Modulation of oxidative and nitrosative stress attenuates microvascular hyperpermeability in ovine model of Pseudomonas aeruginosa sepsis

Fukuda, Seisuke; Niimi, Yosuke; Hirasawa, Yasutaka; Manyeza, Ennert; Garner, C. Edwin; Southan, Garry J.; Salzman, Andrew L.; Prough, Donald S.; Enkhbaatar, Perenlei

doi:10.1038/s41598-021-03320-w

Cited by 4 publications

(3 citation statements)

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“…The sheep were euthanized at the end of 24 h monitoring or at the time of reaching the euthanasia criteria by using intravenous infusion of ketamine (40mg/kg), xylazine (3.0mg/kg), and buprenorphine (0.01 mg/kg) ( 35 ). The euthanasia criteria included reduced mean arterial pressure (MAP) <40 mmHg, reduced heart rate (HR) <40 beats/min, increased PaCO 2 > 90 mmHg, or decreased PaO 2 <50 mmHg at 100% FiO 2 for at least an hour.…”

Section: Methodsmentioning

confidence: 99%

Mesenchymal stem cell-derived exosomes for treatment of sepsis

et al. 2023

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IntroductionThe pathogenesis of sepsis is an imbalance between pro-inflammatory and anti-inflammatory responses. At the onset of sepsis, the lungs are severely affected, and the injury progresses to acute respiratory distress syndrome (ARDS), with a mortality rate of up to 40%. Currently, there is no effective treatment for sepsis. Cellular therapies using mesenchymal stem cells (MSCs) have been initiated in clinical trials for both ARDS and sepsis based on a wealth of pre-clinical data. However, there remains concern that MSCs may pose a tumor risk when administered to patients. Recent pre-clinical studies have demonstrated the beneficial effects of MSC-derived extracellular vesicles (EVs) for the treatment of acute lung injury (ALI) and sepsis.MethodsAfter recovery of initial surgical preparation, pneumonia/sepsis was induced in 14 adult female sheep by the instillation of Pseudomonas aeruginosa (~1.0×1011 CFU) into the lungs by bronchoscope under anesthesia and analgesia. After the injury, sheep were mechanically ventilated and continuously monitored for 24 h in a conscious state in an ICU setting. After the injury, sheep were randomly allocated into two groups: Control, septic sheep treated with vehicle, n=7; and Treatment, septic sheep treated with MSC-EVs, n=7. MSC-EVs infusions (4ml) were given intravenously one hour after the injury.ResultsThe infusion of MSCs-EVs was well tolerated without adverse events. PaO2/FiO2 ratio in the treatment group tended to be higher than the control from 6 to 21 h after the lung injury, with no significant differences between the groups. No significant differences were found between the two groups in other pulmonary functions. Although vasopressor requirement in the treatment group tended to be lower than in the control, the net fluid balance was similarly increased in both groups as the severity of sepsis progressed. The variables reflecting microvascular hyperpermeability were comparable in both groups.ConclusionWe have previously demonstrated the beneficial effects of bone marrow-derived MSCs (10×106 cells/kg) in the same model of sepsis. However, despite some improvement in pulmonary gas exchange, the present study demonstrated that EVs isolated from the same amount of bone marrow-derived MSCs failed to attenuate the severity of multiorgan dysfunctions.

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Section: Methodsmentioning

confidence: 99%

Mesenchymal stem cell-derived exosomes for treatment of sepsis

et al. 2023

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“…The fluid resuscitation was initiated with a rate of 2 mL/kg/h and was further adjusted every 3 h to keep hematocrit close to baseline (±3%). The sheep were euthanized at the end of 24-h monitoring or at the time of reaching the euthanasia criteria by using intravenous infusion of ketamine (40 mg/kg), xylazine (3.0 mg/kg), and buprenorphine (0.01 mg/kg) (20). The euthanasia criteria included reduced MAP <40 mm Hg, reduced HR <40 beats per minute, increased Pa co 2 > 90 mm Hg, or decreased Pao 2 < 50 mm Hg at 100% Fio 2 for at least an hour.…”

Section: Methodsmentioning

confidence: 99%

“…The modified q-SOFA score was considered positive when the presence of two or more of the three following criteria: RR ≥ 22, SBP ≤100, and SSNAA <11. The mSOFA score was calculated following the method described previously (Supplemental Table 2, http://links.lww.com/SHK/B651) (20).…”

Section: Methodsmentioning

confidence: 99%

Gender-Related Variations in Pathophysiological Responses to Methicillin-Resistant Staphylococcus Aureus Pneumonia and Sepsis

Homma

Liu

Niimi

et al. 2023

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In preclinical studies, the protective effects of female sex hormones and the immunosuppressive effects of male sex hormones were demonstrated. However, gender-related differences in multiorgan failure and mortality in clinical trials have not been consistently explained. This study aims to investigate gender-related differences in the development and progression of sepsis using a clinically relevant ovine model of sepsis. Adult Merino male (n=7) and female (n=7) sheep were surgically prepared with multiple catheters before the study. To induce sepsis, bronchoscopy instilled methicillin-resistant Staphylococcus aureus into sheep's lungs. The time from the bacterial inoculation until the modified Quick Sequential Organ Failure Assessment (q-SOFA) score became positive was measured and analyzed primarily. We also compared the SOFA score between these male and female sheep over time. Survival, hemodynamic changes, the severity of pulmonary dysfunction, and microvascular hyperpermeability were also compared. The time from the onset of bacterial inoculation to the positive q-SOFA in male sheep was significantly shorter than in female sheep. Mortality was not different between these sheep (14% vs. 14%). There were no significant differences in hemodynamic changes and pulmonary function between the two groups at any time point. Similar changes in hematocrit, urine output, and fluid balance were observed between females and males. The present data indicate that the onset of multiple organ failure and progression of sepsis is faster in male sheep than in female sheep, even though the severity of cardiopulmonary function is comparable over time. Further studies are warranted to validate the above results.

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