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  • 1
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    Online Resource
    Neutrophil extracellular trap (NET) degradation attenuates acute lung injury and protects mice from ricin-induced acute respiratory distress syndrome (ARDS)
    The American Association of Immunologists ; 2023
    In:  The Journal of Immunology Vol. 210, No. 1_Supplement ( 2023-05-01), p. 70.05-70.05
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 210, No. 1_Supplement ( 2023-05-01), p. 70.05-70.05
    Abstract: ARDS is a life-threatening respiratory condition associated with pulmonary vascular hyperpermeability and loss of aerated lung tissue. Ricin is a plant-toxin derived from the seeds of Ricinus communis, irreversibly inactivates ribosomes and arrests protein synthesis. Pulmonary exposure to ricin represents a bona fide model for ARDS, is characterized by pulmonary inflammation with massive neutrophil recruitment and severe disruption of the alveolar-capillary barrier leading to pulmonary edema, compromised gas exchange and respiratory failure. We have shown that upon ricin exposure, neutrophil infiltration into lungs, a hallmark of ARDS, mediate proteolysis of junction proteins. Recently, there is an increasing concern about the deleterious effect of NETs in sterile inflammation, such as in ricin case. During NETosis, PAD4 drives histone citrullination and chromatin decondensation. Decondensed chromatin decorated with citrullinated histones (citH3) and cytoplasmic granular enzymes, such as MPO is expelled from the neutrophil. Herein, we show increasing levels of PAD4, citH3 and MPO in the BALF of ricin exposed mice. BALF neutrophils efficiently produced NETs which were associated with MPO and citH3. Immunohistology of lung sections upon ricin exposure demonstrated propagating NETosis. Treatment of ricin exposed mice with recombinant DNase, targeted against NET-associated extracellular DNA, administrated with anti-ricin antibodies, dramatically decreased the level of extracellular DNA and proinflammatory cytokines in the lungs and conferred higher protection levels to mice in comparison to sole administration of antitoxin. This data highlights the potential clinical benefit of NET inhibiting drugs in ARDS.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.210.Supp.70.05
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2023
    detail.hit.zdb_id: 1475085-5
    detail.hit.zdb_id: 3056-9
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  • 2
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    Clinical manifestations following intramuscular exposure of mice to a lethal dose of ricin
    The American Association of Immunologists ; 2019
    In:  The Journal of Immunology Vol. 202, No. 1_Supplement ( 2019-05-01), p. 187.32-187.32
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 202, No. 1_Supplement ( 2019-05-01), p. 187.32-187.32
    Abstract: Ricin a plant toxin derived from seeds of Ricinus communis, irreversibly inactivates ribosomes by site-specific depurination, thereby arresting cell protein synthesis, while its clinical manifestations following intramuscular exposure have not yet been investigated in depth. Here we report an extensive pathological study of intramuscular intoxication with a lethal dose of ricin in a murine model. Ricin injection caused neutrophilia, thrombocytopenia and coagulopathy. Although histopathological alternations including hemorrhages, vessel congestion and focal necrosis were observed in various organs, major insults were limited to the spleen, bone marrow (BM) and cardiovascular system. Intensive atrophy, evident in the BM and splenic white pulps, were accompanied be severe depletion of megakaryocytes in both organs. Moreover, splenic T and B lymphocytes, NK cells, macrophages and dendritic cells decreased significantly. The most striking damage was in the heart, where we observed diffuse hemorrhages, myocyte disconnection, loss of striation, interstitial edema, collagen deposition and elevated levels of serum cardiac troponin. Finally, echocardiography revealed marked thickening of the walls, along with sequential decrease in left ventricular volume. These were accompanied by a significant reduction in stroke volume and cardiac output, while the ejection fraction remained unaltered. Measurements of the toxin direct catalytic performance in the spleen, BM and heart of the ricin-intoxicated mice revealed no substantial 28S rRNA depurination. The lack of measurable ricin catalytic activity in conjunction with the striking clinical disorders observed, suggests that ricin affects these organs in an indirect manner.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.202.Supp.187.32
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2019
    detail.hit.zdb_id: 1475085-5
    detail.hit.zdb_id: 3056-9
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  • 3
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    Post-Exposure Anti-Ricin Treatment Protects Swine against Lethal Systemic and Pulmonary Exposures
    MDPI AG ; 2020
    In:  Toxins Vol. 12, No. 6 ( 2020-05-28), p. 354-
    Details
    In: Toxins, MDPI AG, Vol. 12, No. 6 ( 2020-05-28), p. 354-
    Abstract: Ricin, a plant-derived toxin originating from the seeds of Ricinus communis (castor bean plant), is one of the most lethal toxins known. To date, there is no approved post-exposure therapy for ricin exposures. This work demonstrates for the first time the therapeutic efficacy of equine-derived anti-ricin F(ab’)2 antibodies against lethal pulmonary and systemic ricin exposures in swine. While administration of the antitoxin at 18 h post-exposure protected more than 80% of both intratracheally and intramuscularly ricin-intoxicated swine, treatment at 24 h post-exposure protected 58% of the intramuscular-exposed swine, as opposed to 26% of the intratracheally exposed animals. Quantitation of the anti-ricin neutralizing units in the anti-toxin preparations confirmed that the disparate protection conferred to swine subjected to the two routes of exposure stems from variance between the two models. Furthermore, dose response experiments showed that approximately 3 times lesser amounts of antibody are needed for high-level protection of the intramuscularly compared to the intratracheally intoxicated swine. This study, which demonstrates the high-level post-exposure efficacy of anti-ricin antitoxin at clinically relevant time-points in a large animal model, can serve as the basis for the formulation of post-exposure countermeasures against ricin poisoning in humans.
