title: Inhibition of Toll-like receptor 4 signaling ameliorates lung ischemia-reperfusion injury in acute hyperglycemic conditions.
abstract: Recent lung transplantation studies have shown that peri-operative hyperglycemia is an important factor affecting recipient survival; however, its underlying mechanisms are not well understood. We hypothesized that acute hyperglycemia exacerbates lung ischemia-reperfusion injury (IRI) through up-regulation of Toll-like receptor 4 (TLR4) signaling pathways.
  
  
  
  C57BL/6Ncr mice were divided into 3 treatment groups: sham; IRI; and IRI under acute hyperglycemic conditions (IRI+HG). Mice in the IRI and IRI+HG groups were exposed to IRI via clamping the left hilum for 1 hour, followed by reperfusion for 2 hours. Acute hyperglycemia was established by glucose injection. The severity of lung injury and TLR4 signaling pathway activity were assessed. Further, we performed a pharmacologic blockade of TLR4 signaling to determine the effect of TLR4 signaling inhibition on lung injury.
  
  
  
  Compared with normoglycemic mice, hyperglycemic mice had 2-fold higher blood glucose levels (p < 0.001). Pulmonary compliance was significantly lower, and airway resistance was significantly higher, in the IRI+HG group than in the IRI group (p < 0.05). Levels of inflammatory cytokines in bronchoalveolar lavage fluid were significantly higher in the IRI+HG group than in the IRI group. Correspondingly, TLR4 signaling pathways were up-regulated in the IRI+HG group. Moreover, pharmacologic inhibition of TLR4 signaling significantly decreased lung injury markers under hyperglycemic conditions.
  
  
  
  Acute hyperglycemia exacerbated lung IRI and was associated with up-regulation of TLR4 signaling pathways. Pharmacologic inhibition of TLR4 signaling ameliorated lung IRI with acute hyperglycemia. Targeting TLR4 appears to be a promising approach to managing coexisting pathologies in lung transplant recipients.
authors.affiliation: Department of Thoracic Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Mamoru
authors.initials: M
authors.lastname: Takahashi
authors.affiliation: Department of Thoracic Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Toyofumi F
authors.initials: TF
authors.lastname: Chen-Yoshikawa
authors.affiliation: Department of Thoracic Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Toshi
authors.initials: T
authors.lastname: Menju
authors.affiliation: Department of Thoracic Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Keiji
authors.initials: K
authors.lastname: Ohata
authors.affiliation: Department of Thoracic Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kondo
authors.affiliation: Department of Thoracic Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Motoyama
authors.affiliation: Department of Thoracic Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Kyoko
authors.initials: K
authors.lastname: Hijiya
authors.affiliation: Department of Thoracic Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Aoyama
authors.affiliation: Department of Thoracic Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan. Electronic address: hdate@kuhp.kyoto-u.ac.jp.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Date
mesh_terms: D000818:Animals; D008168:Lung; D051379:Mice; D008810:Mice, Inbred C57BL; D015427:Reperfusion Injury; D015398:Signal Transduction; D051197:Toll-Like Receptor 4
chemical_list: C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4
keywords: Toll-like receptor 4; acute hyperglycemia; lung ischemia-reperfusion injury; pro-inflammatory cytokines; pulmonary function