Effect of cortisol-synthesis inhibition on endotoxin-induced porcine acutelung 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 b ronchoalveolar lavage (BAL) was performed. Control animals received only en dotoxin (CON-ETOX group, n = 6) or metyrapone (MET-CON group, n = 4). The f ollowing results are presented as means +/- SEM. It was found that metyrapo ne successfully blocked endogenous cortisol synthesis (plasma cortisol leve ls 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 increas ed systemic hypotension compared to the CON-ETOX group (mean arterial press ure 26.7 +/- 4.3 vs. 77.7 +/- 12.2 mmHg, P <0.01), decreased dynamic lung c ompliance (10.9 +/- 0.7 vs. 13.7 +/- 0,6 mL/cmH(2)O, P < 0.01), increased p ercentage of BAL neutrophils (28.4 +/- 6.5 vs. 6.6 +/- 1.8, P < 0.01), pulm onary 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 a nd 3 h after start of endotoxin infusion and a trend toward significantly i ncreased levels of plasma interleukin-8 (P = 0.052). Arterial pCO(2), pO(2) /FiO(2), plasma endothelin-1, plasma TNF alpha, and blood leukocytes were n ot markedly influenced by the plasma cortisol levels. Nitric oxide producti on did not seem to be altered by endotoxin infusion in this model, in contr ast 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 o ccurring as a result of the endotoxin-induced acute lung injury and shock a re greatly enhanced and that therefore pretreatment: with metyrapone might be an important addition to this model with specific pathogen-free pigs.