Increased susceptibility of aged rats to haemorrhage and intravascular hypercoagulation following endotoxin administered in a generalized Shwartzman regime

Carthew, P.; Dorman, B.M.; Edwards, Richard E.

doi:10.1016/s0021-9975(08)80200-9

Cited by 7 publications

(3 citation statements)

References 22 publications

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“…Elderly individuals are susceptible to endotoxin-induced effects than the young, 14 and aged rats demonstrate increased susceptibility to hemorrhage and intravascular hypercoagulation following endotoxin administration. 15 These LPS-mediated changes result in an increased mortality of aged rats as compared to young rats. 15 In these studies, a larger increase in PAI-1 activity and a more significant decrease in the total PA activity were demonstrated in plasma of aged rats treated with endotoxin in comparison with young rats.…”

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“…15 These LPS-mediated changes result in an increased mortality of aged rats as compared to young rats. 15 In these studies, a larger increase in PAI-1 activity and a more significant decrease in the total PA activity were demonstrated in plasma of aged rats treated with endotoxin in comparison with young rats. 16 These observations suggest that aged animals may tend to develop thrombosis due to the high anti-fibrinolytic potential in endotoxemia and in inflammatory processes.…”

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Aging Accelerates Endotoxin-Induced Thrombosis

Yamamoto

Shimokawa

et al. 2002

The American Journal of Pathology

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Although older subjects are susceptible to thrombosis under septic conditions, the underlying molecular mechanisms have not been fully elucidated. Since elevated plasminogen activator inhibitor-1 (PAI-1) primarily contributes to endotoxin-induced thrombosis, we first compared the induction of PAI-1 by lipopolysaccharide (LPS) between young and aged mice. The higher induction of PAI-1 antigen and mRNA with increased renal glomerular fibrin deposition was observed in LPS-treated aged mice compared to young mice. In situ hybridization analysis showed that the aging-associated induction of PAI-1 mRNA by LPS was pronounced in hepatocytes and in renal glomerular cells. The increased magnitude of the response of aged mice to lower doses of LPS was observed in terms of renal glomerular fibrin deposition and PAI-1 mRNA induction in the tissues. Furthermore, older PAI-1 deficient mice treated with LPS developed much less fibrin deposition in kidneys. Importantly, a larger induction of receptor molecules for LPS (eg, CD14 and Toll-like receptor 4) was demonstrated in LPS-treated aged mice as compared with young mice. The enhanced LPS signaling in aged mice was also demonstrated by the marked induction of nuclear factor-kappaB in the tissues after endotoxin treatment. As a consequence, increases in an inflammatory cytokine, tumor necrosis factor-alpha, were pronounced in plasma and tissues of LPS-treated aged mice. These results emphasize the key role played by PAI-1 in aging-associated deterioration in this thrombosis model, and suggest that the hyperresponse of PAI-1 gene to LPS results from the enhanced LPS signaling and the subsequent inflammatory response in aged mice.

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confidence: 99%

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confidence: 99%

Aging Accelerates Endotoxin-Induced Thrombosis

Yamamoto

Shimokawa

et al. 2002

The American Journal of Pathology

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“…The fibrin deposition in the glomerule was reported to increase in lipopolysaccharide (LPS)-treated aged mice (Yamamoto et al 2002). In addition, elderly individuals are more susceptible to inflammatory stimuli than the young, and aged rats demonstrate more serious inflammatory injury and an increased mortality following endotoxin administration as compared to young rats (Carthew et al 1991). However, whether an ageing-related hypercoagulation state enhances the susceptibility to inflammatory stimuli in elderly animals is as yet unclear.…”

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confidence: 99%

Roles of fibrin deposition and protease activated receptor-1 in renal cytokine/chemokine production and inflammatory cell infiltration in rats of different ages

Lin

Sun

Shu

et al. 2011

JAB

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The present study aimed to investigate the roles of fibrin deposition and protease activated receptor-1 (PAR-1) in renal cytokine/chemokine production and inflammatory cell infiltration in rats of different ages. Acute inflammation was induced by lipopolysaccharide (LPS) in rats which were then treated with tranexamic acid (TA), TA+urokinase (UK) or TA+low-molecular-weight heparin (HP). Fibrin deposition, inflammatory cells and expressions of PAR-1, monocyte chemoattractant protein-1 (MCP-1) and intercellular adhesion molecule 1 (ICAM-1) were detected. A reduction in fibrin deposition and PAR-1 expression in the LPS+TA+HP group was associated with decreased infiltration of inflammatory cells and down-regulated expressions of MCP-1 and ICAM-1. In the LPS+TA+UK group, the fibrin deposition, but not the PAR-1 expression, was reduced, However, the infiltration of inflammatory cells decreased and the expressions of MCP-1 and ICAM-1 down-regulated. There were significant differences in the fibrin deposition, infiltration of inflammatory cells and expression of PAR-1, MCP-1 and ICAM-1 between young and old rats undergoing the same treatment. These findings demonstrated that fibrin deposition plays more important roles than PAR-1 dose in cytokine/chemokine production and inflammatory cell infiltration in vivo, and ageing may deteriorate the fibrin deposition-induced production of cytokines/chemokines and infiltration of inflammatory cells.

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Pathological mechanisms of hepatic tumour formation in rats exposed chronically to dietary hexachlorobenzene

Carthew

Smith

1994

J of Applied Toxicology

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The chronic dietary administration of hexachlorobenzene (HCB) to rats for a year or more results in the formation of liver tumours described as hepatocellular carcinomas, hepatomas or haemangiomas. The hepatotoxicity of HCB, which is greatest in hamsters and rats, gives rise to peliosis and necrosis with haemosiderosis. This pattern of hepatotoxicity indicates vascular damage, which through haemosiderosis could increase not only the toxic effect of HCB to hepatocytes but also its tumourogenic potential. The present study confirmed vascular damage by the identification of widespread fibrin deposits in the livers of rats chronically exposed to HCB, using an antibody to rat fibrin. Based on our study we suggest that the formation of hepatomas and haemangiomas with elements of peliosis (cystic blood-filled cavities) could be explained by the compensatory hyperplastic responses to hepatocellular necrosis and by the simultaneous loss of hepatocellular cords. The accumulation of iron in the liver would strongly potentiate the development of hepatic tumours, as has been found in HCB and polychlorinated biphenyl-treated mice with iron overload. The implications of this non-genotoxic mechanism of hepatoma formation for the assessment of human health risk are discussed.

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Increased susceptibility of aged rats to haemorrhage and intravascular hypercoagulation following endotoxin administered in a generalized Shwartzman regime

Cited by 7 publications

References 22 publications

Aging Accelerates Endotoxin-Induced Thrombosis

Aging Accelerates Endotoxin-Induced Thrombosis

Roles of fibrin deposition and protease activated receptor-1 in renal cytokine/chemokine production and inflammatory cell infiltration in rats of different ages

Pathological mechanisms of hepatic tumour formation in rats exposed chronically to dietary hexachlorobenzene

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