Cell-free hemoglobin: a novel mediator of acute lung injury

Abstract

Patients with the acute respiratory distress syndrome (ARDS) have elevated levels of cell-free hemoglobin (CFH) in the air space, but the contribution of CFH to the pathogenesis of acute lung injury is unknown. In the present study, we demonstrate that levels of CFH in the air space correlate with measures of alveolar-capillary barrier dysfunction in humans with ARDS (r = 0.89, P < 0.001) and in mice with ventilator-induced acute lung injury (r = 0.89, P < 0.001). To investigate the specific contribution of CFH to ARDS, we studied the impact of purified CFH in the mouse lung and on cultured mouse lung epithelial (MLE-12) cells. Intratracheal delivery of CFH in mice causes acute lung injury with air space inflammation and alveolar-capillary barrier disruption. Similarly, in MLE-12 cells, CFH increases proinflammatory cytokine expression and increases paracellular permeability as measured by electrical cell-substrate impedance sensing. Next, to determine whether these effects are mediated by the iron-containing heme moiety of CFH, we treated mice with intratracheal hemin, the chloride salt of heme, and found that hemin was sufficient to increase alveolar permeability but failed to induce proinflammatory cytokine expression or epithelial cell injury. Together, these data identify CFH in the air space as a previously unrecognized driver of lung epithelial injury in human and experimental ARDS and suggest that CFH and hemin may contribute to ARDS through different mechanisms. Interventions targeting CFH and heme in the air space could provide a new therapeutic approach for ARDS.

Cell-free hemoglobin promotes primary graft dysfunction through oxidative lung endothelial injury

“…For example, in sepsis, elevated levels of circulating CFH are associated with increased mortality and organ dysfunction (29). In the airspace, elevated levels of CFH are associated with lung epithelial injury and disruption of the alveolar-capillary barrier (30,31). Whether CFH contributes to the pathogenesis of PGD is unknown.…”

The precautionary principle and use of Group A plasma in recipients of unknown ABO blood group

“…It is believed that more moderate, not easily visualized hemolysis contributes to severe morbidity in sickle cell anemia and paroxysmal nocturnal hemoglobinuria, as well as being a prognostic marker for mortality in critically ill patients. 7,8 Such patients, independent of the etiology of increased free hemoglobin, frequently experience infection, thrombosis, vasculopathy, and organ failure, 7,9 probably in part due to hemolysis. 10 The pathophysiology of how increased free hemoglobin occurs is different in patients who have sickle cell disease/paroxysmal nocturnal hemoglobinuria compared with those who have ABOimmune hemolysis.…”

Heme Impairs Alveolar Epithelial Sodium Channels Post Toxic Gas Inhalation

“…In a recent publication, Shaver et al found that cell-free hemoglobin levels in the air space correlated with alveolar-capillary barrier dysfunction in humans with acute respiratory distress syndrome (ARDS) (20). Further, they demonstrated that the intratracheal administration of cell-free hemoglobin to mice resulted in alveolar-capillary barrier disruption and acute lung injury (20).…”

“…In a recent publication, Shaver et al found that cell-free hemoglobin levels in the air space correlated with alveolar-capillary barrier dysfunction in humans with acute respiratory distress syndrome (ARDS) (20). Further, they demonstrated that the intratracheal administration of cell-free hemoglobin to mice resulted in alveolar-capillary barrier disruption and acute lung injury (20). Interestingly, they also found that the effects of cell-free hemoglobin were mediated by the iron-containing heme moiety of cell-free hemoglobin, as intratracheal administration of free heme was sufficient to increase alveolar permeability in mice (20).…”

“…Further, they demonstrated that the intratracheal administration of cell-free hemoglobin to mice resulted in alveolar-capillary barrier disruption and acute lung injury (20). Interestingly, they also found that the effects of cell-free hemoglobin were mediated by the iron-containing heme moiety of cell-free hemoglobin, as intratracheal administration of free heme was sufficient to increase alveolar permeability in mice (20). In fact in our recent studies, we found that patients with chronic obstructive pulmonary disease (COPD) also had elevated levels of CFH (8) which correlated with the severity of the disease.…”