During the last half-century, numerous
antiinflammatory agents were tested in dozens of clinical trials and have proven ineffective for treating
septic shock. The observation in multiple studies that cell-free
hemoglobin (CFH) levels are elevated during clinical
sepsis and that the degree of increase correlates with higher mortality suggests an alternative approach. Human
haptoglobin binds CFH with high affinity and, therefore, can potentially reduce
iron availability and oxidative activity. CFH levels are elevated over approximately 24-48 hours in our
antibiotic-treated canine model of S. aureus
pneumonia that simulates the
cardiovascular abnormalities of human
septic shock. In this 96-hour model, resuscitative treatments,
mechanical ventilation, sedation, and continuous care are translatable to management in human intensive care units. We found, in this S. aureus
pneumonia model inducing
septic shock, that commercial human
haptoglobin concentrate infusions over 48-hours bind canine CFH, increase CFH clearance, and lower circulating
iron. Over the 96-hour study, this treatment was associated with an improved metabolic profile (pH,
lactate), less
lung injury, reversal of
shock, and increased survival.
Haptoglobin binding compartmentalized CFH to the intravascular space. This observation, in combination with increasing CFHs clearance, reduced available
iron as a potential source of bacterial nutrition while decreasing the ability for CFH and
iron to cause extravascular oxidative tissue injury. In contrast,
haptoglobin therapy had no measurable antiinflammatory effect on elevations in proinflammatory
C-reactive protein and
cytokine levels.
Haptoglobin therapy enhances normal host defense mechanisms in contrast to previously studied antiinflammatory
sepsis therapies, making it a biologically plausible novel approach to treat
septic shock.