Dataset Information

Bacillus anthracis cell wall peptidoglycan but not lethal or edema toxins produces changes consistent with disseminated intravascular coagulation in a rat model.

ABSTRACT:

Background

Disseminated intravascular coagulation (DIC) appears to be important in the pathogenesis of Bacillus anthracis infection, but its causes are unclear. Although lethal toxin (LT) and edema toxin (ET) could contribute, B. anthracis cell wall peptidoglycan (PGN), not the toxins, stimulates inflammatory responses associated with DIC.

Methods and results

To better understand the pathogenesis of DIC during anthrax, we compared the effects of 24-hour infusions of PGN, LT, ET, or diluent (control) on coagulation measures 6, 24, or 48 hours after infusion initiation in 135 rats. No control recipient died. Lethality rates (approximately 30%) did not differ among PGN, LT, and ET recipients (P = .78). Thirty-three of 35 deaths (94%) occurred between 6 and 24 hours after the start of challenge. Among challenge components, PGN most consistently altered coagulation measures. Compared with control at 6 hours, PGN decreased platelet and fibrinogen levels and increased prothrombin and activated partial thromboplastin times and tissue factor, tissue factor pathway inhibitor, protein C, plasminogen activator inhibitor (PAI), and thrombin-antithrombin complex levels, whereas LT and ET only decreased the fibrinogen level or increased the PAI level (P ? .05). Nearly all effects associated with PGN infusion significantly differed from changes associated with toxin infusion (P ? .05 for all comparisons except for PAI level).

Conclusion

DIC during B. anthracis infection may be related more to components such as PGN than to LT or ET.

SUBMITTER: Qiu P

PROVIDER: S-EPMC3749004 | biostudies-literature | 2013 Sep

REPOSITORIES: biostudies-literature

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Publications

Bacillus anthracis cell wall peptidoglycan but not lethal or edema toxins produces changes consistent with disseminated intravascular coagulation in a rat model.

Qiu Ping P Li Yan Y Shiloach Joseph J Cui Xizhong X Sun Junfeng J Trinh Loc L Kubler-Kielb Joanna J Vinogradov Evgeny E Mani Haresh H Al-Hamad Mariam M Fitz Yvonne Y Eichacker Peter Q PQ

The Journal of infectious diseases 20130603 6

<h4>Background</h4>Disseminated intravascular coagulation (DIC) appears to be important in the pathogenesis of Bacillus anthracis infection, but its causes are unclear. Although lethal toxin (LT) and edema toxin (ET) could contribute, B. anthracis cell wall peptidoglycan (PGN), not the toxins, stimulates inflammatory responses associated with DIC.<h4>Methods and results</h4>To better understand the pathogenesis of DIC during anthrax, we compared the effects of 24-hour infusions of PGN, LT, ET, o ...[more]

PMID: 23737601

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Project description:The thrombomodulin (TM)/activated protein C (APC) system plays an important role in maintaining the homeostasis of thrombosis and hemostasis and maintaining vascular integrity in vivo. TM expressed on vascular endothelium binds to thrombin, forming a 1:1 complex and acts as an anticoagulant. In addition, the thrombin-TM complex activates protein C to produce APC, which inactivates factors VIIIa and Va in the presence of protein S, thereby inhibiting further thrombin formation. Intriguingly, APC possesses anti-inflammatory as well as cytoprotective activities. Moreover, the extracellular domain of TM also possesses APC-independent anti-inflammatory and cytoprotective activities. Of note, the TM/APC system is compromised in disseminated intravascular coagulation (DIC) caused by sepsis due to various mechanisms, including cleavage of cell-surface TM by exaggerated cytokines and proteases produced by activated inflammatory cells. Thus, it is reasonable to assume that reconstitution of the TM/APC system by recombinant proteins would alleviate sepsis and DIC. On the basis of the success of the Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) trial, the FDA approved the use of recombinant human APC (rhAPC) for severe sepsis patients in 2002. However, subsequent clinical trials failed to show clinical benefits for rhAPC, and an increased incidence of hemorrhage-related adverse events was noted, which prompted the industry to withdraw rhAPC from the market. On the other hand, recombinant human soluble TM (rTM) has been used for treatment of individuals with DIC since 2008 in Japan, and a phase III clinical trial evaluating the efficacy of rTM in severe sepsis patients with coagulopathy is now ongoing in the USA, South America, Asia, Australia, European Union, and other countries. This review article discusses the molecular mechanisms by which the TM/APC system produces anticoagulant as well as anti-inflammatory and cytoprotective activities in septic DIC patients.

Dataset Information

Bacillus anthracis cell wall peptidoglycan but not lethal or edema toxins produces changes consistent with disseminated intravascular coagulation in a rat model.

Background

Methods and results

Conclusion

Publications

Bacillus anthracis cell wall peptidoglycan but not lethal or edema toxins produces changes consistent with disseminated intravascular coagulation in a rat model.

Similar Datasets

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