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Haptoglobin improves shock, lung injury, and survival in canine pneumonia.

ABSTRACT: 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.

SUBMITTER: Remy KE

PROVIDER: S-EPMC6237235 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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Haptoglobin improves shock, lung injury, and survival in canine pneumonia.

Remy Kenneth E KE Cortés-Puch Irene I Solomon Steven B SB Sun Junfeng J Pockros Benjamin M BM Feng Jing J Lertora Juan J JJ Hantgan Roy R RR Liu Xiaohua X Perlegas Andreas A Warren H Shaw HS Gladwin Mark T MT Kim-Shapiro Daniel B DB Klein Harvey G HG Natanson Charles C

JCI insight 20180920 18

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 ...[more]

PMID: 30232287

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Project description:BackgroundNeonatal sepsis represents a unique therapeutic challenge owing to an immature immune system. Necroptosis is a form of programmed cell death that has been identified as an important mechanism of inflammation-induced cell death. Receptor-interacting protein kinase 1 plays a key role in mediating this process. We hypothesized that pharmacologic blockade of receptor-interacting protein kinase 1 activity would be protective in neonatal sepsis.MethodsSepsis was induced in C57BL/6 mouse pups (5-7 days old) by intraperitoneal injection of adult cecal slurry. At 1 hour after cecal slurry injection, the receptor-interacting protein kinase 1 inhibitor necrostatin-1 (10 µg/g body weight) or vehicle (5% dimethyl sulfoxide in phosphate buffered saline) was administered via retro-orbital injection. At 20 hours after cecal slurry injection, blood and lung tissues were collected for various analyses.ResultsAt 20 hours after sepsis induction, vehicle-treated pups showed a marked increase in serum levels of interleukin 6, interleukin 1-beta, and interleukin 18 compared to sham. With necrostatin-1 treatment, serum levels of interleukin 6, interleukin 1-beta, and interleukin 18 were decreased by 77%, 81%, and 63%, respectively, compared to vehicle. In the lungs, sepsis induction resulted in a 232-, 10-, and 2.8-fold increase in interleukin 6, interleukin 1-beta, and interleukin 18 mRNA levels compared to sham, while necrostatin-1 treatment decreased these levels to 40-, 4-, and 0.8-fold, respectively. Expressions of the neutrophil chemokines keratinocyte chemoattractant and macrophage-inflammatory-protein-2 were also increased in the lungs in sepsis, while necrostatin-1 treatment decreased these levels by 81% and 61%, respectively, compared to vehicle. In addition, necrostatin-1 treatment significantly improved the lung histologic injury score and decreased lung apoptosis in septic pups. Finally, treatment with necrostatin-1 increased the 7-day survival rate from 0% in the vehicle-treated septic pups to 29% (P = .11).ConclusionInhibition of receptor-interacting protein kinase 1 by necrostatin-1 decreases systemic and pulmonary inflammation, decreases lung injury, and increases survival in neonatal mice with sepsis. Targeting the necroptosis pathway might represent a new therapeutic strategy for neonatal sepsis.

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Haptoglobin improves shock, lung injury, and survival in canine pneumonia.

Publications

Haptoglobin improves shock, lung injury, and survival in canine pneumonia.

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