Recombinant human soluble thrombomodulin prevents acute lung injury in a rat cardiopulmonary bypass model

Hirao, Shigekazu; Minakata, Kenji; Masumoto, Hidetoshi; Yamazaki, Kazuhiro; Ikeda, Tadashi; Minatoya, Kenji; Sakata, Ryuzo

doi:10.1016/j.jtcvs.2017.05.051

Cited by 21 publications

(21 citation statements)

References 38 publications

(46 reference statements)

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“…Following CPB, pulmonary changes were seen in form of structural alveolar changes and a slight increase in cellular infiltration. These results corroborate previous findings in a rat model of CPB [ 29 , 30 ]. Our findings did not show a significant increase in pulmonary macrophage infiltration, which is in concordance with previous work done by Francis et al [ 31 ] who found a significant increase in macrophage infiltration as late as 24–48 h after induction of lung injury.…”

Section: Discussionsupporting

confidence: 93%

Blood cytokine expression correlates with early multi-organ damage in a mouse model of moderate hypothermia with circulatory arrest using cardiopulmonary bypass

et al. 2018

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Cardiopulmonary bypass (CPB) with moderate hypothermic cardiac arrest (MHCA) is essential for prolonged complex procedures in cardiac surgery and is associated with postoperative complications. Although cytokine release provoked through MHCA under CPB plays a pivotal role in postoperative organ damage, the pathomechanisms are unclear. Here, we investigated the cytokine release pattern and histological organ damage after MHCA using a recently described mouse CPB model. Eight BALB/c mice underwent 60 minutes of circulatory arrest under CPB, were successively rewarmed and reperfused. Blood cytokine concentrations and liver and kidney function parameters were measured and histological changes to these organs were compared to control animals. Our results showed a marked increase in proinflammatory cytokines and histological changes in the kidney, lung, and liver after CPB. Furthermore, clinical chemistry showed signs of hemolysis and acute kidney injury. These results suggest early onset of solid organ injury which correlates with increased leukocyte infiltration. A better understanding of the interplay between pro-inflammatory cytokine activation and solid organ injury in this model of CBP with MHCA will inform strategies to reduce organ damage during cardiac surgeries in the clinic.

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Section: Discussionsupporting

confidence: 93%

Blood cytokine expression correlates with early multi-organ damage in a mouse model of moderate hypothermia with circulatory arrest using cardiopulmonary bypass

et al. 2018

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“…The CPB circuit was constructed with a 20-ml venous reservoir, roller pump (Cole Parmer instrument company, Chicago, USA) and membrane oxygenator (MeicroPort, Dongguan, Guangdong, China). Before CPB, the circuit was primed with 0.2 ml of heparin, 11 ml of hydroxyethyl starch solution and 0.5 ml of 7% sodium bicarbonate solution [16]. During the experiment, the rectal temperature was monitored and maintained within 36-38°C by a heat blanket.…”

Section: In Vivo Experiments Rat Cpb Modelmentioning

confidence: 99%

Endothelial colony-forming cells reduced the lung injury induced by cardiopulmonary bypass in rats

