Recombinant Activated Protein C Induces Dose-Dependent Changes in Inflammatory Mediators, Tissue Damage, and Apoptosis in in Vivo Rat Model of Sepsis

Shires, G. Tom; Fisher, Orna; Murphy, Patrick S.; Williams, Shelley; Barber, Annabel; Johnson, Gayle C.; Davis, Brett A.; Pahulu, Stacey

doi:10.1089/sur.2006.082

Cited by 7 publications

(2 citation statements)

References 29 publications

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“…Over the ensuing quarter century, many of his pupils continued to formulate seminal concepts underlying our understanding of injury, infections, and malignant diseases. Indeed, Tom's last published manuscript [1] and editorial commentary [2] continued to demonstrate his commitment to the biology of injury. A sample of his professional progeny from those years underscores the passion for scientific and clinical excellence he instilled (Fig.…”

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confidence: 99%

The Evolution of an Inflammatory Response

Lowry¹

2009

Surgical Infections

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Background: The past 25 years have witnessed immense progress in our understanding of the systemic, tissue-specific, and cellular consequences of severe injury and infection. Despite such insights, considerable controversy remains regarding appropriate biologic and management interventions to prevent or ameliorate the associated adverse outcomes. Methods: A review of several scientific developments arising from studies initiated at Cornell University Medical College during the tenure of Dr. G. Tom Shires. The implications of those and subsequent studies are discussed. Results: An understanding of patient-specific variation and adaptability could direct individualized biologic and management interventions for severe injury and infection. Conclusion: Despite more detailed appreciation of the molecular mechanisms of danger and pathogen recognition and response biology, we have much to learn about the complexity of severe injury and infection. There is a great need to extend our investigation of these mechanisms to experimental and stress-modified clinical scenarios.

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confidence: 99%

The Evolution of an Inflammatory Response

Lowry¹

2009

Surgical Infections

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“…ED is also known to promote inflammation, thrombosis and vascular leakage (20–22) and to reduce levels of thrombomodulin and activated protein C (23–26). These pathophysiological events contribute to progression toward sepsis, multiple organ failure and death (25, 27). Thus, by reversing radiation-induced ED it may be possible to increase survival, delay onset of acute mortality and prevent late effects of radiation.…”

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confidence: 99%

Nuclear Countermeasure Activity of TP508 Linked to Restoration of Endothelial Function and Acceleration of DNA Repair

et al. 2016

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There is increasing evidence that radiation-induced damage to endothelial cells and loss of endothelial function may contribute to both acute radiation syndromes and long-term effects of whole-body nuclear irradiation. Therefore, several drugs are being developed to mitigate the effects of nuclear radiation, most of these drugs will target and protect or regenerate leukocytes and platelets. Our laboratory has demonstrated that TP508, a 23-amino acid thrombin peptide, activates endothelial cells and stem cells to revascularize and regenerate tissues. We now show that TP508 can mitigate radiation-induced damage to endothelial cells in vitro and in vivo. Our in vitro results demonstrate that human endothelial cells irradiation attenuates nitric oxide (NO) signaling, disrupts tube formation and induces DNA double-strand breaks (DSB). TP508 treatment reverses radiation effects on NO signaling, restores tube formation and accelerates the repair of radiation-induced DSB. The radiation-mitigating effects of TP508 on endothelial cells were also seen in CD-1 mice where systemic injection of TP508 stimulated endothelial cell sprouting from aortic explants after 8 Gy irradiation. Systemic doses of TP508 that mitigated radiation-induced endothelial cell damage, also significantly increased survival of CD-1 mice when injected 24 h after 8.5 Gy exposure. These data suggest that increased survival observed with TP508 treatment may be due to its effects on vascular and microvascular endothelial cells. Our study supports the usage of a regenerative drug such as TP508 to activate endothelial cells as a countermeasure for mitigating the effects of nuclear radiation.

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Administration of Human Protein-C concentrate prevents apoptotic brain cell death after experimental sepsis

Memos

Betrosian²,

Messaris

et al. 2009

Brain Research

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Recombinant Activated Protein C Induces Dose-Dependent Changes in Inflammatory Mediators, Tissue Damage, and Apoptosis in in Vivo Rat Model of Sepsis

Abstract: These data can assist in establishing an optimal dose and infusion time of this drug for extrapolation to therapy of human beings. The goal now is to elucidate these findings further so that the maximum benefit of the drug may be achieved with the least possible harmful effects.

Cited by 7 publications

References 29 publications

The Evolution of an Inflammatory Response

The Evolution of an Inflammatory Response

Nuclear Countermeasure Activity of TP508 Linked to Restoration of Endothelial Function and Acceleration of DNA Repair

Administration of Human Protein-C concentrate prevents apoptotic brain cell death after experimental sepsis

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