The signaling pathway for tumor necrosis factor-a （TNF-a） and its receptors is up-regulated during ex- tracorporeal circulation （ECC）, and recruits blood neutrophil into the lung tissue, which results in acute lun...The signaling pathway for tumor necrosis factor-a （TNF-a） and its receptors is up-regulated during ex- tracorporeal circulation （ECC）, and recruits blood neutrophil into the lung tissue, which results in acute lung injury （ALl） In this study, we evaluated the role of tumor necrosis factor receptor I （TNFR1） in ECC-induced ALl by blocking TNF-a binding to TNFR1 with CAY10500. Anesthetized Sprague-Dawley （SD） rats were pretreated intravenously with phos- phate buffered saline （PBS） or vehicle （0.3 ml ethanol IV） or CAY10500, and then underwent ECC for 2 h. The oxy- genation index （OI） and pulmonary inflammation were assessed after ECC. OI was significantly decreased, while TNF-a and neutrophil in bronchoalveolar lavage fluid （BALF） and plasma TNF-a increased after ECC. Pretreatment of CAY10500 decreased plasma TNF-a level, but did not decrease TNF-a levels and neutrophil counts in BALF or improve OI. Lung histopathology showed significant alveolar congestion, infiltration of the leukocytes in the airspace, and increased thickness of the alveolar wall in all ECC-treated groups. CAY10500 pretreatment slightly reduced leukocyte infiltration in lungs, but did not change the wet/dry ratio in the lung tissue. Blocking TNF-a binding to TNFR1 by CAY10500 intravenously slightly mitigates pulmonary inflammation, but cannot improve the pulmonary function, indicating the limited role of TNFR1 pathway in circulating inflammatory cell in ECC-induced ALl.展开更多
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 ...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 ofreperfusion 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 FR 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-1 β,interleukin-6,and tumor necrosis factor-α） 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.展开更多
基金Project supported by the National Natural Science Foundation of China （No. 81171651） and the Science and Technology Breakthrough Project of the Science and Technology Department of Sichuan Province （No. 2010FZ0044）, China
文摘The signaling pathway for tumor necrosis factor-a （TNF-a） and its receptors is up-regulated during ex- tracorporeal circulation （ECC）, and recruits blood neutrophil into the lung tissue, which results in acute lung injury （ALl） In this study, we evaluated the role of tumor necrosis factor receptor I （TNFR1） in ECC-induced ALl by blocking TNF-a binding to TNFR1 with CAY10500. Anesthetized Sprague-Dawley （SD） rats were pretreated intravenously with phos- phate buffered saline （PBS） or vehicle （0.3 ml ethanol IV） or CAY10500, and then underwent ECC for 2 h. The oxy- genation index （OI） and pulmonary inflammation were assessed after ECC. OI was significantly decreased, while TNF-a and neutrophil in bronchoalveolar lavage fluid （BALF） and plasma TNF-a increased after ECC. Pretreatment of CAY10500 decreased plasma TNF-a level, but did not decrease TNF-a levels and neutrophil counts in BALF or improve OI. Lung histopathology showed significant alveolar congestion, infiltration of the leukocytes in the airspace, and increased thickness of the alveolar wall in all ECC-treated groups. CAY10500 pretreatment slightly reduced leukocyte infiltration in lungs, but did not change the wet/dry ratio in the lung tissue. Blocking TNF-a binding to TNFR1 by CAY10500 intravenously slightly mitigates pulmonary inflammation, but cannot improve the pulmonary function, indicating the limited role of TNFR1 pathway in circulating inflammatory cell in ECC-induced ALl.
文摘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 ofreperfusion 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 FR 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-1 β,interleukin-6,and tumor necrosis factor-α） 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.