et al. 2020

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Background: Cardiopulmonary bypass (CPB) results in severe lung injury via inflammation and endothelial injury. The aim of this study was to evaluate the effect of endothelial colony-forming cells (ECFCs) on lung injury in rats subjected to CPB. Methods: Thirty-two rats were randomized into the sham, CPB, CPB/ECFC and CPB/ECFC/L-NIO groups. The rats in the sham group received anaesthesia, and the rats in the other groups received CPB. The rats also received PBS, ECFCs and L-NIO-pre-treated ECFCs. After 24 h of CPB, pulmonary capillary permeability, including the PaO 2 /FiO 2 ratio, protein levels in bronchoalveolar lavage fluid (BALF) and lung tissue wet/dry weight were evaluated. The cell numbers and cytokines in BALF and peripheral blood were tested. Endothelial injury, lung histological injury and apoptosis were assessed. The oxidative stress response and apoptosis-related proteins were analysed. Results: After CPB, all the data deteriorated compared with those obtained in the S group (sham vs CPB vs CPB/ ECFC vs CPB/ECFC/L-NIO: histological score 1.62 ± 0.51 vs 5.37 ± 0.91 vs 3.37 ± 0.89 vs 4.37 ± 0.74; PaO 2 /FiO 2 389 ± 12 vs 233 ± 36 vs 338 ± 28 vs 287 ± 30; wet/dry weight 3.11 ± 0.32 vs 6.71 ± 0.73 vs 4.66 ± 0.55 vs 5.52 ± 0.57; protein levels in BALF: 134 ± 22 vs 442 ± 99 vs 225 ± 41 vs 337 ± 53, all P < 0.05). Compared to the CPB treatment, ECFCs significantly improved pulmonary capillary permeability and PaO 2 /FiO 2. Similarly, ECFCs also decreased the inflammatory cell number and pro-inflammatory factors in BALF and peripheral blood, as well as the oxidative stress response in the lung tissue. ECFCs reduced the lung histological injury score and apoptosis and regulated apoptosis-related proteins in the lung tissue. Compared with the CPB/ECFC group, all the indicators were partly reversed by the L-NIO. Conclusions: ECFCs significantly reduced lung injury induced by inflammation after CPB.

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“…HMGB1 levels in the lung were elevated in ARDS mice, and rTM administration decreased the development of ARDS that correlated with an increased T-reg cell population [74]. Other researchers evaluated the possible therapeutic effect of rTM in attenuating animal models of ARDS [75, 76] and reported HMGB1 and proinflammatory cytokine levels were significantly lowered by rTM administration. These findings confirm the anti-inflammatory effect of rTM by potential inhibition of HMGB1 pathway, which may subsequently be translated to better survival outcome.…”

Section: The Efficacy Of Rtm In Respiratory Diseasesmentioning

confidence: 99%

Thrombomodulin in disseminated intravascular coagulation and other critical conditions—a multi-faceted anticoagulant protein with therapeutic potential

et al. 2019

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Thrombomodulin plays a vital role in maintaining intravascular patency due to its anticoagulant, antiinflammatory, and cytoprotective properties. However, under pathological conditions such as sepsis and systemic inflammation, endothelial thrombomodulin expression is downregulated and its function impaired. As a result, administering thrombomodulin represents a potential therapeutic modality. Recently, the effect of recombinant thrombomodulin administration in sepsis-induced coagulopathy was evaluated in a randomized controlled study (SCARLET). A 2.6% 28-day absolute mortality reduction (26.8% vs. 29.4%) was reported in 800 patients studied that was not statistically significant; however, a post hoc analysis revealed a 5.4% absolute mortality reduction among the patients who fulfilled the entry criterion at baseline. The risk of bleeding did not increase compared to placebo control. Favorable effects of thrombomodulin administration have been reported not only in sepsis-induced coagulopathy but also in disseminated intravascular coagulations with various backgrounds. Interestingly, beneficial effects of recombinant thrombomodulin in respiratory, renal, and cardiovascular diseases might depend on its anti-inflammatory mechanisms. In this review, we summarize the accumulated knowledge of endogenous as well as recombinant thrombomodulin from basic to clinical aspects and suggest future directions for this novel therapeutic agent.

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Recombinant human soluble thrombomodulin prevents acute lung injury in a rat cardiopulmonary bypass model

Cited by 21 publications

References 38 publications

Blood cytokine expression correlates with early multi-organ damage in a mouse model of moderate hypothermia with circulatory arrest using cardiopulmonary bypass

Blood cytokine expression correlates with early multi-organ damage in a mouse model of moderate hypothermia with circulatory arrest using cardiopulmonary bypass

Endothelial colony-forming cells reduced the lung injury induced by cardiopulmonary bypass in rats

Thrombomodulin in disseminated intravascular coagulation and other critical conditions—a multi-faceted anticoagulant protein with therapeutic potential

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