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 ARDS. While 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 to HPV alone. Pulmonary expression of proinflammatory cytokines such as IL-6 and TNF-α did not differ between mice with LPV+CFH or LPV but increased significantly in mice receiving HPV. Norepinephrine 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 to mice with HPV or HPV+NE. Analyzing 437 critically ill patients with severe ARDS and therapy with veno-venous 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 pro-inflammatory and pro-edematous effects of CFH-induced hypertension. Associated with reduced pulmonary compliance also in humans, increased CFH plasma-concentrations might be a future therapeutical target.a.