Do soluble mediators cause ventilator-induced lung injury and multi-organ failure?

Significant advances in the management of patients with acute respiratory distress syndrome have been few in the recent past despite considerable efforts in clinical testing and experimental work. The biotrauma hypothesis of ventilator-associated lung injury (VALI), suggesting that mechanical ventilation induces the release of injurious mediators from the lung, implies that pharmaceutical interventions targeting these circulating pathogenic mediators would be clinically beneficial. Among the commonly reported classes of ventilation-associated mediators are cytokines, coagulation factors, hormones (e.g., angiotensin-II), lipid-derived mediators and oxidants, yet proof of their pathogenicity is lacking. This review discusses evidence surrounding the roles of these mediators in VALI and describes how definitive proof could be provided based on Koch's postulates, using an isolated perfused lung model. According to this experimental concept, candidate mediators would fulfill certain criteria, including increased accumulation in perfusate during injurious ventilation and induction of injury during non-injurious ventilation. Accumulation of mediators in the perfusate would facilitate isolation and characterization by standard biochemical means, from broad determination of physical and chemical properties to precise identification of individual molecules (e.g., by modern omic approaches such as mass spectrometry). Finally, confirmation by exogenous administration of mediators or antagonists can assess effects on injury and its mechanisms such as cell permeability or cytotoxicity. Adaptation of Koch's postulates to the biotrauma hypothesis of VALI could provide important insights. Translation of the acquired knowledge into clinical testing is challenged by the heterogeneity of the patient population (e.g., etiology, co-morbidity, genetics or concomitant therapy) and the specificity and efficacy of the therapeutic intervention on the cellular/molecular level.