scholarly journals Pseudomonas aeruginosa Ventilator-Associated Pneumonia Rabbit Model for Preclinical Drug Development

2021 ◽  
Author(s):  
Nhu T.Q. Nguyen ◽  
Emmanuelle Gras ◽  
Nguyen D. Tran ◽  
Nhi N.Y. Nguyen ◽  
Hanh H. Lam ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Supportive Care ◽  
Rabbit Model ◽  
Fluid Challenge ◽  
Arterial Oxygen ◽  
Large Animal ◽  
Ventilator Associated Pneumonia ◽  
Dosing Regimen ◽  
Large Animal Models ◽  
Severe Hypotension

Development and validation of large animal models of Pseudomonas aeruginosa ventilator-associated pneumonia is needed for testing new drug candidates in a manner mimicking how they will be used clinically. We have developed a new model in which rabbits were ventilated with low-tidal volume and challenged with P. aeruginosa to recapitulate hallmark clinical features of acute respiratory distress syndrome (ARDS): acute lung injury and inflammation, progressive decrease in arterial oxygen partial pressure to fractional inspired oxygen PaO2:FiO2, leukopenia, neutropenia, thrombocytopenia, hyperlactatemia, severe hypotension, bacterial dissemination from lung to other organs, multiorgan dysfunction, and ultimately death. We evaluated the predictive power of this rabbit model for antibiotic efficacy testing by determining whether a humanized dosing regimen of meropenem, a potent antipseudomonal β-lactam antibiotic, when administered with or without intensive care unit (ICU)-supportive care (fluid challenge and norepinephrine), could halt or reverse natural disease progression. Our humanized meropenem dosing regimen produced plasma concentration-time profile in the rabbit model similar to those reported in patients with ventilator-associated bacterial pneumonia. In this rabbit model, treatment with humanized meropenem and ICU-supportive care achieved the highest level of survival, halted the worsening of ARDS biomarkers and reversed lethal hypotension, although treatment with humanized meropenem alone also conferred some protection when compared to treatment with placebo (saline) alone or placebo plus ICU-supportive care. In conclusion, this rabbit model could help predict whether an antibiotic will be efficacious for the treatment of human ventilator-associated pneumonia.

Anti-virulence Bispecific Monoclonal Antibody Mediated Protection Against Pseudomonas aeruginosa Ventilator-Associated Pneumonia in a Rabbit Model

2021 ◽  
Author(s):  
Fábio Aguiar-Alves ◽  
Hoan N. Le ◽  
Vuvi G. Tran ◽  
Emmanuelle Gras ◽  
Trang Vu ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Rabbit Model ◽  
Arterial Oxygen ◽  
Rank Test ◽  
Ventilator Associated Pneumonia ◽  
Exact Test ◽  
Cytokines And Chemokines ◽  
Potential Clinical Utility ◽  
Human Igg1 ◽  
Type 3

Ventilator-associated pneumonia is an important clinical manifestation of the nosocomial pathogen Pseudomonas aeruginosa . We characterized the correlates of protection of MEDI3902, a bispecific human IgG1 mAb that targets the P. aeruginosa type-3-secretion PcrV protein and the Psl exopolysaccharide, in a rabbit model of ventilator-associated pneumonia using lung-protective, low-tidal volume mechanical ventilation. Rabbits infused with MEDI3902 prophylactically were protected, whereas those pretreated with irrelevant isotype-control IgG (c-IgG) succumbed between 12 and 44 hours post infection [100% (8/8) vs. 0% (8/8) survival, P <0.01 by log-rank test]. Lungs from rabbits pretreated with c-IgG, but not those with MEDI3902, had bilateral, multifocal areas of marked necrosis, hemorrhage, neutrophilic inflammatory infiltrate, diffuse fibrinous edema in alveolar spaces. All rabbits pretreated with c-IgG developed worsening bacteremia that peaked at the time of death, whereas only 38% (3/8) rabbits pretreated with MEDI3902 developed such high-grade bacteremia (two-sided Fisher’s exact test, P =0.026). Biomarkers associated with acute respiratory distress syndrome were evaluated longitudinally in blood samples collected every 2-4 hours to assess systemic pathophysiological changes in rabbits pretreated with MEDI3902 or c-IgG. Biomarkers were sharply increased or decreased in rabbits pretreated with c-IgG, but not those pretreated with MEDI3902, including ratio of arterial oxygen partial pressure to fractional inspired oxygen PaO 2 /FiO 2 <300, hypercapnia or hypocapnia, severe lactic acidosis, leukopenia and neutropenia. Cytokines and chemokines associated with ARDS were significantly downregulated in lungs from rabbits pretreated with MEDI3902 compared with c-IgG. These results suggest that MEDI3902 prophylaxis could have potential clinical utility for decreasing severity of P. aeruginosa ventilator-associated pneumonia.

scholarly journals Comparative Analysis of Methods to Induce Myocardial Infarction in a Closed-Chest Rabbit Model

