Probucol attenuates hyperoxia-induced lung injury in mice

Tomonobu Kawaguchi,Toyoshi Yanagihara,Kunihiro Suzuki,Tetsuya Yokoyama,Kazuyoshi Kuwano,Takashige Maeyama,Saiko Suetsugu-Ogata,Chika Harada-Ikeda,Yoichi Nakanishi,Naoki Hamada,Shama Ahmad

doi:10.1371/journal.pone.0175129

Abstract

Hyperoxic lung injury is pathologically characterized by alveolar edema, interlobular septal edema, hyaline membrane disease, lung inflammation, and alveolar hemorrhage. Although the precise mechanism by which hyperoxia causes lung injury is not well defined, oxidative stress, epithelial cell death, and proinflammatory cytokines are thought to be involved. Probucol—a commercially available drug for treating hypercholesterolemia—has been suggested to have antioxidant and antiapoptotic effects. This study aimed to assess whether probucol could attenuate hyperoxic lung injury in mice. Mice were exposed to 95% O2 for 72 h, with or without pre-treatment with 130 μg/kg probucol intratracheally. Probucol treatment significantly decreased both the number of inflammatory cells in the bronchoalveolar lavage fluid and the degree of lung injury in hyperoxia-exposed mice. Probucol treatment reduced the number of cells positive for 8-hydroxyl-2′-deoxyguanosine or terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and suppressed NF-κB activation, Bax expression, and caspase-9 activation in lung tissues from hyperoxia-exposed mice. These results suggest that probucol can reduce oxidative DNA damage, apoptotic cell death, and inflammation in lung tissues. Intratracheal administration of probucol may be a novel treatment for lung diseases induced by oxidative stress, such as hyperoxic lung injury and acute respiratory distress syndrome.

Highlights

Oxygen therapy is required for patients with hypoxemia to prevent serious pulmonary or cardiac disorders
The numbers of total cells, macrophages, neutrophils, and lymphocytes in BALF significantly increased in hyperoxia-exposed mice compared with those in room-air-exposed mice
Correlated with BALF findings (Fig 1A), lung tissues from room-air-exposed mice with and without probucol treatment showed no inflammation or lung injury (Fig 1C and 1B, respectively) while those from hyperoxia-exposed mice showed thickened alveolar walls infiltrated with neutrophils and lymphocytes, alveolar hemorrhage and parenchymal edema (Fig 1D)

Summary

Introduction

Oxygen therapy is required for patients with hypoxemia to prevent serious pulmonary or cardiac disorders. Prolonged exposure to high levels of oxygen can result in higher intensive care unit mortality [1] and may lead to acute respiratory distress syndrome (ARDS). Animal models of hyperoxic lung injury are pathologically characterized by alveolar and interlobular septal edema, hyaline membrane disease, inflammatory cell infiltration, and alveolar hemorrhage [2]. Hyperoxic lung injury in experimental animals is regarded as an established model of ARDS [3].

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