title: Inflammatory gene expression in response to sub-lethal ricin exposure in Balb/c mice.
abstract: The toxin ricin has been shown to cause inflammatory lung damage, leading to pulmonary oedema and, at higher doses, mortality. In order to understand the genetic basis of this inflammatory cascade a custom microarray platform (1509 genes) directed towards immune and inflammatory markers was used to investigate the temporal expression profiles of genes in a Balb/c mouse model of inhalational ricin exposure. To facilitate examination of those genes involved in both inflammatory cascades and wound repair the dose which was investigated was sub-lethal across a 96-h time course. Histopathology of the lung was mapped across the time course and genetic responses considered in the context of overall lung pathology. Six hundred and eighty-five genes were found to be statistically significantly different compared to controls, across the time course and these genes have been investigated in the context of their biological function in ricin poisoning. As well as confirming key inflammatory markers associated with ricin intoxication (TNFalpha and IL1beta) several pathways that are altered in expression were identified following pulmonary exposure to ricin. These genes included those involved in cytokine-cytokine signalling cascades (IL1, IL1r, IL1r2, Ccl 4, 6, 10), focal adhesion (Fn1, ICAM1) and tissue remodelling (VEGF, Pim1). Furthermore, the observed alteration in expression of matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) indicates a key role in membrane integrity and cellular adhesion in ricin poisoning. Data captured using this transcriptomic approach could be used to develop a specific approach to the treatment of inhalational ricin exposure. This work was conducted as part of a wider programme of work to compare a number of militarily relevant lung damaging agents, with a view to establishing a rational basis for the identification of more generic medical countermeasures.
authors.affiliation: Immunotoxicology Group, Biology, Biomedical Sciences, Defence Science and Technology Laboratory, Salisbury, Wiltshire, SP4 0JQ, UK. jdavid@dstl.gov.uk
authors.forename: Jonathan
authors.initials: J
authors.lastname: David
authors.forename: Lucy J
authors.initials: LJ
authors.lastname: Wilkinson
authors.forename: Gareth D
authors.initials: GD
authors.lastname: Griffiths
mesh_terms: D000280:Administration, Inhalation; D000818:Animals; D018925:Chemokines / Q000096:biosynthesis / Q000235:genetics; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D005260:Female; D007202:Indicators and Reagents; D007249:Inflammation / Q000235:genetics*; D018836:Inflammation Mediators; D008168:Lung / Q000473:pathology; D020782:Matrix Metalloproteinases / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D020411:Oligonucleotide Array Sequence Analysis; D011654:Pulmonary Edema / Q000139:chemically induced / Q000235:genetics / Q000473:pathology; D012313:RNA / Q000096:biosynthesis / Q000302:isolation & purification; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012276:Ricin / Q000633:toxicity*; D019714:Tissue Inhibitor of Metalloproteinases / Q000096:biosynthesis / Q000235:genetics
chemical_list: D018925:Chemokines; D016207:Cytokines; D007202:Indicators and Reagents; D018836:Inflammation Mediators; D019714:Tissue Inhibitor of Metalloproteinases; D012313:RNA; D012276:Ricin; D020782:Matrix Metalloproteinases