1. ¹Division of Nephrology, Department of Medicine, University of Virginia Health Sciences Center, Charlottesville, VA, USA
2. ²Department of Microbiology, University of Virginia Health Sciences Center, Charlottesville, VA, USA
3. ³Department of Pediatrics, Research Institute for Children, Louisiana State University Health Sciences Center, New Orleans, LA, USA
4. ⁴Department of Microbiology, Research Institute for Children, Louisiana State University Health Sciences Center, New Orleans, LA, USA

Correspondence: Dr TG Obrig, PhD, Department of Microbiology and Immunology, 660 W. Redwood St., Baltimore, MD 21201, USA. E-mail: Tobrig@som.umaryland.edu

Received 12 March 2008; Revised 29 May 2008; Accepted 7 June 2008; Published online 8 September 2008.

Abstract

Effects in the liver of fatal intoxication with the binary toxin ricin are unclear. We report a robust neutrophil influx into the liver of C57BL/6 mice after lethal parenteral ricin challenge, occurring in peri-portal and centro-lobular hepatic areas within 2 h, followed by the abrupt disappearance of hepatic macrophages/Kupffer cells. Chemokine profiles determined by microarray, ribonuclease protection assays, northern blotting, and enzyme-linked immunosorbent assays showed rapid (2 h) upregulation and persistence of those for neutrophils (CXCL1/KC, CXCL2/MIP-2) and monocytes (CCL2/MCP-1). Red blood cell pooling (8–12 h), loss of hepatocyte glycogen (8–48 h) associated with progressive hypoglycemia, fibrin deposition (24–48 h), and death (72–96 h) followed. Monoclonal antibody to ricin A chain, administered intravenously, blunted hypoglycemia, and abrogated death. This outcome was observed when anti-ricin antibody was given before toxin exposure as well as when administered approximately 10 h after toxin exposure. Targeting antibody to specific amino-acid sequences on the ricin A chain (HAEL and QXXWXXA) was critical to the therapeutic effect. Re-emergence of liver macrophages/Kupffer cells and replenishment of glycogen in previously depleted hepatocytes preceded full recovery of the host. These data identify critical events for liver injury and healing in ricin intoxication, as well as a new means and specific targets for post-exposure therapeutic intervention.