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Mesenchymal stem cells improve survival in a mice model of severe pneumococcal pneumonia
Abstracts
Abstract Effects of lipopolysaccharide on RBC alteration in mice endotoxemic model Seolju Parka, Jeihak Myungc, Yeonhee Kimb, Sungmook Yood, Jaekwan Limd, Choonhak Lima a
Korea University Anam Hospital, Republic of Korea Korea University Ansan Hospital, Republic of Korea c Korea University Medicine Graduate School, Republic of Korea d Korean Artificial Organ Research Center, Republic of Korea b
Background/Purpose: Sepsis is a complex pathophysiological process that involves both alterations in the microcirculation (vessels with a diameter b100 m) and changes in the biochemical and physiological characteristics of the blood constituents. Alterations in RBC rheology participate in the alterations of the microcirculation. Early alterations of RBC rheology are reported to be seen commonly in the septic patients. However, time course of RBC alterations is not revealed. Therefore, we evaluated the change of RBC deformability and RBC aggregation in the mice endotoxemic model using lipopolysaccharide (LPS). Methods: Six-week-old male BALB/c mice were used in this study. The LPS-induced sepsis mice received LPS (20 mg/kg) intraperitoneally. Elongation indices (EIs) and aggregation indices (AIs) were tested at shear stresses of 1, 3, 7, 10, and 20 Pa for 0.5, 1, 2, 4, 6, 9, 12, and 24 hours after LPS. Results: There were no difference in AIs on 0.5, 1, 2, 4, 6, 9, 12, and 24 hours after LPS; however, EIs significantly decreased in only 10 and 20 Pa at 24 hours after LPS (P b .05). Conclusions: Our results suggested that change of RBC deformability was revealed on 24 hours after LPS injection, and choice of an appropriate shear stress may detect alterations of RBC deformability in LPS-induced sepsis mice. Keywords: Lipopolysaccharide, RBC deformability, RBC aggregation, Shear stress http://dx.doi.org/10.1016/j.jcrc.2015.04.023
Abstract Mesenchymal stem cells improve survival in a mice model of severe pneumococcal pneumonia Marcos I Restrepoa,b, Luis F Reyesa,d, Cecilia A. Hinojosaa, Dirk A. Huntc, Alejandro Rodrigueze, Robbie Johnsonc, Nilam Sonia,b, Antonio Anzuetoa,b, Jay I. Petersa,b, Mary Pat Moyerc, Carlos J. Orihuelaa a
University of Texas Health Science Center at San Antonio, USA South Texas Veterans Health Care System (STVHCS), USA c INCELL Corporation, USA d Universidad de La Sabana, Colombia e Hospital Joan XXIII, Spain b
Background/Purpose: Community-acquired pneumonia is the leading cause of morbidity and mortality worldwide. Streptococcus pneumoniae is a principal etiology of community-acquired pneumonia. Therapy with human adipose tissue–derived mesenchymal stem cells (Ad-MSCs) could reduce mortality by inhibiting bacterial growth, modulating the often excessive host-immune response, and enhancing tissue repair. Limited data are available regarding the impact of Ad-MSCs in pneumococcal pneumonia. This proof-ofconcept pilot study tested the hypothesis that intratracheal Ad-MSCs improve survival in a murine pneumococcal pneumonia model. Methods: Mice were infected intranasally with 107 colony forming units of S pneumoniae. After 24 hours, mice with pneumonia
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received live, prelabeled intratracheally delivered 106 Ad-MSCs (n = 7) vs control (n = 8, Ad-MSCs carrying solution). Disease severity was tested by weight loss and the presence of bacteremia at 12-hour intervals. Animals were followed until they developed a moribund state. Cumulative survival analysis was performed. Results: Ad-MSCs accumulated in the lungs as measured by tissue visualization of the prelabeled cells. No differences among groups were observed for the lung injury score and bacterial growth. Survival analysis revealed no deaths in both groups at 12- and 24-hour periods. A larger proportion of mice survived in the Ad-MSC group at 36 (100% vs 75%, P = .48), 48 (57% vs 37%, P = .62), and 60 hours (43% vs 0%, P = .08) postinfection when compared to the control group. Conclusions: There is a tendency toward higher survival among intratracheally treated mice Ad-MSCs with invasive pneumococcal pneumonia. Translation of these findings to other species including humans may improve the survival due to invasive pneumococcal pneumonia. Keywords: Pneumonia, Sepsis, Stem cells http://dx.doi.org/10.1016/j.jcrc.2015.04.024
