Protective effects of inhaled carbon monoxide in pig lungs during cardiopulmonary bypass are mediated via an induction of the heat shock response.
BACKGROUND
Cardiopulmonary bypass (CPB) may cause acute lung injury leading to increased morbidity and mortality after cardiac surgery. Preconditioning by inhaled carbon monoxide reduces pulmonary inflammation during CPB. We hypothesized that inhaled carbon monoxide mediates its anti-inflammatory and cytoprotective effects during CPB via induction of pulmonary heat shock proteins (Hsps).


METHODS
Pigs were randomized either to a control group, to standard CPB, to carbon monoxide+CPB, or to quercetin (a flavonoid and unspecific inhibitor of the heat shock response)+control, to quercetin+CPB, and to quercetin+carbon monoxide+CPB. In the carbon monoxide groups, lungs were ventilated with 250 ppm carbon monoxide in addition to standard ventilation before CPB. At various time points, lung biopsies were obtained and pulmonary Hsp and cytokine concentrations determined.


RESULTS
Haemodynamic parameters were largely unaffected by CPB, carbon monoxide inhalation, or administration of quercetin. Compared with standard CPB, carbon monoxide inhalation significantly increased the pulmonary expression of the Hsps 70 [27 (SD 3) vs 69 (10) ng ml(-1) at 120 min post-CPB, P<0.05] and 90 [0.3 (0.03) vs 0.52 (0.05) after 120 min CPB, P<0.05], induced the DNA binding of heat shock factor-1, reduced interleukin-6 protein expression [936 (75) vs 320 (138) at 120 min post-CPB, P<0.001], and decreased CPB-associated lung injury (assessed by lung biopsy). These carbon monoxide-mediated effects were inhibited by quercetin.


CONCLUSIONS
As quercetin, a Hsp inhibitor, reversed carbon monoxide-mediated pulmonary effects, we conclude that the anti-inflammatory and protective effects of preconditioning by inhaled carbon monoxide during CPB in pigs are mediated by an activation of the heat shock response.
Goebel
U
U
Department of Anaesthesia and Critical Care Medicine, University Medical Center, Hugstetterstrasse 55, D-79106 Freiburg im Breisgau, Germany.
Mecklenburg
A
A
Siepe
M
M
Roesslein
M
M
Schwer
C I
CI
Pahl
H L
HL
Priebe
H J
HJ
Schlensak
C
C
Loop
T
T
D055371:Acute Lung Injury / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D000280:Administration, Inhalation; D000818:Animals; D000975:Antioxidants / Q000627:therapeutic use; D002248:Carbon Monoxide / Q000494:pharmacology* / Q000627:therapeutic use; D002315:Cardiopulmonary Bypass / Q000009:adverse effects*; D006360:Heat-Shock Proteins / Q000378:metabolism; D018869:Heat-Shock Response / Q000187:drug effects*; D006439:Hemodynamics / Q000502:physiology; D006706:Homeostasis / Q000502:physiology; D015850:Interleukin-6 / Q000378:metabolism; D019194:Ischemic Preconditioning / Q000379:methods; D008168:Lung / Q000378:metabolism / Q000473:pathology; D016676:Macrophages, Alveolar / Q000473:pathology; D011794:Quercetin / Q000627:therapeutic use; D011897:Random Allocation; D034421:Sus scrofa
D000975:Antioxidants; D006360:Heat-Shock Proteins; D015850:Interleukin-6; D002248:Carbon Monoxide; D011794:Quercetin