Phosphodiesterase type 4 inhibitor prevents acute lung injury induced by cardiopulmonary bypass in a rat model☆

Hamamoto, Masaki; Suga, Michiharu; Nakatani, Takeshi; Takahashi, Yūzō; Satô, Yukio; Inamori, Shuji; Yagihara, Toshikatsu; Kitamura, Soichiro

doi:10.1016/j.ejcts.2004.01.054

Cited by 21 publications

(16 citation statements)

References 18 publications

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“…These data are consistent with a previous study (27) that showed an increase in the W/D ratio of the lung and pulmonary edema in a rat CPB model. Our new finding is that this increase in the W/D ratio was attenuated with H2 insufflation.…”

Section: Discussionsupporting

confidence: 95%

Insufflation of Hydrogen Gas Restrains the Inflammatory Response of Cardiopulmonary Bypass in a Rat Model

Fujii

Shirai²,

Inamori

et al. 2012

Artificial Organs

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Systemic inflammatory responses in patients receiving cardiac surgery with the use of the cardiopulmonary bypass (CPB) significantly contribute to CPB-associated morbidity and mortality. We hypothesized that insufflated hydrogen gas (H₂) would provide systemic anti-inflammatory and anti-apoptotic effects during CPB, therefore reducing proinflammatory cytokine levels. In this study, we examined the protective effect of H₂ on a rat CPB model. Rats were divided into three groups: the sham operation (SHAM) group, received sternotomy only; the CPB group, which was initiated and maintained for 60 min; and the CPB + H₂ group in which H₂ was given via an oxygenator during CPB for 60 min. We collected blood samples before, 20 min, and 60 min after the initiation of CPB. We measured the serum cytokine levels of (tumor necrosis factor-α, interleukin-6, and interleukin-10) and biochemical markers (lactate dehydrogenase, aspartate aminotransferase, and alanine aminotransferase). We also measured the wet-to-dry weight (W/D) ratio of the left lung 60 min after the initiation of CPB. In the CPB group, the cytokine and biochemical marker levels significantly increased 20 min after the CPB initiation and further increased 60 min after the CPB initiation as compared with the SHAM group. In the CPB + H₂ group, however, such increases were significantly suppressed at 60 min after the CPB initiation. Although the W/D ratio in the CPB group significantly increased as compared with that in the SHAM group, such an increase was also suppressed significantly in the CPB + H₂ group. We suggest that H₂ insufflation is a possible new potential therapy for counteracting CPB-induced systemic inflammation.

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Section: Discussionsupporting

confidence: 95%

Insufflation of Hydrogen Gas Restrains the Inflammatory Response of Cardiopulmonary Bypass in a Rat Model

Fujii

Shirai²,

Inamori

et al. 2012

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“…Interestingly, rolipram has also been shown to attenuate increased vascular permeability in rodent models attributable ischemia/reperfusion injury (25), cardiopulmonary bypass (26), and high peak inflation pressures (27). When rolipram was administered to intubated, sedated rats before administering thapsigargin, perivascular cuff formation was largely prevented (Fig.…”

Section: Resultsmentioning

confidence: 99%

Perivascular fluid cuffs decrease lung compliance by increasing tissue resistance*

Lowe

Alvarez

King

et al. 2010

Critical Care Medicine

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Objective-Lung inflammation causes perivascular fluid cuffs to form around extra-alveolar blood vessels; however, the physiologic consequences of such cuffs remain poorly understood. Herein, we tested the hypothesis that perivascular fluid cuffs, without concomitant alveolar edema, are sufficient to decrease lung compliance.Design-Prospective, randomized, controlled study. Setting-Research laboratory. Subjects-One hundred twenty male CD40 rats.Interventions-To test this hypothesis, the plant alkaloid thapsigargin was used to activate store-operated calcium entry and increase cytosolic calcium in endothelium. Thapsigargin was infused into a central venous catheter of intact, sedated, and mechanically ventilated rats.Measurements-Static and dynamic lung mechanics and hemodynamics were measured continuously.Main Results-Thapsigargin produced perivascular fluid cuffs along extra-alveolar vessels but did not cause alveolar flooding or blood gas abnormalities. Lung compliance dose-dependently decreased after thapsigargin infusion, attributable to an increase in tissue resistance that was attributed to increased tissue damping and tissue elastance. Airway resistance was not changed. Neither central venous pressure nor left ventricular end diastolic pressure was altered by thapsigargin. Heart rate did not change, although thapsigargin decreased pressure over time sufficient to reduce cardiac output by 50%. Infusion of the type 4 phosphodiesterase inhibitor, rolipram, prevented thapsigargin from inducing perivascular cuffs and decreasing lung compliance. Rolipram also normalized pressure over time and corrected the deficit in cardiac output.Conclusions-Our findings resolve for the first time that perivascular cuff formation negatively impacts mechanical coupling between the bronchovascular bundle and the lung parenchyma, decreasing lung compliance without impacting central venous pressure. Keywordspermeability; endothelium; thapsigargin; store-operated calcium entry; acute respiratory distress syndromeThe authors have not disclosed any potential conflicts of interest. The pulmonary endothelium normally serves as a tightly regulated barrier between blood and interstitium. However, endothelial barrier function is compromised in the blood vessels of critically ill patients with acute lung injury or acute respiratory distress syndrome (ARDS). Endothelial cell barrier disruption causes fluid accumulation in the lung parenchyma, which ultimately leads to inefficient gas exchange and decreased alveolar ventilation, and also in perivascular spaces surrounding extra-alveolar arteries and veins (1). Traditional thinking advocates that capillary endothelial cell barrier disruption increases interstitial fluid accumulation that is pulled by negative interstitial pressure into perivascular spaces of larger vessels as a safety mechanism that limits alveolar flooding. However, recent acute lung injury and pulmonary edema animal models indicate that extra-alveolar vessels exhibit greater permeability responses than do capillarie...

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“…Therapeutic effects of PDE4 inhibitors such as rolipram, roflumilast, and cilomilast have been tested in lung injury models. For example, rolipram has been shown to inhibit lung injury and/or inflammation induced by LPS (61), hyperoxia (62), and cardiopulmonary bypass (63). Treatment with roflumilast inhibited lung injury induced by cigarette smoke (64) and bleomycin (65).…”

Section: Phosphodiesterase Inhibitorsmentioning

confidence: 99%

Mitigation of Chlorine Lung Injury by Increasing Cyclic AMP Levels

Hoyle

2010

Proceedings of the American Thoracic Society

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Phosphodiesterase type 4 inhibitor prevents acute lung injury induced by cardiopulmonary bypass in a rat model☆

Abstract: These results suggest that rolipram prevents acute lung injury via the inhibition of neutrophil activation during and after CPB in this setting of a rat model.

Cited by 21 publications

References 18 publications

Insufflation of Hydrogen Gas Restrains the Inflammatory Response of Cardiopulmonary Bypass in a Rat Model

Insufflation of Hydrogen Gas Restrains the Inflammatory Response of Cardiopulmonary Bypass in a Rat Model

Perivascular fluid cuffs decrease lung compliance by increasing tissue resistance*

Mitigation of Chlorine Lung Injury by Increasing Cyclic AMP Levels

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