Abstract Niacin and selenium attenuate sepsis-induced lung injury by up-regulating Nrf2 signaling Woon yong Kwona, Gil joon Suha, Kyung su Kima, Yoon sun Jungb, Sung hee Kima a
Seoul National University College of Medicine, Republic of Korea National Medical Center, Republic of Korea
b
Background/Purpose: To investigate whether the combination therapy of clinically relevant doses of niacin and selenium attenuates lung injury and improves survival during sepsis in rats and to determine if its therapeutic benefits are associated with an activation of the glutathione redox cycle and up-regulation of Nrf2. Methods: In LPS-exposed HMVEC-L cells, the dose-related effects of niacin and selenium were assessed, and then the antioxidant and anti-inflammatory effects of the combination therapy of niacin (0.9 mM) and selenium (1.5 μM) were evaluated. The role of Nrf2 in combination therapy was also determined using Nrf2 knockdown cells. In endotoxemic rats and CLP-operated male Sprague-Dawley rats, the therapeutic effects of the combination therapy of niacin (360 mg/kg) and selenium (60 μg/kg) were also evaluated. Results: Combination therapy reduced hydrogen peroxide by the synergistic activation of the glutathione redox cycle, which involves niacin-induced increases in glutathione reductase activity and reduced glutathione level and a selenium-induced increase in glutathione peroxidase activity. Combination therapy contributed to an upregulation of Nrf2, enhancement of glutathione synthesis, and downregulation of NF-κB signaling, but Nrf2 knockdown inhibited the enhancement of glutathione synthesis and down-regulation of the NFκB pathway by combination therapy. In addition, combination therapy attenuated lung injury and improved survival during sepsis in rats. Conclusions: The combination therapy of clinically relevant doses of niacin and selenium attenuated lung injury and improved survival during sepsis. Its therapeutic benefits were associated with a synergistic activation of the glutathione redox cycle, reduction of hydrogen peroxide, up-regulation of Nrf2, and down-regulation of the NF-κB pathway. Keywords: Sepsis, Reactive oxygen species, Glutathione, Lung http://dx.doi.org/10.1016/j.jcrc.2015.04.025
Abstract Effects of lipopolysaccharide on RBC alteration in mice endotoxemic model Seolju Parka, Jeihak Myungc, Yeonhee Kimb, Sungmook Yood, Jaekwan Limd, Choonhak Lima a
Korea University Anam Hospital, Republic of Korea Korea University Ansan Hospital, Republic of Korea c Korea University Medicine Graduate School, Republic of Korea d Korean Artificial Organ Research Center, Republic of Korea b
Background/Purpose: Sepsis is a complex pathophysiological process that involves both alterations in the microcirculation (vessels with a diameter b100 m) and changes in the biochemical and physiological characteristics of the blood constituents. Alterations in RBC rheology participate in the alterations of the microcirculation. Early alterations of RBC rheology are reported to be seen commonly in the septic patients. However, time course of RBC alterations is not revealed. Therefore, we evaluated the change of RBC deformability and RBC aggregation in the mice endotoxemic model using lipopolysaccharide (LPS). Methods: Six-week-old male BALB/c mice were used in this study. The LPS-induced sepsis mice received LPS (20 mg/kg) intraperitoneally. Elongation indices (EIs) and aggregation indices (AIs) were tested at shear stresses of 1, 3, 7, 10, and 20 Pa for 0.5, 1, 2, 4, 6, 9, 12, and 24 hours after LPS. Results: There were no difference in AIs on 0.5, 1, 2, 4, 6, 9, 12, and 24 hours after LPS; however, EIs significantly decreased in only 10 and 20 Pa at 24 hours after LPS (P b .05). Conclusions: Our results suggested that change of RBC deformability was revealed on 24 hours after LPS injection, and choice of an appropriate shear stress may detect alterations of RBC deformability in LPS-induced sepsis mice. Keywords: Lipopolysaccharide, RBC deformability, RBC aggregation, Shear stress http://dx.doi.org/10.1016/j.jcrc.2015.04.023
Abstract Mesenchymal stem cells improve survival in a mice model of severe pneumococcal pneumonia Marcos I Restrepoa,b, Luis F Reyesa,d, Cecilia A. Hinojosaa, Dirk A. Huntc, Alejandro Rodrigueze, Robbie Johnsonc, Nilam Sonia,b, Antonio Anzuetoa,b, Jay I. Petersa,b, Mary Pat Moyerc, Carlos J. Orihuelaa a
