Inhaled carbon monoxide prevents acute kidney injury in pigs after cardiopulmonary bypass by inducing a heat shock response.
BACKGROUND
Cardiopulmonary bypass (CPB) may be associated with acute kidney injury (AKI). Inhaled carbon monoxide (CO) is cyto- and organ-protective. We hypothesized that pretreatment with inhaled CO prevents CPB-associated AKI.


METHODS
Pigs (n = 38) were nonrandomly assigned to SHAM, standard CPB, pretreatment with inhaled CO (250 ppm, 1 hour) before SHAM or CPB, to pretreatment with quercetin (an inhibitor of the heat shock response), and to pretreatment with SnPPIX (an inhibitor of endogenously derived CO), before CO inhalation and CPB. The primary outcome variables were markers of AKI (urea, uric acid, creatinine, cystatin C, neutrophil gelatinase-associated lipocalin, interleukin-6, tumor necrosis factor-alpha), which were determined 120 minutes after CPB. Secondary outcome variables were heat shock protein (HSP)-70 and heme oxygenase-1 protein expressions as indicators of CO-mediated heat shock response.


RESULTS
Pretreatment with inhaled CO attenuated (all P < 0.001) CPB-associated, (1) increases in serum concentrations of cystatin C (64 +/- 14 vs 28 +/- 9 ng/mL), neutrophil gelatinase-associated lipocalin (391 +/- 65 vs 183 +/- 56 ng/mL), renal tumor necrosis factor-alpha (450 +/- 73 vs 179 +/- 110 pg/mL), and interleukin-6 (483 +/- 102 vs 125 +/- 67 pg/mL); (2) increase in renal caspase-3 activity (550 +/- 66 vs 259 +/- 52 relative fluorescent units); and (3) histological evidence of AKI. These effects were accompanied by activation of HSP-70 (196 +/- 64 vs 554 +/- 149 ng/mL, P < 0.001). Pretreatment with the heat shock response inhibitor quercetin counteracted the CO-associated biochemical and histological renoprotective effects (all P < 0.001), whereas the heme oxygenase inhibitor SnPPIX only partially counteracted the CO-associated renoprotection and the activation of the heat shock response.


CONCLUSIONS
CO treatment before CPB was associated with evidence of renoprotection, demonstrated by fewer histological injuries and decreased cystatin C concentrations. The findings that the antiinflammatory and antiapoptotic effects of CO were accompanied by activation of HSP-70, which in turn were reversed by quercetin, suggest that renoprotection by pretreatment with inhaled CO before CPB is mediated by activation of the renal heat shock response.
Goebel
Ulrich
U
Department of Anesthesiology and Critical Care Medicine, University Medical Centre, Hugstetterstrasse 55, D-79106 Freiburg im Breisgau, Germany.
Siepe
Matthias
M
Schwer
Christian I
CI
Schibilsky
David
D
Foerster
Katharina
K
Neumann
Jens
J
Wiech
Thorsten
T
Priebe
Hans-Joachim
HJ
Schlensak
Christian
C
Loop
Torsten
T
D000208:Acute Disease; D000280:Administration, Inhalation; D000818:Animals; D002248:Carbon Monoxide / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D002315:Cardiopulmonary Bypass / Q000009:adverse effects*; D053148:Caspase 3 / Q000096:biosynthesis; D006360:Heat-Shock Proteins / Q000096:biosynthesis*; D018869:Heat-Shock Response / Q000187:drug effects* / Q000502:physiology*; D006419:Heme Oxygenase (Decyclizing) / Q000096:biosynthesis; D006439:Hemodynamics / Q000187:drug effects; D015850:Interleukin-6 / Q000096:biosynthesis; D007668:Kidney / Q000473:pathology; D007674:Kidney Diseases / Q000209:etiology* / Q000473:pathology / Q000517:prevention & control*; D007677:Kidney Function Tests; D012313:RNA / Q000096:biosynthesis / Q000235:genetics; D013552:Swine; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D006360:Heat-Shock Proteins; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D012313:RNA; D002248:Carbon Monoxide; D006419:Heme Oxygenase (Decyclizing); D053148:Caspase 3