Haptoglobin improves shock, lung injury, and survival in canine pneumonia
| Autor: | Mark T. Gladwin, Juan J Lertora, Roy R. Hantgan, H. Shaw Warren, Kenneth E. Remy, Irene Cortés-Puch, Benjamin M Pockros, Xiaohua Liu, Junfeng Sun, Charles Natanson, Andreas Perlegas, Jing Feng, Harvey G. Klein, Steven B. Solomon, Daniel B. Kim-Shapiro |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Staphylococcus aureus medicine.medical_treatment Iron Cardiovascular Abnormalities Anti-Inflammatory Agents Kaplan-Meier Estimate 030204 cardiovascular system & hematology Lung injury Pulmonary Artery Proinflammatory cytokine Sepsis 03 medical and health sciences 0302 clinical medicine Dogs Intensive care Medicine Animals Humans Haptoglobin binding biology Haptoglobins business.industry Septic shock Haptoglobin General Medicine Lung Injury Pneumonia medicine.disease Shock Septic Immunity Innate Anti-Bacterial Agents Disease Models Animal 030104 developmental biology Cytokine Hematocrit Immunology biology.protein Cytokines Blood Gas Analysis business Research Article |
| Zdroj: | JCI insight. 3(18) |
| ISSN: | 2379-3708 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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