Plasma‐derived human antithrombin attenuates ventilator‐induced coagulopathy but not inflammation in a Streptococcus pneumoniae pneumonia model in rats

Arazi, Hamid; Haitsma, Jack J.; Hofstra, JJ; Florquin, Sandrine; Santos, Claudia C. dos; Streutker, Cathy; Zhang, H.; Levi, Marcel; Slutsky, Arthur S.; Schultz, Marcus J.

doi:10.1111/j.1538-7836.2012.04622.x

Cited by 2 publications

(4 citation statements)

References 61 publications

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“…Differences in the applied animal models may attribute to the different outcomes as discussed below. This study confirms previous research [18, 19] that AT does not affect pulmonary or systemic inflammatory parameters in in vivo models [26].…”

Section: Discussionsupporting

confidence: 93%

“…Interestingly, this present experiment did not find a beneficial effect of AT on pulmonary coagulopathy and thereby contradicts previous studies administering the same dosage of AT [18, 19]. Differences in the applied animal models may attribute to the different outcomes as discussed below.…”

Section: Discussioncontrasting

confidence: 69%

“…Many previous preclinical studies chose to give AT or A1PI as a pre-treatment, hence before induction of lung injury—which is clinically less relevant [29, 30, 35, 36]. With regard to drug dosage, a dosage of 250 IU/kg has been proven to attenuate enhanced coagulation, but did not have a beneficial effect on inflammation in rat models [18, 19]. With regard to A1PI, the dosage used proved to be effective in previous murine models [20, 29].…”

Section: Discussionmentioning

confidence: 99%

“…Control animals received neither LPS, nor ventilation, nor treatment ( N = 4). Administered dosages of intervention drugs were based on previous preclinical research [18–20].…”

Section: Methodsmentioning

confidence: 99%

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Antithrombin plus alpha-1 protease inhibitor does not affect coagulation and inflammation in two murine models of acute lung injury

Juschten

Ingelse

Maas

et al. 2019

ICMx

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Background In acute respiratory distress syndrome (ARDS), uncontrolled production of activators of coagulation and proinflammatory mediators results in a shift from an adequate local innate immune response to hypercoagulability and inflammation. This study aimed to investigate whether the protease inhibitors antithrombin (AT) and alpha-1 protease inhibitor (A1PI) may attenuate an exaggerated pulmonary immune response. Methods Lung injury was induced either by single intranasal administration of lipopolysaccharide (LPS) (5 mg/kg) in BALB/c mice or by combination of an intravenous injection of LPS (10 mg/kg) with subsequent injurious ventilation using high tidal volumes (12–15 ml/kg) for 4 h in RccHan Wistar rats. Animals received either a single bolus of AT (250 IU/kg) or A1PI (60 mg/kg) alone or in combination, with or without intravenous low-dose heparin (100 U/kg). Control animals received saline. Additional controls received neither LPS, nor ventilation, nor treatment. Endpoints were local and systemic markers of coagulation, e.g., thrombin–antithrombin complexes (TATc), and inflammation, e.g., interleukin-6. Results Both lung injury models resulted in a pronounced immune response within the pulmonary compartment shown by elevated levels of markers of coagulation and inflammation. The two-hit lung injury model also induced profound systemic coagulopathy and inflammation. Monotherapy with AT or A1PI did not reduce pulmonary coagulopathy or inflammation in any lung injury model. Nor did combination therapy with AT and A1PI result in a decrease of coagulation or inflammatory parameters. AT markedly reduced systemic levels of TATc in the two-hit lung injury model. Systemic inflammation was not affected by the different interventions. Additional administration of heparin did not lead to macroscopic bleeding incidences. Conclusions In two different murine models of acute lung injury, neither single therapy with AT or A1PI nor combination of both agents attenuates the pronounced pulmonary coagulation or inflammatory response.

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Section: Discussionsupporting

confidence: 93%

Section: Discussioncontrasting

confidence: 69%

Section: Discussionmentioning

confidence: 99%

“…Control animals received neither LPS, nor ventilation, nor treatment ( N = 4). Administered dosages of intervention drugs were based on previous preclinical research [18–20].…”

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

Antithrombin plus alpha-1 protease inhibitor does not affect coagulation and inflammation in two murine models of acute lung injury

Juschten

Ingelse

Maas

et al. 2019

ICMx

View full text Add to dashboard Cite

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Refinement of Animal Models of Sepsis and Septic Shock

Lilley¹,

Armstrong

Clark

et al. 2015

Shock

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This report aims to facilitate the implementation of the Three Rs (replacement, reduction, and refinement) in the use of animal models or procedures involving sepsis and septic shock, an area where there is the potential of high levels of suffering for animals. The emphasis is on refinement because this has the greatest potential for immediate implementation. Specific welfare issues are identified and discussed, and practical measures are proposed to reduce animal use and suffering as well as reducing experimental variability and increasing translatability. The report is based on discussions and submissions from a nonregulatory expert working group consisting of veterinarians, animal technologists, and scientists with expert knowledge relevant to the field.

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Plasma‐derived human antithrombin attenuates ventilator‐induced coagulopathy but not inflammation in a Streptococcus pneumoniae pneumonia model in rats

Abstract: Plasma-derived human AT attenuates ventilator-induced coagulopathy, but not inflammation and bacterial outgrowth in a S. pneumoniae pneumonia model in rats.

Cited by 2 publications

References 61 publications

Antithrombin plus alpha-1 protease inhibitor does not affect coagulation and inflammation in two murine models of acute lung injury

Antithrombin plus alpha-1 protease inhibitor does not affect coagulation and inflammation in two murine models of acute lung injury

Refinement of Animal Models of Sepsis and Septic Shock

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