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

• Published in: Experimental and therapeutic medicine 2019-05, Vol.17 (5), p.3429-3440
• Main Authors: Kumada, Yuta, Takahashi, Toru, Shimizu, Hiroko, Nakamura, Ryu, Omori, Emiko, Inoue, Kazuyoshi, Morimatsu, Hiroshi
• Format: Article
• Language: English
• Subjects: Adult respiratory distress syndrome; Apoptosis; Blood gas analysis; Blood pressure; Carbon monoxide; Care and treatment; Complications and side effects; Cytokines; Drug dosages; Edema; Experiments; Fluorescein; Gene expression; Genes; Health aspects; Hemorrhagic shock; Inflammation; Interleukins; Laboratory animals; Liver; Lung diseases; Macrophages; Necrosis; Nitric oxide; Nitrogen oxides; Physiological aspects; Physiology; Pulmonary edema; Resuscitation; Rodents; Shock; Studies; Tumors; Veins & arteries; Vital signs; Xenobiotics
• ISSN: 1792-0981; 1792-1015
• DOI: 10.3892/etm.2019.7390

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.