Mechanistic insights into cell-free hemoglobin-induced injury during septic shock

Abstract

Rationale:Cell-free hemoglobin (CFH) levels are elevated in septic shock and higher in non-survivors. Whether CFH is only a marker of sepsis severity or is involved in pathogenesis is unknown. Objective:To investigate whether CFH worsens sepsis-associated injuries and to determine potential mechanisms of harm. Methods&Results:Fifty-one, 10-12kg purpose-bred beagles were randomized to receive Staphylococcus aureus intrapulmonary challenges or saline followed by CFH infusions (oxyhemoglobin >80%) or placebo. Animals received antibiotics, and intensive care-support for 96h. CFH significantly increased mean pulmonary arterial pressures and right ventricular afterload in both septic and non-septic animals, effects that were significantly greater in non-survivors. These findings are consistent with CFH-associated nitric oxide (NO) scavenging and were associated with significantly depressed cardiac function, and worsened shock, lactate levels, metabolic acidosis and multi-organ failure. In septic animals only, CFH administration significantly increased mean alveolar-arterial oxygenation gradients, also to a significantly greater degree in non-survivors. CFH associated iron levels were significantly suppressed in infected animals, suggesting that bacterial iron uptake worsened the pneumonia. Notably, cytokine levels were similar in survivors and non-survivors and not predictive of outcome. Conclusions:In the absence and presence of infection, CFH infusions resulted in pulmonary hypertension, cardiogenic shock and multi-organ failure, likely through NO scavenging. In the presence of infection alone, CFH infusions worsened oxygen exchange and lung injury, presumably by supplying iron that promoted bacterial growth. CFH elevation, a known consequence of clinical septic shock, adversely impacts sepsis outcomes through more than one mechanism and is a biologically plausible, non-antibiotic, non-cytokine target for therapeutic intervention.

Serum proteome profiling of naturally acquired Babesia rossi infection in dogs

“…It functions as an iron scavenger and modulator of signaling pathways, leading to the moderation of pro-inflammatory pathway activation during sepsis, thus playing a role in reducing tissue damage 33 , 34 . Cell-free haemoglobin (a major source of iron) has been shown to play an important role in the pathogenesis and outcome in a canine model of sepsis 35 . Scavenging the free iron that results from haemolysis would thus be an important host protective response 36 .…”

Plasma Nitric Oxide Consumption Is Elevated and Associated With Adverse Outcomes in Critically Ill Patients

“…The case-control analysis was adjusted for age, sex, and CFH concentration. We used clinical judgment and prior literature (12,(19)(20)(21) to choose RBC transfusion prior to study measurements, CFH, age, and Charlson comorbidity index (22) as covariables potentially confounding the comparisons of plasma NOC in groups of critically ill patients.…”

“…In contrast, CFH rapidly scavenges NO, causing impairments in vascular function (9, 35). In an experimental sepsis model, CFH infusion caused shock, microcirculatory impairment, organ failure, and death, presumably because of NO scavenging (20). Elevated plasma NOC has been previously demonstrated in clinical conditions associated with hemolysis, including sickle cell disease, cardiopulmonary bypass, hemodialysis, and RBC transfusion (9–12, 36).…”

Serum proteome profiling of naturally acquired Babesia rossi infection in dogs

“…It functions as an iron scavenger and modulator of signaling pathways, leading to the moderation of pro-in ammatory pathway activation during sepsis, thus playing a role in reducing tissue damage 33,34 . Cell-free haemoglobin (a major source of iron) has been shown to play an important role in the pathogenesis and outcome in a canine model of sepsis 35 . Scavenging the free iron that results from haemolysis would thus be an important host protective response 36 .…”