title: Biliverdin Protects the Isolated Rat Lungs from Ischemia-reperfusion Injury via Antioxidative, Anti-inflammatory and Anti-apoptotic Effects.
abstract: BACKGROUND
  Biliverdin (BV) has a protective role against ischemia-reperfusion injury (IRI). However, the protective role and potential mechanisms of BV on lung IRI (LIRI) remain to be elucidated. Thus, we aimed to investigate the protective role and potential mechanisms of BV on LIRI.
  
  
  METHODS
  Lungs were isolated from Sprague-Dawley rats to establish an ex vivo LIRI model. After an initial 15 min stabilization period, the isolated lungs were subjected to ischemia for 60 min, followed by 90 min of reperfusion with or without BV treatment.
  
  
  RESULTS
  Lungs in the I/R group exhibited significant decrease in tidal volume (1.44 ± 0.23 ml/min in I/R group vs. 2.41 ± 0.31 ml/min in sham group; P< 0.001), lung compliance (0.27 ± 0.06 ml/cmH2O in I/R group vs. 0.44 ± 0.09 ml/cmH2O in sham group; P< 0.001; 1 cmH2O=0.098 kPa), and oxygen partial pressure (PaO2) levels (64.12 ± 12 mmHg in I/R group vs. 114 ± 8.0 mmHg in sham group; P< 0.001; 1 mmHg = 0.133 kPa). In contrast, these parameters in the BV group (2.27 ± 0.37 ml/min of tidal volume, 0.41 ± 0.10 ml/cmH2O of compliance, and 98.7 ± 9.7 mmHg of PaO2) were significantly higher compared with the I/R group (P = 0.004, P< 0.001, and P< 0.001, respectively). Compared to the I/R group, the contents of superoxide dismutase were significantly higher (47.07 ± 7.91 U/mg protein vs. 33.84 ± 10.15 U/mg protein; P = 0.005) while the wet/dry weight ratio (P < 0.01), methane dicarboxylic aldehyde (1.92 ± 0.25 nmol/mg protein vs. 2.67 ± 0.46 nmol/mg protein; P< 0.001), and adenosine triphosphate contents (297.05 ± 47.45 nmol/mg protein vs. 208.09 ± 29.11 nmol/mg protein; P = 0.005) were markedly lower in BV-treated lungs. Histological analysis revealed that BV alleviated LIRI. Furthermore, the expression of inflammatory cytokines (interleukin-1β, interleukin-6, and tumor necrosis factor-β) was downregulated and the expression of cyclooxygenase-2, inducible nitric oxide synthase, and Jun N-terminal kinase was significantly reduced in BV group (all P< 0.01 compared to I/R group). Finally, the apoptosis index in the BV group was significantly decreased (P < 0.01 compared to I/R group).
  
  
  CONCLUSIONS
  BV protects lung IRI through its antioxidative, anti-inflammatory, and anti-apoptotic effects.
authors.affiliation: Department of Pathophysiology, Wuxi Medical School, Jiangnan University, Wuxi, Jiangsu 214122, China.
authors.forename: Wen-Fang
authors.initials: WF
authors.lastname: Tian
authors.affiliation: Department of Pathophysiology, Wuxi Medical School, Jiangnan University, Wuxi, Jiangsu 214122, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Weng
authors.affiliation: Department of Pathophysiology, Wuxi Medical School, Jiangnan University, Wuxi, Jiangsu 214122, China.
authors.forename: Qiong
authors.initials: Q
authors.lastname: Sheng
authors.affiliation: Department of Pathophysiology, Wuxi Medical School, Jiangnan University, Wuxi, Jiangsu 214122, China.
authors.forename: Jun-Liang
authors.initials: JL
authors.lastname: Chen
authors.affiliation: Department of Pathophysiology, Wuxi Medical School, Jiangnan University, Wuxi, Jiangsu 214122, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Zhang
authors.affiliation: Department of Anesthesia, Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu 214122, China.
authors.forename: Ji-Ru
authors.initials: JR
authors.lastname: Zhang
authors.affiliation: Department of Pathophysiology, Wuxi Medical School, Jiangnan University, Wuxi, Jiangsu 214122, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Du
authors.affiliation: Department of Pathophysiology, Wuxi Medical School, Jiangnan University, Wuxi, Jiangsu 214122, China.
authors.forename: Min-Chen
authors.initials: MC
authors.lastname: Wu
authors.affiliation: Department of Pathophysiology, Wuxi Medical School, Jiangnan University, Wuxi, Jiangsu 214122, China.
authors.forename: Qing-Feng
authors.initials: QF
authors.lastname: Pang
authors.affiliation: Department of Anesthesia, Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu 214122, China.
authors.forename: Jian-Jun
authors.initials: JJ
authors.lastname: Chu
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D000975:Antioxidants / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001664:Biliverdine / Q000627:therapeutic use*; D015153:Blotting, Western; D051546:Cyclooxygenase 2 / Q000378:metabolism; D020287:In Situ Nick-End Labeling; D053583:Interleukin-1beta / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008168:Lung / Q000187:drug effects* / Q000473:pathology; D008233:Lymphotoxin-alpha / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D015427:Reperfusion Injury / Q000517:prevention & control*; D013482:Superoxide Dismutase / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D000975:Antioxidants; D053583:Interleukin-1beta; D015850:Interleukin-6; D008233:Lymphotoxin-alpha; D052247:Nitric Oxide Synthase Type II; D051546:Cyclooxygenase 2; D013482:Superoxide Dismutase; D048031:JNK Mitogen-Activated Protein Kinases; D001664:Biliverdine