    Type of Medium: Online Resource
    ISSN: 2072-6651
    URL: Article
    DOI: 10.3390/toxins12060354
    Language: English
    Publisher: MDPI AG
    Publication Date: 2020
    detail.hit.zdb_id: 2518395-3
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  • 4
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    Long-Term Pulmonary Damage in Surviving Antitoxin-Treated Mice following a Lethal Ricin Intoxication
    MDPI AG ; 2024
    In:  Toxins Vol. 16, No. 2 ( 2024-02-12), p. 103-
    Details
    In: Toxins, MDPI AG, Vol. 16, No. 2 ( 2024-02-12), p. 103-
    Abstract: Ricin, a highly potent plant-derived toxin, is considered a potential bioterrorism weapon due to its pronounced toxicity, high availability, and ease of preparation. Acute damage following pulmonary ricinosis is characterized by local cytokine storm, massive neutrophil infiltration, and edema formation, resulting in respiratory insufficiency and death. A designated equine polyclonal antibody-based (antitoxin) treatment was developed in our laboratory and proved efficacious in alleviating lung injury and increasing survival rates. Although short-term pathogenesis was thoroughly characterized in antitoxin-treated mice, the long-term damage in surviving mice was never determined. In this study, long-term consequences of ricin intoxication were evaluated 30 days post-exposure in mice that survived antitoxin treatment. Significant pulmonary sequelae were demonstrated in surviving antitoxin-treated mice, as reflected by prominent histopathological changes, moderate fibrosis, increased lung hyperpermeability, and decreased lung compliance. The presented data highlight, for the first time to our knowledge, the possibility of long-term damage development in mice that survived lethal-dose pulmonary exposure to ricin due to antitoxin treatment.
    Type of Medium: Online Resource
    ISSN: 2072-6651
    URL: Article
    DOI: 10.3390/toxins16020103
    Language: English
    Publisher: MDPI AG
    Publication Date: 2024
    detail.hit.zdb_id: 2518395-3
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  • 5
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    Online Resource
    Mice with induced pulmonary morbidities display severe lung inflammation and mortality following exposure to SARS-CoV-2
    American Society for Clinical Investigation ; 2021
    In:  JCI Insight Vol. 6, No. 12 ( 2021-6-22)
    Details
    In: JCI Insight, American Society for Clinical Investigation, Vol. 6, No. 12 ( 2021-6-22)
    Type of Medium: Online Resource
    ISSN: 2379-3708
    URL: Article
    URL: Article
    DOI: 10.1172/jci.insight.145916
    DOI: 10.1172/jci.insight.145916DS1
    Language: English
    Publisher: American Society for Clinical Investigation
    Publication Date: 2021
    detail.hit.zdb_id: 2874757-4
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  • 6
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    Short- and long-term outcomes of pulmonary exposure to a sublethal dose of ricin in mice
    Springer Science and Business Media LLC ; 2024
    In:  Scientific Reports Vol. 14, No. 1 ( 2024-05-21)
    Details
    In: Scientific Reports, Springer Science and Business Media LLC, Vol. 14, No. 1 ( 2024-05-21)
    Abstract: Ricin, an extremely potent toxin produced from the seeds of castor plant, Ricinus communis , is ribosome-inactivating protein that blocks cell-protein synthesis. It is considered a biological threat due to worldwide availability of castor beans, massive quantities as a by-product of castor oil production, high stability and ease of production. The consequence of exposure to lethal dose of ricin was extensively described in various animal models. However, it is assumed that in case of aerosolized ricin bioterror attack, the majority of individuals would be exposed to sublethal doses rather than to lethal ones. Therefore, the purpose of current study was to assess short- and long-term effects on physiological parameters and function following sublethal pulmonary exposure. We show that in the short-term, sublethal exposure of mice to ricin resulted in acute lung injury, including interstitial pneumonia, cytokine storm, neutrophil influx, edema and cellular death. This damage was manifested in reduced lung performance and physiological function. Interestingly, although in the long-term, mice recovered from acute lung damage and restored pulmonary and physiological functionality, the reparative process was associated with lasting fibrotic lesions. Therefore, restriction of short-term acute phase of the disease and management of long-term pulmonary fibrosis by medical countermeasures is expected to facilitate the quality of life of exposed survivors.
