Therapeutic effect of carbon monoxide‑releasing molecule‑3 on acute lung injury after hemorrhagic shock and resuscitation

Kumada,Yuta; Takahashi,Toru; Shimizu,Hiroko; Nakamura,Ryu; Omori,Emiko; Inoue,Kazuyoshi; Morimatsu,Hiroshi

doi:10.3892/etm.2019.7390

Therapeutic effect of carbon monoxide‑releasing molecule‑3 on acute lung injury after hemorrhagic shock and resuscitation

Authors:
- Yuta Kumada
- Toru Takahashi
- Hiroko Shimizu
- Ryu Nakamura
- Emiko Omori
- Kazuyoshi Inoue
- Hiroshi Morimatsu
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Affiliations: Department of Anesthesiology and Resuscitology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700‑8558, Japan, Faculty of Health and Welfare Science, Okayama Prefectural University, Soja, Okayama 719‑1197, Japan, Department of Anesthesiology, Kagawa Prefectural Central Hospital, Takamatsu, Kagawa 760‑8557, Japan
Published online on: March 13, 2019 https://doi.org/10.3892/etm.2019.7390
Pages: 3429-3440
Copyright: © Kumada et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Hemorrhagic shock and resuscitation (HSR) induces a pulmonary inflammatory response and frequently causes acute lung injury. Carbon monoxide‑releasing molecule‑3 (CORM‑3) has been reported to liberate and deliver CO under physiological conditions, which exerts organ‑protective effects during systemic insults. The present study aimed to determine whether the administration of CORM‑3 following HSR exerts a therapeutic effect against HSR‑induced lung injury without any detrimental effects on oxygenation and hemodynamics. To induce hemorrhagic shock, rats were bled to a mean arterial blood pressure of 30 mmHg for 45 min and then resuscitated with the shed blood. CORM‑3 or a vehicle was intravenously administered immediately following the completion of resuscitation. The rats were divided into four groups, including sham, HSR, HSR/CORM‑3 and HSR/inactive CORM‑3 groups. Arterial blood gas parameters and vital signs were recorded during HSR. The histopathological changes to the lungs were evaluated using a lung injury score, while pulmonary edema was evaluated on the basis of the protein concentration in bronchoalveolar lavage fluid and the lung wet/dry ratio. We also investigated the pulmonary expression levels of inflammatory mediators and apoptotic markers such as cleaved caspase-3 and transferase-mediated dUTP-fluorescein isothiocyanate nick-end labeling (TUNEL) staining. Although HSR caused significant lung histopathological damage and pulmonary edema, CORM‑3 significantly ameliorated this damage. CORM‑3 also attenuated the HSR‑induced upregulation of tumor necrosis factor‑α, inducible nitric oxide synthase and interleukin‑1β genes, and the expression of interleukin‑1β and macrophage inflammatory protein‑2. In addition, the expression of interleukin‑10, an anti‑inflammatory cytokine, was inversely enhanced by CORM‑3, which also reduced the number of TUNEL‑positive cells and the expression of cleaved caspase‑3 following HSR. Although CORM‑3 was administered during the acute phase of HSR, it did not exert any influence on arterial blood gas analysis data and vital signs during HSR. Therefore, treatment with CORM‑3 ameliorated HSR‑induced lung injury, at least partially, through anti‑inflammatory and anti‑apoptotic effects, without any detrimental effects on oxygenation and hemodynamics.

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