2015 ◽  
Vol 2015 ◽  
pp. 1-9 ◽  
Author(s):  
Marc-Antoine Isorni ◽  
Amaury Casanova ◽  
Julie Piquet ◽  
Valérie Bellamy ◽  
Charly Pignon ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Animal Models ◽  
Rabbit Model ◽  
Left Ventricular ◽  
Balloon Occlusion ◽  
Gelatin Sponge ◽  
Large Animal ◽  
Alcohol Injection ◽  
Closed Chest ◽  
Large Animal Models

Objective.To develop a rabbit model of closed-chest catheter-induced myocardial infarction.Background.Limitations of rodent and large animal models justify the search for clinically relevant alternatives.Methods.Microcatheterization of the heart was performed in 47 anesthetized 3-4 kg New Zealand rabbits to test five techniques of myocardial ischemia: free coils (n=4), interlocking coils (n=4), thrombogenic gelatin sponge (n=4), balloon occlusion (n=4), and alcohol injection (n=8). In order to limit ventricular fibrillation, an antiarrhythmic protocol was implemented, with beta-blockers/amiodarone before and xylocaine infusion during the procedure. Clinical, angiographic, and echographic data were gathered. End points included demonstration of vessel occlusion (TIMI flow grades 0 and 1 on the angiogram), impairment of left ventricular function at 2 weeks after procedure (by echocardiography), and pathologically confirmed myocardial infarction.Results.The best arterial access was determined to be through the right carotid artery. The internal mammary guiding catheter 4-Fr was selected as the optimal device for selective intracoronary injection. Free coils deployed prematurely and tended to prolapse into the aorta. Interlocking coils did not deploy completely and failed to provide reliable results. Gelatin sponge was difficult to handle, adhered to the catheter, and could not be clearly visualized by fluoroscopy. Balloon occlusion yielded inconsistent results. Alcohol injection was the most efficient and reproducible method for inducing myocardial infarction (4 out of 6 animals), the extent of which could be fine-tuned by using a coaxial balloon catheter as a microcatheter (0.52 mm) to achieve a superselective injection of 0.2 mL of alcohol. This approach resulted in a 20% decrease in LVEF and infarcted myocardium was confirmed histologically.Conclusions.By following a stepwise approach, a minimally invasive, effective, and reproducible rabbit model of catheter-induced myocardial infarction has been developed which addresses the limitations of rodent experiments while avoiding the logistical and cost issues associated with large animal models.

scholarly journals Physioxia Expanded Bone Marrow Derived Mesenchymal Stem Cells Have Improved Cartilage Repair in an Early Osteoarthritic Focal Defect Model

Biology ◽  
2020 ◽  
Vol 9 (8) ◽  
pp. 230
Author(s):  
Girish Pattappa ◽  
Jonas Krueckel ◽  
Ruth Schewior ◽  
Dustin Franke ◽  
Alexander Mench ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Cartilage Repair ◽  
Rabbit Model ◽  
Cartilage Regeneration ◽  
Cartilage Defects ◽  
Large Animal ◽  
Large Animal Models ◽  
Early Oa

Focal early osteoarthritis (OA) or degenerative lesions account for 60% of treated cartilage defects each year. The current cell-based regenerative treatments have an increased failure rate for treating degenerative lesions compared to traumatic defects. Mesenchymal stem cells (MSCs) are an alternative cell source for treating early OA defects, due to their greater chondrogenic potential, compared to early OA chondrocytes. Low oxygen tension or physioxia has been shown to enhance MSC chondrogenic matrix content and could improve functional outcomes of regenerative therapies. The present investigation sought to develop a focal early OA animal model to evaluate cartilage regeneration and hypothesized that physioxic MSCs improve in vivo cartilage repair in both, post-trauma and focal early OA defects. Using a rabbit model, a focal defect was created, that developed signs of focal early OA after six weeks. MSCs cultured under physioxia had significantly enhanced in vitro MSC chondrogenic GAG content under hyperoxia with or without the presence of interleukin-1β (IL-1β). In both post-traumatic and focal early OA defect models, physioxic MSC treatment demonstrated a significant improvement in cartilage repair score, compared to hyperoxic MSCs and respective control defects. Future investigations will seek to understand whether these results are replicated in large animal models and the underlying mechanisms involved in in vivo cartilage regeneration.

scholarly journals Development of a large animal rabbit model for chronic periprosthetic joint infection

2021 ◽  
Vol 10 (3) ◽  
pp. 156-165
Author(s):  
Haruyo Yagi ◽  
Shinsuke Kihara ◽  
Peter N. Mittwede ◽  
Patrick L. Maher ◽  
Adam C. Rothenberg ◽  
...  
Keyword(s):  
Joint Infection ◽  
Rabbit Model ◽  
Treatment Strategies ◽  
Bone Tunnel ◽  
Bacterial Suspension ◽  
Large Animal ◽  
Large Animal Models ◽  
Planktonic Bacteria ◽  
Bone Tunnels ◽  
Screw Group