    Type of Medium: Online Resource
    ISSN: 2045-2322
    URL: Article
    DOI: 10.1038/s41598-024-62222-9
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2024
    detail.hit.zdb_id: 2615211-3
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  • 7
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    Implementation of Adenovirus-Mediated Pulmonary Expression of Human ACE2 in HLA Transgenic Mice Enables Establishment of a COVID-19 Murine Model for Assessment of Immune Responses to SARS-CoV-2 Infection
    MDPI AG ; 2021
    In:  Pathogens Vol. 10, No. 8 ( 2021-07-26), p. 940-
    Details
    In: Pathogens, MDPI AG, Vol. 10, No. 8 ( 2021-07-26), p. 940-
    Abstract: HLA transgenic mice are instrumental for evaluation of human-specific immune responses to viral infection. Mice do not develop COVID-19 upon infection with SARS-CoV-2 due to the strict tropism of the virus to the human ACE2 receptor. The aim of the current study was the implementation of an adenovirus-mediated infection protocol for human ACE2 expression in HLA transgenic mice. Transient pulmonary expression of the human ACE2 receptor in these mice results in their sensitisation to SARS-CoV-2 infection, consequently providing a valuable animal model for COVID-19. Infection results in a transient loss in body weight starting 3 days post-infection, reaching 20–30% loss of weight at day 7 and full recovery at days 11–13 post-infection. The evolution of the disease revealed high reproducibility and very low variability among individual mice. The method was implemented in two different strains of HLA immunized mice. Infected animals developed strong protective humoral and cellular immune responses specific to the viral spike-protein, strictly depending on the adenovirus-mediated human ACE2 expression. Convalescent animals were protected against a subsequent re-infection with SARS-CoV-2, demonstrating that the model may be applied for assessment of efficacy of anti-viral immune responses.
    Type of Medium: Online Resource
    ISSN: 2076-0817
    URL: Article
    DOI: 10.3390/pathogens10080940
    Language: English
    Publisher: MDPI AG
    Publication Date: 2021
    detail.hit.zdb_id: 2695572-6
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  • 8
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    Characterization of Lung Injury following Abrin Pulmonary Intoxication in Mice: Comparison to Ricin Poisoning
    MDPI AG ; 2022
    In:  Toxins Vol. 14, No. 9 ( 2022-09-02), p. 614-
    Details
    In: Toxins, MDPI AG, Vol. 14, No. 9 ( 2022-09-02), p. 614-
    Abstract: Abrin is a highly toxic protein obtained from the seeds of the rosary pea plant Abrus precatorius, and it is closely related to ricin in terms of its structure and chemical properties. Both toxins inhibit ribosomal function, halt protein synthesis and lead to cellular death. The major clinical manifestations following pulmonary exposure to these toxins consist of severe lung inflammation and consequent respiratory insufficiency. Despite the high similarity between abrin and ricin in terms of disease progression, the ability to protect mice against these toxins by postexposure antibody-mediated treatment differs significantly, with a markedly higher level of protection achieved against abrin intoxication. In this study, we conducted an in-depth comparison between the kinetics of in vivo abrin and ricin intoxication in a murine model. The data demonstrated differential binding of abrin and ricin to the parenchymal cells of the lungs. Accordingly, toxin-mediated injury to the nonhematopoietic compartment was shown to be markedly lower in the case of abrin intoxication. Thus, profiling of alveolar epithelial cells demonstrated that although toxin-induced damage was restricted to alveolar epithelial type II cells following abrin intoxication, as previously reported for ricin, it was less pronounced. Furthermore, unlike following ricin intoxication, no direct damage was detected in the lung endothelial cell population following abrin exposure. Reduced impairment of intercellular junction molecules following abrin intoxication was detected as well. In contrast, similar damage to the endothelial surface glycocalyx layer was observed for the two toxins. We assume that the reduced damage to the lung stroma, which maintains a higher level of tissue integrity following pulmonary exposure to abrin compared to ricin, contributes to the high efficiency of the anti-abrin antibody treatment at late time points after exposure.
