Division of Health Chemistry, Department of Healthcare and Regulatory Sciences, School of Pharmacy, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo, 142-8555, Japan.
Division of Pharmacotherapeutics, Department of Clinical Pharmacy, School of Pharmacy, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo, 142-8555, Japan.
Redox Biol. 2023 Oct;66:102850. doi: 10.1016/j.redox.2023.102850. Epub 2023 Aug 12.
Long-chain acyl-CoA synthetase (ACSL) 4 converts polyunsaturated fatty acids (PUFAs) into their acyl-CoAs and plays an important role in maintaining PUFA-containing membrane phospholipids. Here we demonstrated decreases in various kinds of PUFA-containing phospholipid species in ACSL4-deficient murine lung. We then examined the effects of ACSL4 gene deletion on lung injury by treating mice with two pulmonary toxic chemicals: paraquat (PQ) and methotrexate (MTX). The results showed that ACSL4 deficiency attenuated PQ-induced acute lung lesion and decreased mortality. PQ-induced lung inflammation and neutrophil migration were also suppressed in ACSL4-deficient mice. PQ administration increased the levels of phospholipid hydroperoxides in the lung, but ACSL4 gene deletion suppressed their increment. We further found that ACSL4 deficiency attenuated MTX-induced pulmonary fibrosis. These results suggested that ACSL4 gene deletion might confer protection against pulmonary toxic chemical-induced lung injury by reducing PUFA-containing membrane phospholipids, leading to the suppression of lipid peroxidation. Inhibition of ACSL4 may be promising for the prevention and treatment of chemical-induced lung injury.
长链酰基辅酶 A 合成酶（ACSL）4 将多不饱和脂肪酸（PUFAs）转化为其酰基辅酶 A，并在维持含有 PUFA 的膜磷脂方面发挥重要作用。在这里，我们证明了 ACSL4 缺陷型小鼠肺中各种含有 PUFA 的磷脂种类减少。然后，我们通过用两种肺毒性化学物质：百草枯（PQ）和甲氨蝶呤（MTX）处理小鼠，检查了 ACSL4 基因缺失对肺损伤的影响。结果表明，ACSL4 缺乏可减轻 PQ 诱导的急性肺损伤并降低死亡率。ACSL4 缺陷型小鼠中的 PQ 诱导的肺炎症和中性粒细胞迁移也受到抑制。PQ 给药增加了肺中磷脂氢过氧化物的水平，但 ACSL4 基因缺失抑制了它们的增加。我们进一步发现，ACSL4 缺乏可减轻 MTX 诱导的肺纤维化。这些结果表明，ACSL4 基因缺失可能通过减少含有 PUFA 的膜磷脂来减轻肺毒性化学物质诱导的肺损伤，从而抑制脂质过氧化。抑制 ACSL4 可能是预防和治疗化学诱导性肺损伤的有希望的方法。
