Post-exposure targeting of specific epitopes on ricin toxin abrogates toxin-induced hypoglycemia, hepatic injury, and lethality in a mouse model
| Autor: | Tom G. Obrig, Regina M. Seaner, Seth H. Pincus, Matthew K. Stone, James K. Roche, Lisa K. Gross, Matthew H. Lindner |
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| Rok vydání: | 2008 |
| Předmět: |
Male
Kupffer Cells Ricin Pharmacology medicine.disease_cause Article Pathology and Forensic Medicine Epitopes Mice chemistry.chemical_compound Antibody Specificity medicine Animals Chemical Warfare Agents Molecular Biology Oligonucleotide Array Sequence Analysis Liver injury biology Toxin Poisoning Monocyte Antibodies Monoclonal Recovery of Function Cell Biology medicine.disease Hypoglycemia CXCL1 Disease Models Animal CXCL2 medicine.anatomical_structure chemistry Hepatocyte Immunology Hepatocytes biology.protein Antibody Glycogen |
| Zdroj: | Laboratory Investigation. 88:1178-1191 |
| ISSN: | 0023-6837 |
| DOI: | 10.1038/labinvest.2008.83 |
| Popis: | The role of the liver in fatal intoxication with the binary toxin ricin is undefined. Means to reverse pathological events in the liver and to gain host survival after exposure to this toxin have not been described. We report a robust 7/4+ neutrophil influx into the liver of C57BL/6 mice after parenteral ricin challenge. This influx occurs in peri-portal and centro-lobular hepatic areas within 2 hours, followed by the abrupt disappearance of hepatic macrophages/Kupffer cells at 8–12 hours. Microarray, ribonuclease protection assays, Northern blotting, and enzyme-linked immunosorbent assays showed chemokine mRNA and protein for neutrophils (CXCL1/KC, CXCL2/MIP-2) and macrophages (CCL2/MCP-1) increased in the liver by 2 hours and persisted for more than 40 hours after ricin injection. A specific sequence of intra-hepatic pathophysiological events followed ricin injection, including red blood cell pooling (8–12 h), loss of hepatocyte glycogen (8–48 h) associated with progressive hypoglycemia, and fibrin deposition (24–48 h). Monoclonal antibody to ricin A chain administered intravenously blunted hypoglycemia and abrogated death. This outcome was observed when anti-ricin antibody was present prior to toxin exposure or when administered up to 10 hours post-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 define the pathobiology of liver injury in ricin intoxication, as well as a new means and specific targets for post-exposure therapeutic intervention. |
| Databáze: | OpenAIRE |
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