Role of p38 MAP kinase pathway in a toxin-induced model of hemolytic uremic syndrome

Abstract

The role of proinflammatory cytokines in a rat model of toxin-induced hemolytic uremic syndrome (HUS) was studied. Male Sprague-Dawley rats underwent continuous saline infusion (6 ml/h) via a tail vein and received a bolus injection of saline (control), lipopolysaccharide (LPS, 10 microg/100 g body weight), ricin (6.7 microg/100 g body weight), or ricin with LPS (ricin+LPS). They were then observed for 8 h. Blood samples and kidney tissues were obtained at the end of the experiment. The effects of FR 167653, a potent inhibitor of interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha) production, were also examined in ricin+LPS-treated rats. Only ricin+LPS-treated rats developed significant thrombocytopenia, hemolysis, and oliguric acute renal failure with extensive glomerular thrombotic microangiopathy, which was characterized by glomerular microthrombi and apoptosis of glomerular endothelial cells. Thrombotic microangiopathy was not detected in other organs, including the brain, liver, spleen, pancreas, lung, colon, and intestine. Significantly elevated levels of serum IL-1beta and TNF-alpha were detected only in ricin+LPS-treated rats. Treatment of ricin+LPS-treated rats with FR 167653 significantly reduced the serum levels of IL-1beta and TNF-alpha, accompanied by improvement of the oliguric renal failure and glomerular thrombotic microangiopathy. These findings indicate that the increased serum levels of IL-1beta and TNF-alpha, which probably result in the apoptosis of glomerular endothelial cells, play a pivotal role in the development of this rat model of toxin-induced HUS. The findings also suggest that inhibition of these proinflammatory cytokines may prevent the development of HUS.

Shiga Toxin 2 Targets the Murine Renal Collecting Duct Epithelium

“…7C). The initial increase in urine osmolality was reproduced by injection with LPS alone (data not shown), as published previously (17). Mice given Stx2 plus LPS or Stx2 alone developed polyuria and osmotically dilute urine between 48 and 72 h postinjection (Fig.…”

Lethal Ricin Intoxication in Two Adult Dogs: Toxicologic and Histopathologic Findings

“…This ricin-induced lesion has been proposed as a model for hemolytic uremia syndrome. 9,22 In both dogs in the current study, several renal changes could be detected, but the presence of fibrin thrombi could not be demonstrated in the glomerular capillary loops, perhaps because of species differences, the possibility that the rodents were sacrificed after advanced toxicosis occurred, or both. 9,22,23 Another explanation for the absence of fibrin deposits could be fibrinolysis.…”

“…1 Clearly, similar lesions can be seen in different species, but some of them are only described in laboratory models. 9,22,23 In experimental model studies with rats and mice, the major lesion associated with a lethal dose of ricin was impairment of renal function with a typical histopathologic lesion called ''glomerular thrombotic microangiopathy.'' This ricin-induced lesion has been proposed as a model for hemolytic uremia syndrome.…”

Proinflammatory responses of human airway cells to ricin involve stress-activated protein kinases and NF-κB

“…It is generally believed that the primary targets of ricin intoxication are endothelial cells (20) and macrophages (6). Treatment of endothelial cells results in apoptosis (6,31,43).…”