Inhalation of carbon monoxide prevents liver injury and inflammation following hind limb ischemia/reperfusion

Ott, Michael; Scott, Jeffrey R.; Bihari, Aurelia; Badhwar, Amit; Otterbein, Leo E.; Gray, Daryl; Harris, Kenneth A.; Potter, Richard F.

doi:10.1096/fj.04-2514fje

Cited by 55 publications

(38 citation statements)

References 51 publications

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“…These data suggest a cytoprotective role for bilirubin that is mediated, at least in part, through the inhibition of iNOS expression and, potentially, through stimulation of local PGE 2 production. Inhalation of CO during HO inhibition significantly reduced microcirculatory deficits, hepatic inflammation, and injury in response to hind limb ischemia-reperfusion, suggesting that HO-derived hepatic protection is mediated by CO (Ott et al, 2005). Inhalation of low concentrations of CO may represent a novel therapeutic approach to prevent remote organ injury during systemic inflammatory response syndrome (SIRS).…”

Section: K Hepatic Injurymentioning

confidence: 99%

Pharmacological and Clinical Aspects of Heme Oxygenase

Abraham

Kappas²

2008

Pharmacol Rev

1,002

988

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Section: K Hepatic Injurymentioning

confidence: 99%

Pharmacological and Clinical Aspects of Heme Oxygenase

Abraham

Kappas²

2008

Pharmacol Rev

1,002

988

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“…Random views of sinusoids were recorded in the peri-central and peri-portal zones of liver acini, as well as post-sinusoidal venules for analysis as previously described [ 24 ] . Upon video playback, a representative frame with optimal resolution was chosen for assessment.…”

Section: Microscopy Of Liver Sinusoids and Post-sinusoidal Venulesmentioning

confidence: 99%

Detrimental effects of prolonged warm renal ischaemia‐reperfusion injury are abrogated by supplemental hydrogen sulphide: an analysis using real‐time intravital microscopy and polymerase chain reaction

Zhu¹,

Kalbfleisch²,

Yang³

et al. 2012

BJU International

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What's known on the subject? and What does the study add?Hydrogen sulphide (H2S) has recently been classified as a member of the gasotransmitter family. Its physiological and pathophysiological effects are rapidly expanding with numerous studies highlighting the protective effects of H2S on ischaemia‐reperfusion injury (IRI) in various organ systems, e.g. heart, liver, CNS and lungs. The mechanisms behind its protective effects reside in its vasodilatory, anti‐inflammatory and anti‐oxidant characteristics. These specific mechanistic profiles appear to be different across different tissues and models of IRI.We recently showed that supplementation of preservation solutions with H2S during periods of prolonged cold renal storage and subsequent renal transplantation leads to a massive and significant survival, functional and tissue protective advantage compared with storage in standard preservation solution alone. However, there have only been a few studies that have evaluated the effects of H2S against warm renal IRI; although these studies have focused primarily upon shorter periods of warm renal pedicle clamping, they have shown a clear survival benefit to H2S supplementation. The present study adds to the existing literature by evaluating the effects of H2S in a model of warm IRI with clinically relevant, prolonged warm ischaemia‐reperfusion times (1 h ischaemia, 2 h reperfusion). We show an unprecedented view into real‐time renal and hepatic perfusion with intravital microscopy throughout the reperfusion period. We show, for the first time, that supplemental H2S has multiple protective functions against the warm IRI‐induced tissue damage, which may be clinically applicable to both donation after cardiac death models of renal transplantation, as well as to uro‐oncological practices requiring surgical clamping of the renal pedicle, e.g. during a partial nephrectomy.OBJECTIVE To determine the protective role of supplemental hydrogen sulphide (H2S) in prolonged warm renal ischaemia‐reperfusion injury (IRI) using real‐time intravital microscopy (IVM). MATERIALS AND METHODS Uninephrectomised Lewis rats underwent 1 h of warm ischaemia and 2 h of reperfusion during intraperitoneal treatment with phosphate buffer saline (IRI, n= 10) or 150 µmol/L NaHS (IRI+H2S, n= 12) and were compared with sham‐operated rats (n= 9). Blood was collected for measurement of serum creatinine (Cr), alanine aminotransferase (ALT) and aspartate aminotransferase (AST). IVM was performed to assess renal and hepatic microcirculation. Kidneys were sectioned for histology and real‐time quantitative polymerase chain reaction for markers of inflammation. RESULTS The mean (sd) Cr concentration raised to 72.8 (2.5) µmol/L after IRI from 11.0 (0.7) µmol/L (sham) but was partially inhibited with H2S to 62.8 (0.9) µmol/L (P < 0.05). H2S supplementation during IRI increased renal capillary perfusion on IVM, and improved acute tubular necrosis and apoptotic scores on histology (P < 0.05). Supplemental H2S decreased expression of the pro‐inflammatory markers toll‐like receptor 4, tumour necrosis factor α, interleukin 8, C‐C chemokine receptor type 5, interferon γ and interleukin 2 (P < 0.05). Distant organ (liver) dysfunction after renal IRI was limited with H2S supplementation: blunting of the ALT and AST surge, decreased hepatic sinusoidal vasodilation, and decreased leukocyte infiltration in post‐sinusoidal venules (P < 0.05). H2S supplementation directly inhibited interleukin 8‐induced neutrophil chemotaxis in vitro (P < 0.05). CONCLUSIONS These findings are the first to show the real‐time protective role of supplemental H2S in prolonged periods of warm renal IRI, perhaps acting by decreasing leukocyte migration and limiting inflammatory responses. The protective effects of H2S suggest potential clinical applications in both donors after cardiac death models of renal transplantation and oncological practices requiring vascular clamping.

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“…Biliverdin reductase converts biliverdin into bilirubin, and bilirubin alleviates oxidative damage at injury sites in experimental autoimmune encephalomyelitis models and inhibits lipopolysaccharide-induced NO production in macrophages (Liu et al, 2003;Wang et al, 2004). Carbon monoxide attenuates bronchial inflammation induced by aeroallergen and prevents liver inflammation (Chapman et al, 2001;Ott et al, 2005). And finally, ferrous iron released by HO activity rapidly induces expression of ferritin, protecting cells under oxidizing conditions by sequestering free cytosolic iron (Ward et al, 1994).…”

Section: Introductionmentioning

confidence: 99%