Conventional and Specific-Pathogen Free Rats Respond Differently to Anesthesia and Surgical Trauma

Letson, Hayley L.; Morris, Jodie L.; Biroš, Erik; Dobson, Geoffrey P.

doi:10.1038/s41598-019-45871-z

Cited by 24 publications

(27 citation statements)

References 33 publications

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“…Moreover, frequent use of specific pathogenfree (SPF) animals in sepsis research, where alterations of the gut microbiome may markedly alter the animal's immune and inflammatory functions and susceptibility to infection, may also contribute to the disconnect between animal studies showing promising drug development and failure to translate to humans. In an interesting recent study a more straightforward comparison of response to anesthesia and surgical trauma was made between conventional and SPF rats (20). Comparison between conventional and SPF animals within one species and even strain (Spraque-Dawley) revealed decreased tolerance to anesthesia, hemodynamic instability, aberrant hematology, traumatic bleeding, and reduced physiological reserve in SPF animals.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of Mesenchymal Stem Cell Therapy for Sepsis: A Randomized Controlled Porcine Study

et al. 2020

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Background: Treatment with mesenchymal stem cells (MSCs) has elicited considerable interest as an adjunctive therapy in sepsis. However, the encouraging effects of experiments with MSC in rodents have not been adequately studied in large-animal models with better relevance to human sepsis. Objectives: Here, we aimed to assess safety and efficacy of bone marrow-derived MSCs in a clinically relevant porcine model of progressive peritonitis-induced sepsis. Methods: Thirty-two anesthetized, mechanically ventilated, and instrumented pigs were randomly assigned into four groups (n = 8 per group): (1) sham-operated group (CONTROL); (2) sham-operated group treated with MSCs (MSC-CONTROL); (3) sepsis group with standard supportive care (SEPSIS); and (4) sepsis group treated with MSCs (MSC-SEPSIS). Peritoneal sepsis was induced by inoculating cultivated autologous feces. MSCs (1 × 10 6 /kg) were administered intravenously at 6 h after sepsis induction. Results: Before, 12, 18, and 24 h after the induction of peritonitis, we measured systemic, regional, and microvascular hemodynamics, multiple-organ functions, mitochondrial energy metabolism, systemic immune-inflammatory response, and oxidative stress. Administration of MSCs in the MSC-CONTROL group did not elicit any measurable acute effects. Treatment of septic animals with MSCs failed to mitigate sepsis-induced hemodynamic alterations or the gradual rise in Sepsis-related organ failure assessment scores. MSCs did not confer any protection against sepsis-mediated cellular myocardial depression and mitochondrial dysfunction. MSCs also failed to modulate the deregulated immune-inflammatory response. Horak et al. Stem Cell Therapy for Sepsis Conclusion: Intravenous administration of bone marrow-derived MSCs to healthy animals was well-tolerated. However, in this large-animal, clinically relevant peritonitis-induced sepsis model, MSCs were not capable of reversing any of the sepsis-induced disturbances in multiple biological, organ, and cellular systems.

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Section: Discussionmentioning

confidence: 99%

Evaluation of Mesenchymal Stem Cell Therapy for Sepsis: A Randomized Controlled Porcine Study

et al. 2020

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“…Infectious complications may also arise from reduced blood flow to the gut wall and leakiness with bacteria, or their active metabolic products (lipopolysaccharides, cytokines, neuropeptides, and protein messengers to passing across the ischemic wall into the circulation, and further exacerbating inflammation, coagulopathy, immunosuppression and limiting tissue O 2 supply [ 93 ]. After major surgery, the patient's gut microbiome has been reported to change in composition, and is linked to the CNS dysfunction through vagal afferents and HPA axis modulation [ 77 , [93] , [94] , [95] , [96] ], and other complications [ 97 ]. This is further exacerbated by the use of postoperative antibiotics.…”

