Department of Advanced Preventive Medicine for Infectious Disease, Tohoku University Graduate School of Medicine.
Yaotome Ekimae Clinic of Internal Medicine.
Tohoku J Exp Med. 2019 Apr;247(4):215-222. doi: 10.1620/tjem.247.215.
Carbon monoxide (CO) and nitric oxide (NO) exhibit physiological properties that include the activation of guanylate cyclase. NO inhibits replication of rhinovirus (RV), a major cause of the common cold and exacerbation of bronchial asthma and chronic obstructive pulmonary disease. However, the anti-rhinoviral effects of CO remain unclear. This study investigated whether the exogenous application of low-dose CO could inhibit RV replication in human alveolar and airway epithelial cells. A549 human lung carcinoma cells with alveolar epithelial features and primary cultures of human tracheal epithelial (HTE) cells were pretreated with CO (100 ppm) and infected with a major group RV, type 14 RV (RV14). CO exposure reduced RV14 titers in the supernatants and RV RNA levels in A549 and HTE cells. The treatment with a guanylate cyclase inhibitor, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, reversed the inhibitory effects of CO exposure on RV14 replication in A549 cells. Pretreatment of A549 cells with 8-Br-cGMP, a cell-permeable cGMP analog, caused the decrease in RV14 replication, while CO exposure increased cGMP production. CO exposure also increased the expression levels of interferon (IFN)-γ mRNA and protein. In contrast, pretreatment with CO did not increase DNA fragmentation and did not reduce the expression of intercellular adhesion molecule-1, the RV14 receptor, or the number of acidic endosomes, through which RV RNA enters the cytoplasm. These findings suggest that low-dose CO may decrease RV14 replication in alveolar and airway epithelial cells. IFN-γ production, which is induced by CO exposure via guanylate cyclase activation-mediated cGMP production, may be involved in RV14 replication inhibition.
一氧化碳（CO）和一氧化氮（NO）具有激活鸟苷酸环化酶的生理特性。NO 可抑制鼻病毒（RV）的复制，RV 是普通感冒、支气管哮喘和慢性阻塞性肺疾病恶化的主要原因。然而，CO 的抗鼻病毒作用尚不清楚。本研究旨在探讨外源性应用低剂量 CO 是否能抑制人肺泡和气道上皮细胞中的 RV 复制。用 CO（100ppm）预处理具有肺泡上皮特征的 A549 人肺癌细胞和原代培养的人气管上皮（HTE）细胞，然后用主要组 RV 型 14 型 RV（RV14）感染。CO 暴露降低了上清液中的 RV14 滴度和 A549 和 HTE 细胞中的 RV RNA 水平。鸟苷酸环化酶抑制剂 1H-[1,2,4]恶二唑[4,3-a]喹喔啉-1-酮的处理逆转了 CO 暴露对 A549 细胞中 RV14 复制的抑制作用。用细胞可渗透的 cGMP 类似物 8-Br-cGMP 预处理 A549 细胞可导致 RV14 复制减少，而 CO 暴露可增加 cGMP 产生。CO 暴露还增加了干扰素（IFN）-γ mRNA 和蛋白的表达水平。相反，CO 预处理不会增加 DNA 片段化，也不会降低 RV14 受体细胞间黏附分子-1 的表达或降低酸性内体的数量，RV RNA 通过这些内体进入细胞质。这些发现表明，低剂量 CO 可能会减少肺泡和气道上皮细胞中的 RV14 复制。CO 暴露通过激活鸟苷酸环化酶介导的 cGMP 产生诱导 IFN-γ 产生，可能参与 RV14 复制抑制。
