Biliverdin Protects the Isolated Rat Lungs from Ischemia-reperfusion Injury via Antioxidative, Anti-inflammatory and Anti-apoptotic Effects

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 IR group vs. 2.41 +/- 0.31 ml/min in sham group; P < 0.001), lung compliance (0.27 +/- 0.06 ml/cmH(2)O in IR group vs. 0.44 +/- 0.09 ml/cmH(2)O in sham group; P < 0.001; 1 cmH(2)O=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/ cmH(2)O of compliance, and 98.7 +/- 9.7 mmHg of PaO2) were significantly higher compared with the FR 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 nmollmg 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-1 beta, interleukin-6, and tumor necrosis factor-alpha) 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). Conclusion: BV protects lung IRI through its antioxidative, anti-inflammatory, and anti-apoptotic effects.