Section: A Working Hypothesis To Reduce Surgical Stressmentioning

confidence: 99%

Trauma of major surgery: A global problem that is not going away

Dobson

2020

International Journal of Surgery

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123

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Globally, a staggering 310 million major surgeries are performed each year; around 40 to 50 million in USA and 20 million in Europe. It is estimated that 1–4% of these patients will die, up to 15% will have serious postoperative morbidity, and 5–15% will be readmitted within 30 days. An annual global mortality of around 8 million patients places major surgery comparable with the leading causes of death from cardiovascular disease and stroke, cancer and injury. If surgical complications were classified as a pandemic, like HIV/AIDS or coronavirus (COVID-19), developed countries would work together and devise an immediate action plan and allocate resources to address it. Seeking to reduce preventable deaths and post-surgical complications would save billions of dollars in healthcare costs. Part of the global problem resides in differences in institutional practice patterns in high- and low-income countries, and part from a lack of effective perioperative drug therapies to protect the patient from surgical stress. We briefly review the history of surgical stress and provide a path forward from a systems-based approach. Key to progress is recognizing that the anesthetized brain is still physiologically ‘awake’ and responsive to the sterile stressors of surgery. New intravenous drug therapies are urgently required after anesthesia and before the first incision to prevent the brain from switching to sympathetic overdrive and activating secondary injury progression such as hyperinflammation, coagulopathy, immune activation and metabolic dysfunction. A systems-based approach targeting central nervous system-mitochondrial coupling may help drive research to improve outcomes following major surgery in civilian and military medicine.

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“…We have argued elsewhere that acute changes in the HPA axis-sympathetic-parasympathetic outflows are associated with immune dysfunction following different trauma states and sepsis (11,12), and responsible for "low-level" persistent inflammation in most chronic inflammatory diseases, such as osteoarthritis and cardiovascular diseases (61,64). Recent studies further demonstrate that the vagus nerve can modulate the host immune response after an infectious or sterile barrier breach (126,168,173), which may also have feedback inputs from changes to the CNS-gut-microbiome-immune axis (61,64,177). Increased vagal outflow to the spleen leads to reduced activation of circulating neutrophils by modulating the expression of CD11b (146).…”

Section: Cns Control Of Inflammation: Crosstalk Between the Nervous And The Immune Systemmentioning

confidence: 99%

Living in a Hostile World: Inflammation, New Drug Development, and Coronavirus

et al. 2021

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We present a brief history of the immune response and show that Metchnikoff’s theory of inflammation and phagocytotic defense was largely ignored in the 20th century. For decades, the immune response was believed to be triggered centrally, until Lafferty and Cunningham proposed the initiating signal came from the tissues. This shift opened the way for Janeway’s pattern recognition receptor theory, and Matzinger’s danger model. All models failed to appreciate that without inflammation, there can be no immune response. The situation changed in the 1990s when cytokine biology was rapidly advancing, and the immune system’s role expanded from host defense, to the maintenance of host health. An inflammatory environment, produced by immune cells themselves, was now recognized as mandatory for their attack, removal and repair functions after an infection or injury. We explore the cellular programs of the immune response, and the role played by cytokines and other mediators to tailor the right response, at the right time. Normally, the immune response is robust, self-limiting and restorative. However, when the antigen load or trauma exceeds the body’s internal tolerances, as witnessed in some COVID-19 patients, excessive inflammation can lead to increased sympathetic outflows, cardiac dysfunction, coagulopathy, endothelial and metabolic dysfunction, multiple organ failure and death. Currently, there are few drug therapies to reduce excessive inflammation and immune dysfunction. We have been developing an intravenous (IV) fluid therapy comprising adenosine, lidocaine and Mg2+ (ALM) that confers a survival advantage by preventing excessive inflammation initiated by sepsis, endotoxemia and sterile trauma. The multi-pronged protection appears to be unique and may provide a tool to examine the intersection points in the immune response to infection or injury, and possible ways to prevent secondary tissue damage, such as that reported in patients with COVID-19.

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Conventional and Specific-Pathogen Free Rats Respond Differently to Anesthesia and Surgical Trauma

Cited by 24 publications

References 33 publications

Evaluation of Mesenchymal Stem Cell Therapy for Sepsis: A Randomized Controlled Porcine Study

Evaluation of Mesenchymal Stem Cell Therapy for Sepsis: A Randomized Controlled Porcine Study

Trauma of major surgery: A global problem that is not going away

Living in a Hostile World: Inflammation, New Drug Development, and Coronavirus

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