    Type of Medium: Online Resource
    ISSN: 2072-6651
    URL: Article
    DOI: 10.3390/toxins14090614
    Language: English
    Publisher: MDPI AG
    Publication Date: 2022
    detail.hit.zdb_id: 2518395-3
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  • 9
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    Online Resource
    Intramuscular Ricin Poisoning of Mice Leads to Widespread Damage in the Heart, Spleen, and Bone Marrow
    MDPI AG ; 2019
    In:  Toxins Vol. 11, No. 6 ( 2019-06-16), p. 344-
    Details
    In: Toxins, MDPI AG, Vol. 11, No. 6 ( 2019-06-16), p. 344-
    Abstract: Ricin, a lethal toxin derived from castor oil beans, is a potential bio-threat due to its high availability and simplicity of preparation. Ricin is prepared according to simple recipes available on the internet, and was recently considered in terrorist, suicide, or homicide attempts involving the parenteral route of exposure. In-depth study of the morbidity developing from parenteral ricin poisoning is mandatory for tailoring appropriate therapeutic measures to mitigate ricin toxicity in such instances. The present study applies various biochemical, hematological, histopathological, molecular, and functional approaches to broadly investigate the systemic effects of parenteral intoxication by a lethal dose of ricin in a murine model. Along with prompt coagulopathy, multi-organ hemorrhages, and thrombocytopenia, ricin induced profound morpho-pathological and functional damage in the spleen, bone marrow, and cardiovascular system. In the heart, diffuse hemorrhages, myocyte necrosis, collagen deposition, and induction in fibrinogen were observed. Severe functional impairment was manifested by marked thickening of the left ventricular wall, decreased ventricular volume, and a significant reduction in stroke volume and cardiac output. Unexpectedly, the differential severity of the ricin-induced damage did not correlate with the respective ricin-dependent catalytic activity measured in the various organs. These findings emphasize the complexity of ricin toxicity and stress the importance of developing novel therapeutic strategies that will combine not only anti-ricin specific therapy, but also will target ricin-induced indirect disturbances.
    Type of Medium: Online Resource
    ISSN: 2072-6651
    URL: Article
    DOI: 10.3390/toxins11060344
    Language: English
    Publisher: MDPI AG
    Publication Date: 2019
    detail.hit.zdb_id: 2518395-3
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  • 10
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    Table_1.DOCX
    Frontiers Media SA ; 2022
    In:  Frontiers in Virology Vol. 2 ( 2022-3-21)
    Details
    In: Frontiers in Virology, Frontiers Media SA, Vol. 2 ( 2022-3-21)
    Abstract: Severe manifestations of coronavirus disease 2019 (COVID-19) are mostly restricted to distinct groups of people who have preexisting morbidities. Most COVID-19 animal models develop a mild pathology that resolves within a relatively short period of time, reflecting the more prevalent asymptomatic-to-mild performance of the disease observed in humans. Mice are normally unaffected by SARS coronavirus-2 infection, because of the inability of the virus to bind effectively to the murine angiotensin-converting enzyme 2 (ACE2) receptor. We have previously demonstrated that induction of mild and transient pulmonary morbidity, by application of low doses of ricin, rendered CD1 mice to be susceptible to this virus, which was displayed by sustained body weight loss and mortality rates & gt;50%. In the present study, we performed transcriptomic analyses charting the major alterations in gene expression of mice that were pre-exposed to low doses of ricin and then subjected to SARS-CoV-2 infection compared to mice that were solely exposed to ricin or infected with SARS-CoV-2. Mice intoxicated and infected with ricin and SARS-CoV-2 demonstrated a marked stimulation of essential immunity genes and biological pathways involved in the activation of natural-killer response, cell death receptors, cytotoxic T-cells, Toll-like receptor signaling and the NLRP3 inflammasome pathway. At the protein level, an induced early and transient interferon response was recorded which was subsequently suppressed. The activation of this array of genes predicts clinical manifestations that are consistent with severe COVID-19 in humans, thereby establishing the suitability of this unique animal model for the study of severe COVID-19 disease.
    Type of Medium: Online Resource
    ISSN: 2673-818X
    URL: Article
    URL: Article
    DOI: 10.3389/fviro.2022.848465
    DOI: 10.3389/fviro.2022.848465.s001
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2022
    detail.hit.zdb_id: 3100943-8
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