Effect of cortisol-synthesis inhibition on endotoxin-induced porcine acute lung injury, shock, and nitric oxide production.
In the process of developing a model of Escherichia coli endotoxin-induced acute lung injury and shock in specific pathogen-free pigs, the effects of pretreatment with metyrapone (a cortisol-synthesis inhibitor) were examined. Metyrapone was administered 1.5 h before start of endotoxin infusion at t = 0 h (MET-ETOX group, n = 6). At the end of the experiments (t = 4 h) a bronchoalveolar lavage (BAL) was performed. Control animals received only endotoxin (CON-ETOX group, n = 6) or metyrapone (MET-CON group, n = 4). The following results are presented as means +/- SEM. It was found that metyrapone successfully blocked endogenous cortisol synthesis (plasma cortisol levels were 41.0 +/- 5.9 nM in MET-ETOX vs. 339.0 +/- 37.7 nM in CON-ETOX at t = 4 h, P <0.01). At t = 4 h the MET-ETOX animals had substantially increased systemic hypotension compared to the CON-ETOX group (mean arterial pressure 26.7 +/- 4.3 vs. 77.7 +/- 12.2 mmHg, P <0.01), decreased dynamic lung compliance (10.9 +/- 0.7 vs. 13.7 +/- 0.6 ml/cmH2O, P <0.01), increased percentage of BAL neutrophils (28.4 +/- 6.5 vs. 6.6 +/-1.8, P <0.01), pulmonary edema (BAL total protein 0.82 +/- 0.21 vs. 0.42 +/- 0.09 mg/mL, P <0.05), elevated levels of interleukin-8 (1924 +/- 275 vs. 324 +/- 131 pg/mL, P <0.01) and acidosis (pH 7.11 +/- 0.03 vs. 7.23 +/- 0.06, P <0.05). The MET-ETOX group also showed an increased pulmonary hypertension between 2 and 3 h after start of endotoxin infusion and a trend toward significantly increased levels of plasma interleukin-8 (P = 0.052). Arterial pCO2, pO2/FiO2, plasma endothelin-1, plasma TNFalpha, and blood leukocytes were not markedly influenced by the plasma cortisol levels. Nitric oxide production did not seem to be altered by endotoxin infusion in this model, in contrast to other animal studies; this discrepancy could be thought to be due to endotoxin-dosage differences or species differences. It is concluded that if endogenous cortisol production is blocked by metyrapone, the reactions occurring as a result of the endotoxin-induced acute lung injury and shock are greatly enhanced and that therefore pretreatment with metyrapone might be an important addition to this model with specific pathogen-free pigs.
Middelveld
R J
RJ
Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
Wanecek
M
M
Bergman
D
D
Weitzberg
E
E
Alving
K
K
D000137:Acid-Base Imbalance / Q000378:metabolism; D000818:Animals; D001784:Blood Gas Analysis; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D004195:Disease Models, Animal; D019332:Endothelin-1 / Q000097:blood; D004731:Endotoxins; D005260:Female; D006854:Hydrocortisone / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000097:blood; D007022:Hypotension / Q000139:chemically induced; D016209:Interleukin-8 / Q000097:blood; D007962:Leukocytes; D008297:Male; D008797:Metyrapone; D009504:Neutrophils / Q000473:pathology; D009569:Nitric Oxide / Q000096:biosynthesis*; D009573:Nitrites / Q000378:metabolism; D009195:Peroxidase / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D011654:Pulmonary Edema / Q000139:chemically induced; D012128:Respiratory Distress Syndrome / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D012129:Respiratory Function Tests; D012769:Shock / Q000378:metabolism*; D013047:Specific Pathogen-Free Organisms; D013552:Swine; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D019332:Endothelin-1; D004731:Endotoxins; D016209:Interleukin-8; D009573:Nitrites; D011506:Proteins; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D009195:Peroxidase; D006854:Hydrocortisone; D008797:Metyrapone