Artificial mechanical ventilation represents a major cause of iatrogenic lung damage in intensive care. It is largely unknown which mediators, if any, contribute to the onset of such complications. We investigated whether stress caused by artificial mechanical ventilation leads to induction, synthesis, and release of cytokines or eicosanoids from lung tissue. We used the isolated perfused and ventilated mouse lung where frequent perfusate sampling allows determination of mediator release into the perfusate. Hyperventilation was executed with either negative (NPV) or positive pressure ventilation (PPV) at a transpulmonary pressure that was increased 2.5-fold above normal. Both modes of hyperventilation resulted in an approximately 1.75-fold increased expression of tumor necrosis factor alpha (TNFalpha) and interleukin-6 (IL-6) mRNA, but not of cyclooxygenase-2 mRNA. After switching to hyperventilation, prostacyclin release into the perfusate increased almost instantaneously from 19 +/- 17 pg/min to 230 +/- 160 pg/min (PPV) or 115 +/- 87 pg/min (NPV). The enhancement in TNFalpha and IL-6 production developed more slowly. In control lungs after 150 min of perfusion and ventilation, TNFalpha and IL-6 production was 23 +/- 20 pg/min and 330 +/- 210 pg/min, respectively. In lungs hyperventilated for 150 min, TNFalpha and IL-6 production were increased to 287 +/- 180 pg/min and more than 1,000 pg/min, respectively. We conclude that artificial ventilation might cause pulmonary and systemic adverse reactions by inducing the release of mediators into the circulation.

Endothelin receptor subtypes were characterized in isolated perfused rat lungs using the peptide ETA-receptor antagonists BQ 610 and BQ 123, the nonpeptide mixed ETA-/ETB-receptor antagonist bosentan, and the ETB-receptor agonist IRL 1620. Intra-arterial injection of 1 nmol IRL 1620 caused an enhanced reduction in pulmonary conductance compared with 1 nmol endothelin (ET-1) or 0.33 nmol IRL 1620. Pretreatment of lungs with BQ 610, BQ 123, or bosentan aggravated the bronchoconstriction induced by 1 nmol ET-1 so that it was comparable to that induced by 1 nmol IRL 1620. Although perfusion with 1 nmol IRL 1620 had only minor effects on vascular conductance, 1 nmol ET-1 caused a marked decrease in this parameter. This vasonconstriction was prevented by BQ 610, BQ 123, or bosentan. High concentrations of the stable prostacyclin metabolite, 6-keto-PGF1 alpha, were found in the perfusate of lungs treated with 1 nmol IRL 1620 or 1 nmol ET-1. The ET-1-induced release of 6-keto-PGF1 alpha was blocked by bosentan, but not by BQ 610. ET-1, but not IRL 1620, provoked the release of thromboxane B2. The main effect of ETA-receptor stimulation is vasoconstriction, whereas ETB-receptor stimulation causes bronchoconstriction. Both actions, however, are attenuated by the other receptor, i.e., the ETA-induced vasoconstriction is attenuated by ETB-receptor-induced release of vasodilators such as prostacyclin, whereas the ETB-receptor-induced bronchoconstriction is attenuated by an unknown ETA-receptor-dependent bronchodilatory mechanism.

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