title: Protective effects of intratracheally administered quercetin on lipopolysaccharide-induced acute lung injury.
abstract: BACKGROUND
  Acute respiratory distress syndrome (ARDS) can result in a life-threatening form of respiratory failure, and established, effective pharmacotherapies are therefore urgently required. Quercetin is one of the most common flavonoids found in fruits and vegetables, and has potent anti-inflammatory and anti-oxidant activities. Quercetin has been demonstrated to exhibit cytoprotective effects through the induction of heme oxygenase (HO)-1. Here, we investigated whether the intratracheal administration of quercetin could suppress lipopolysaccharide (LPS)-induced acute lung injury (ALI) in mice as well as the involvement of HO-1 in quercetin's suppressive effects.
  
  
  METHODS
  Mouse model of ALI were established by challenging intratracheally LPS. The wet lung-to-body weight ratio, matrix metalloproteinase (MMP)-9 activities, and pro-inflammatory cytokine productions, including tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6 in bronchoalveolar lavage fluid (BALF) were examined in ALI mice with or without quercetin pretreatment. We also examined the effects of quercetin on LPS stimulation in the mouse alveolar macrophage cell line, AMJ2-C11 cells.
  
  
  RESULTS
  Intratracheal administration of quercetin decreased the wet lung-to-body weight ratio. Moreover, quercetin decreased MMP-9 activity and the production of pro-inflammatory cytokines in BALF cells activated by LPS in advance. We determined the expression of quercetin-induced HO-1 in mouse lung, e.g., alveolar macrophages (AMs), alveolar and bronchial epithelial cells. When AMJ2-C11 cells were cultured with quercetin, a marked suppression of LPS-induced pro-inflammatory cytokine production was observed. The cytoprotective effects were attenuated by the addition of the HO-1 inhibitor SnPP. These results indicated that quercetin suppressed LPS-induced lung inflammation, and that an HO-1-dependent pathway mediated these cytoprotective effects.
  
  
  CONCLUSIONS
  Our findings indicated that quercetin suppressed LPS-induced lung inflammation, and that an HO-1-dependent pathway mediated these cytoprotective effects. Intratracheal administration of quercetin will lead to new supportive strategies for cytoprotection in these serious lung conditions.
authors.affiliation: Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan. k-takashima@med.nagoya-u.ac.jp.
authors.forename: Koji
authors.initials: K
authors.lastname: Takashima
authors.affiliation: Department of Pathophysiological Laboratory Sciences, Nagoya University Graduate School of Medicine, 1-1-20 Daikou-minami, Higashi-ku, Nagoya, 461-8673, Japan. matsu@met.nagoya-u.ac.jp.
authors.forename: Miyoko
authors.initials: M
authors.lastname: Matsushima
authors.affiliation: Department of Pathophysiological Laboratory Sciences, Nagoya University Graduate School of Medicine, 1-1-20 Daikou-minami, Higashi-ku, Nagoya, 461-8673, Japan. khashimo@met.nagoya-u.ac.jp.
authors.forename: Katsunori
authors.initials: K
authors.lastname: Hashimoto
authors.affiliation: Department of Pathophysiological Laboratory Sciences, Nagoya University Graduate School of Medicine, 1-1-20 Daikou-minami, Higashi-ku, Nagoya, 461-8673, Japan. haruka5316@gmail.com.
authors.forename: Haruka
authors.initials: H
authors.lastname: Nose
authors.affiliation: Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan. msato@med.nagoya-u.ac.jp.
authors.forename: Mitsuo
authors.initials: M
authors.lastname: Sato
authors.affiliation: Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan. hashinao@med.nagoya-u.ac.jp.
authors.forename: Naozumi
authors.initials: N
authors.lastname: Hashimoto
authors.affiliation: Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan. yhasega@med.nagoya-u.ac.jp.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Hasegawa
authors.affiliation: Department of Pathophysiological Laboratory Sciences, Nagoya University Graduate School of Medicine, 1-1-20 Daikou-minami, Higashi-ku, Nagoya, 461-8673, Japan. kawabe@met.nagoya-u.ac.jp.
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Kawabe
mesh_terms: D055371:Acute Lung Injury / Q000139:chemically induced / Q000201:enzymology / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D000280:Administration, Inhalation; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage*; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000276:immunology; D002460:Cell Line; D019610:Cytoprotection; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D051547:Heme Oxygenase-1 / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D007442:Intubation, Intratracheal; D008070:Lipopolysaccharides; D008168:Lung / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000201:enzymology / Q000276:immunology; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D008810:Mice, Inbred C57BL; D011794:Quercetin / Q000008:administration & dosage*; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; C587672:IL1B protein, mouse; D018836:Inflammation Mediators; D053583:Interleukin-1beta; D015850:Interleukin-6; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D014409:Tumor Necrosis Factor-alpha; C577686:interleukin-6, mouse; D011794:Quercetin; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse