Characterization of the baboon responses to Shiga-like toxin: descriptive study of a new primate model of toxic responses to Stx-1.
The baboon response to intravenous infusion of Shiga toxin 1 (Stx-1) varied from acute renal failure, proteinuria, hyperkalemia, and melena with minimal perturbation of host inflammatory and hemostatic systems (high-dose group, 2.0 microg/kg; n = 5) to renal failure with hematuria, proteinuria, thrombocytopenia, schistocytosis, anemia, and melena (low-dose group, 0.05 to 0.2 microg/kg; n = 8). Both groups exhibited renal shutdown and died in 57 hours or less. Both groups produced urine that was positive for tumor necrosis factor and interleukin-6 although neither of these cytokines was detectable (</=5 ng/ml) in the general circulation. Light and electron microscopy showed organelle disintegration and necrosis of the renal proximal tubular epithelium and of the intestinal mucosal epithelium at the tips of the microvilli, both of which were previously shown to bear Gb3 receptors. The renal distal tubular epithelium was spared. The renal proximal tubular epithelial changes were accompanied by swelling of visceral epithelial cells (podocytes) and by swelling and detachment of endothelial cells of the glomerular capillaries. In addition, all of the animals receiving low-dose Stx-1 showed microvascular fibrin deposition and thrombosis in renal glomerular and peritubular capillaries in association with a fall in hematocrit and platelet count and a rise in schistocyte count. The gastrointestinal villous tip lesions were accompanied by varying degrees of mucosal and submucosal congestion, hemorrhage, or necrosis. Electron microscopic images of cerebral cortex and cerebellum showed diffuse unraveling of myelin sheaths with occasional disintegration of neuronal cell bodies. In contrast to the gastrointestinal mucosal and renal proximal tubular epithelium, the Gb3 receptor glycolipid of the renal glomerular and neuronal tissues as determined using toxin overlay thin-layer chromatography plates was below the limit of detection (<13 pM/g wet tissue). We conclude that, depending on the status of the host and amount of toxin infused, Stx-1 can produce a variety of responses ranging from damage to cells carrying the Gb3 receptor (renal proximal tubular epithelial cells and gastrointestinal mucosa) to damage to renal glomerular tissues with microvascular thrombosis as a result of the host's inflammatory response localized to the kidney. We conclude that this thrombotic coagulopathy arises from local changes in the kidney because the appearance of host inflammatory mediators was limited to the urine. This suggests that the initial host response is localized in the kidney, and that the systemic thrombocytopenia, anemia, and schistocytosis may arise secondarily.
Taylor
F B
FB
Cardiovascular Biology Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma 73104, USA.
Tesh
V L
VL
DeBault
L
L
Li
A
A
Chang
A C
AC
Kosanke
S D
SD
Pysher
T J
TJ
Siegler
R L
RL
D000818:Animals; D001427:Bacterial Toxins / Q000633:toxicity*; D001921:Brain / Q000473:pathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D006463:Hemolytic-Uremic Syndrome / Q000097:blood / Q000139:chemically induced* / Q000652:urine; D015850:Interleukin-6 / Q000097:blood / Q000652:urine; D007413:Intestinal Mucosa / Q000473:pathology; D007668:Kidney / Q000473:pathology; D008297:Male; D010215:Papio; D022603:Shiga Toxins; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000652:urine
D001427:Bacterial Toxins; D015850:Interleukin-6; D022603:Shiga Toxins; D014409:Tumor Necrosis Factor-alpha