Intravascular hemolysis aggravates ventilator-induced lung injury in mice

Mechanical ventilation (MV), a common life-saving intervention in critical care medicine, can itself cause pulmonary damage. Intravascular hemolysis is common in sepsis and acute respiratory distress syndrome (ARDS). Although inflammation, infection, or atelectasis can enhance ventilator-induced lung injury (VILI), data are scarce on the interaction between hemolysis and VILI. Therefore, mice were ventilated with either lung-protective MV (LPV) or injurious MV (HPV), and selected mice received an intravascular infusion of hemolyzed murine red blood cells containing cell-free hemoglobin (CFH). Lung edema quantified by wet-to-dry weight ratio did not differ between mice receiving LPV or LPV + CFH but was significantly higher in mice receiving HPV + CFH compared with HPV alone. Pulmonary expression of proinflammatory cytokines such as interleukin-6 (IL-6) and tumor-necrosis factor alpha (TNF-α) did not differ between mice with LPV + CFH or LPV but increased significantly in mice receiving HPV. Norepinephrine (NE), used to simulate CFH-associated hypertension but not CFH itself, further increased IL-6 gene expression and concentration in bronchoalveolar lavage fluid in mice with HPV. However, mice with HPV + CFH showed significantly impaired lung mechanics compared with mice with HPV or HPV + NE. Analyzing 437 critically ill patients with severe ARDS and therapy with venovenous extracorporeal membrane oxygenation (ECMO) confirmed that increased plasma concentrations of CFH were associated with a reduced pulmonary compliance. The findings suggest that mice subjected to HPV + CFH show increased impairment of lung mechanics that is associated with lung edema but cannot be fully explained by the proinflammatory and proedematous effects of CFH-induced hypertension. Associated with reduced pulmonary compliance also in humans, increased CFH plasma concentrations might be a future therapeutical target.NEW & NOTEWORTHY Mechanical ventilation is frequently used in critically ill patients and can itself cause pulmonary damage. Furthermore, hemolysis is common in sepsis and ARDS. Mice receiving mechanical ventilation and an infusion of cell-free hemoglobin (CFH) demonstrated increased impairment of lung mechanics associated with lung edema not fully explainable by the proinflammatory and proedematous effects of CFH. Furthermore, increased plasma concentrations of CFH correlated with reduced pulmonary compliance in patients with severe ARDS and therapy with ECMO.