University of Texas Health Science Center at San Antonio, USA South Texas Veterans Health Care System (STVHCS), USA c INCELL Corporation, USA d Universidad de La Sabana, Colombia e Hospital Joan XXIII, Spain b
Background/Purpose: Community-acquired pneumonia is the leading cause of morbidity and mortality worldwide. Streptococcus pneumoniae is a principal etiology of community-acquired pneumonia. Therapy with human adipose tissue–derived mesenchymal stem cells (Ad-MSCs) could reduce mortality by inhibiting bacterial growth, modulating the often excessive host-immune response, and enhancing tissue repair. Limited data are available regarding the impact of Ad-MSCs in pneumococcal pneumonia. This proof-ofconcept pilot study tested the hypothesis that intratracheal Ad-MSCs improve survival in a murine pneumococcal pneumonia model. Methods: Mice were infected intranasally with 107 colony forming units of S pneumoniae. After 24 hours, mice with pneumonia
829
received live, prelabeled intratracheally delivered 106 Ad-MSCs (n = 7) vs control (n = 8, Ad-MSCs carrying solution). Disease severity was tested by weight loss and the presence of bacteremia at 12-hour intervals. Animals were followed until they developed a moribund state. Cumulative survival analysis was performed. Results: Ad-MSCs accumulated in the lungs as measured by tissue visualization of the prelabeled cells. No differences among groups were observed for the lung injury score and bacterial growth. Survival analysis revealed no deaths in both groups at 12- and 24-hour periods. A larger proportion of mice survived in the Ad-MSC group at 36 (100% vs 75%, P = .48), 48 (57% vs 37%, P = .62), and 60 hours (43% vs 0%, P = .08) postinfection when compared to the control group. Conclusions: There is a tendency toward higher survival among intratracheally treated mice Ad-MSCs with invasive pneumococcal pneumonia. Translation of these findings to other species including humans may improve the survival due to invasive pneumococcal pneumonia. Keywords: Pneumonia, Sepsis, Stem cells http://dx.doi.org/10.1016/j.jcrc.2015.04.024
Abstract Niacin and selenium attenuate sepsis-induced lung injury by up-regulating Nrf2 signaling Woon yong Kwona, Gil joon Suha, Kyung su Kima, Yoon sun Jungb, Sung hee Kima a
Seoul National University College of Medicine, Republic of Korea National Medical Center, Republic of Korea
b
Background/Purpose: To investigate whether the combination therapy of clinically relevant doses of niacin and selenium attenuates lung injury and improves survival during sepsis in rats and to determine if its therapeutic benefits are associated with an activation of the glutathione redox cycle and up-regulation of Nrf2. Methods: In LPS-exposed HMVEC-L cells, the dose-related effects of niacin and selenium were assessed, and then the antioxidant and anti-inflammatory effects of the combination therapy of niacin (0.9 mM) and selenium (1.5 μM) were evaluated. The role of Nrf2 in combination therapy was also determined using Nrf2 knockdown cells. In endotoxemic rats and CLP-operated male Sprague-Dawley rats, the therapeutic effects of the combination therapy of niacin (360 mg/kg) and selenium (60 μg/kg) were also evaluated. Results: Combination therapy reduced hydrogen peroxide by the synergistic activation of the glutathione redox cycle, which involves niacin-induced increases in glutathione reductase activity and reduced glutathione level and a selenium-induced increase in glutathione peroxidase activity. Combination therapy contributed to an upregulation of Nrf2, enhancement of glutathione synthesis, and downregulation of NF-κB signaling, but Nrf2 knockdown inhibited the enhancement of glutathione synthesis and down-regulation of the NFκB pathway by combination therapy. In addition, combination therapy attenuated lung injury and improved survival during sepsis in rats. Conclusions: The combination therapy of clinically relevant doses of niacin and selenium attenuated lung injury and improved survival during sepsis. Its therapeutic benefits were associated with a synergistic activation of the glutathione redox cycle, reduction of hydrogen peroxide, up-regulation of Nrf2, and down-regulation of the NF-κB pathway. Keywords: Sepsis, Reactive oxygen species, Glutathione, Lung http://dx.doi.org/10.1016/j.jcrc.2015.04.025