Vascular Responses and Biological Product Safety and Efficacy

Principal Investigator: Felice D’Agnillo, PhD
Office / Division / Lab: OBRR / DH / LBVB

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Overview

Public Health Issue: Our research addresses two main areas. (i) Hemoglobin-based oxygen carriers (HBOCs) are being developed as oxygen therapeutics for use in trauma resuscitation and surgery. A major safety issue of current HBOCs is their adverse reactivity in the vascular system. To better understand these adverse events, we are investigating the mechanisms of HBOC-mediated toxicity in endothelial cell culture and small animal models of trauma and infection. (ii) Anthrax is a major bioterrorism threat to public health and security. Blood vessel dysfunction at the level of the vascular endothelium is a critical factor in the serious life-threatening consequences of anthrax infection. To address this, we are developing human endothelial cell culture assays to examine the safety and effectiveness of therapies against anthrax toxin, the major virulence factor of Bacillus anthracis. These efforts will also provide insight into the design of safer and more effective therapeutics and new diagnostics.

Regulatory Contribution: (i) Improved preclinical models and biomarkers to evaluate HBOC safety will directly enhance our regulatory approach and assessment of these products and stimulate the development of strategies to limit their adverse reactivity. This knowledge will increase the speed of product development, provide guidance to sponsors, and expand academic and industrial interest in these products. (ii) New anthrax therapies are urgently needed to target the toxin-mediated stages of the disease when antibiotic therapy is no longer effective. Developing relevant preclinical models to evaluate the safety and effectiveness of anthrax therapeutics will enhance the informed review of current and future therapies submitted to the FDA.

Research Approach: Our research focuses on (i) developing endothelial cell culture assays and small animal models to evaluate the safety and efficacy of HBOCs and anthrax therapies, (ii) defining the mechanisms of vascular injury or dysfunction induced by HBOCs and anthrax toxin, and (iii) identifying and assessing strategies to improve the safety and efficacy of HBOCs and anthrax therapies.

Mission Relevance & Outcomes: The overall focus of this research program is to develop cell culture and animal preclinical models to study the safety and efficacy of HBOCs and anthrax therapies. Understanding the underlying mechanisms of vascular dysfunction induced by HBOCs and anthrax toxin will also promote the design of safer and more effective therapeutics and facilitate the establishment of useful biomarkers.

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Publications

Biochem J 2008 Sep 15;414(3):461-9
Acellular haemoglobin attenuates hypoxia-inducible factor-1alpha (HIF-1alpha) and its target genes in haemodiluted rats.
Manalo DJ, Buehler PW, Baek JH, Butt O, D'agnillo F, Alayash AI

J Immunol 2008 Jun 1;180(11):7516-24
Anthrax Lethal Toxin Enhances TNF-Induced Endothelial VCAM-1 Expression via an IFN Regulatory Factor-1-Dependent Mechanism.
Warfel JM, D'Agnillo F

J Pharmacol Exp Ther 2007 Oct;323(1):49-60
Effects of endogenous ascorbate on oxidation, oxygenation and toxicokinetics of cell-free modified hemoglobin after exchange transfusion in rat and guinea pig.
Buehler PW, D'Agnillo F, Hoffman V, Alayash AI

Infect Immun 2007 Aug;75(8):3935-40
The large clostridial toxins from C. sordellii and C. difficile repress glucocorticoid receptor activity.
Tait AS, Dalton M, Geny B, D'Agnillo F, Popoff MR, Sternberg EM

Expert Opin Biol Ther 2007 May;7(5):665-675
First-generation blood substitutes: what have we learned? Biochemical and physiological perspectives.
Alayash AI, D'Agnillo F, Buehler PW

Biochem Biophys Res Commun 2005 Oct 7;337(4):1249-1256
Anthrax lethal toxin enhances cytokine-induced VCAM-1 expression on human endothelial cells.
Steele AD, Warfel JM, D'Agnillo

Am J Pathol 2005 Jun;166(6):1871-81
Anthrax lethal toxin induces endothelial barrier dysfunction.
Warfel JM, Steele AD, D'Agnillo

Am J Physiol Heart Circ Physiol 2004 Oct;287(4):H1875-82
Redox active hemoglobin enhances lipopolysaccharide-induced injury to cultured bovine endothelial cells.
D'Agnillo F