller
authors.affiliation: Institute of Medical Genetics, Medical University of Vienna, Vienna, Austria.
authors.forename: Markus
authors.initials: M
authors.lastname: Hengstschläger
authors.affiliation: Institute of Medical Genetics, Medical University of Vienna, Vienna, Austria. Electronic address: thomas.weichhart@meduniwien.ac.at.
authors.forename: Thomas
authors.initials: T
authors.lastname: Weichhart
mesh_terms: D055371:Acute Lung Injury / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology; D000818:Animals; D004195:Disease Models, Animal; D000068338:Everolimus / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D015850:Interleukin-6 / Q000276:immunology; D008070:Lipopolysaccharides / Q000633:toxicity; D051379:Mice; D019301:Oleic Acid / Q000633:toxicity; D019869:Phosphatidylinositol 3-Kinases / Q000276:immunology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011804:Quinolines / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology
chemical_list: D000068338:Everolimus; D007093:Imidazoles; D015850:Interleukin-6; D008070:Lipopolysaccharides; D019301:Oleic Acid; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011804:Quinolines; D058570:TOR Serine-Threonine Kinases; D014409:Tumor Necrosis Factor-alpha; C546843:mTOR protein, mouse; C531198:dactolisib
keywords: acute lung injury; everolimus; mTOR; pneumonitis