Aims Periprosthetic joint infections (PJIs) and osteomyelitis are clinical challenges that are difficult to eradicate. Well-characterized large animal models necessary for testing and validating new treatment strategies for these conditions are lacking. The purpose of this study was to develop a rabbit model of chronic PJI in the distal femur. Methods Fresh suspensions of Staphylococcus aureus (ATCC 25923) were prepared in phosphate-buffered saline (PBS) (1 × 109 colony-forming units (CFUs)/ml). Periprosthetic osteomyelitis in female New Zealand white rabbits was induced by intraosseous injection of planktonic bacterial suspension into a predrilled bone tunnel prior to implant screw placement, examined at five and 28 days (n = 5/group) after surgery, and compared to a control aseptic screw group. Radiographs were obtained weekly, and blood was collected to measure ESR, CRP, and white blood cell (WBC) counts. Bone samples and implanted screws were harvested on day 28, and processed for histological analysis and viability assay of bacteria, respectively. Results Intraosseous periprosthetic introduction of planktonic bacteria induced an acute rise in ESR and CRP that subsided by day 14, and resulted in radiologically evident periprosthetic osteolysis by day 28 accompanied by elevated WBC counts and histological evidence of bacteria in the bone tunnels after screw removal. The aseptic screw group induced no increase in ESR, and no lysis developed around the implants. Bacterial viability was confirmed by implant sonication fluid culture. Conclusion Intraosseous periprosthetic introduction of planktonic bacteria reliably induces survivable chronic PJI in rabbits. Cite this article: Bone Joint Res 2021;10(3):156–165.

Characteristics and Unmet Clinical Needs Related to Hepatocellular Carcinoma

2017 ◽  
Vol 01 (02) ◽  
pp. 074-082
Author(s):  
Jordan Newson ◽  
Nickolas Kinachtchouk ◽  
Kyle Schachtschneider ◽  
Regina Schwind ◽  
Lawrence Schook
Keyword(s):  
Hepatocellular Carcinoma ◽  
Animal Models ◽  
Biomedical Research ◽  
Human Disease ◽  
Rabbit Model ◽  
In Vitro Study ◽  
Large Animal ◽  
Curative Therapy ◽  
Large Animal Models

AbstractAdvances in biomedical research require animal models that accurately recapitulate human disease. Without such models, progress against human diseases such as cancer is significantly hindered. Here, we present the current landscape on available and emerging hepatocellular carcinoma (HCC) animal models. HCC is the second leading cause of cancer death worldwide, with an annual death toll exceeding 745,000. Stunningly, only 15% of HCC patients are candidates for curative therapy, leading 85% of patients to seek palliative therapeutic options. The VX2 rabbit model is considered the most relevant and widely used HCC model; however, more reliable HCC models are critically needed. In general, animal models for biomedical research should (1) mimic the human disease on a molecular basis, (2) derive from a relevant cell line that lends itself to in vitro study, (3) be reliable and predictable, (4) manifest survival differences, (5) allow for accurate treatment assessment, (6) be readily imaged, and (7) occur in similar background settings as the human disease. Over the past decades, numerous small animal models have been utilized for HCC studies; however, the development of new large animal models as qualified alternatives to murine models represents a key technology to advance research into human clinical trials.

scholarly journals Molecular Mechanisms of Fetal Tendon Regeneration Versus Adult Fibrous Repair

2021 ◽  
Vol 22 (11) ◽  
pp. 5619
Author(s):  
Iris Ribitsch ◽  
Andrea Bileck ◽  
Alexander D. Aldoshin ◽  
Maciej M. Kańduła ◽  
Rupert L. Mayer ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Molecular Mechanisms ◽  
Unmet Need ◽  
Tendon Healing ◽  
Tendon Injury ◽  
Inflammatory Factors ◽  
Large Animal ◽  
Post Injury ◽  
Tendon Regeneration ◽  
Large Animal Models

Tendinopathies are painful, disabling conditions that afflict 25% of the adult human population. Filling an unmet need for realistic large-animal models, we here present an ovine model of tendon injury for the comparative study of adult scarring repair and fetal regeneration. Complete regeneration of the fetal tendon within 28 days is demonstrated, while adult tendon defects remained macroscopically and histologically evident five months post-injury. In addition to a comprehensive histological assessment, proteome analyses of secretomes were performed. Confirming histological data, a specific and pronounced inflammation accompanied by activation of neutrophils in adult tendon defects was observed, corroborated by the significant up-regulation of pro-inflammatory factors, neutrophil attracting chemokines, the release of potentially tissue-damaging antimicrobial and extracellular matrix-degrading enzymes, and a response to oxidative stress. In contrast, secreted proteins of injured fetal tendons included proteins initiating the resolution of inflammation or promoting functional extracellular matrix production. These results demonstrate the power and relevance of our novel ovine fetal tendon regeneration model, which thus promises to accelerate research in the field. First insights from the model already support our molecular understanding of successful fetal tendon healing processes and may guide improved therapeutic strategies.

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