Silicosis is an occupational lung disease caused by prolonged exposure to silica dust in the workplace.It has a complex pathogenesis and currently lacks effective treatments.Homoharringtonine(HHT)is a natural compound...Silicosis is an occupational lung disease caused by prolonged exposure to silica dust in the workplace.It has a complex pathogenesis and currently lacks effective treatments.Homoharringtonine(HHT)is a natural compound approved for the treatment of acute myeloid leukemia,but its effects on silicosis remain unclear.In the present study,we constructed a mouse model of silica(SiO_(2))-induced pulmonary fibrosis and evaluated the preventive and therapeutic effects of HHT.The results showed that HHT significantly attenuated the progression of SiO_(2)-induced pulmonary fibrosis in mice.We then used MRC-5,a human lung fibroblast cell line,to explore the mechanisms underlying HHT's inhibitory effects in vitro and found that HHT significantly inhibited the activation and migratory capacity of MRC-5 cells.Mechanistically,these effects were mediated by enhanced ubiquitination and degradation of the CCR1 protein.Furthermore,HHT exhibited favorable biocompatibility in vivo,and its preventive and therapeutic effects were validated in SiO_(2)-treated mice.Collectively,the current study demonstrates that HHT shows significant potential as a therapeutic agent for silicosis by targeting CCR1 and the PI3K/AKT/m TOR signaling pathway,highlighting it as a promising candidate for clinical translation for silicosis treatment.展开更多
[目的]观察不同浓度大气PM_(2.5)对哮喘大鼠的影响,并初步探索PM_(2.5)诱导大鼠哮喘加重过程中miR155、STAT6、IL-13的变化。[方法]将50只SD大鼠随机分为:对照组,哮喘组,哮喘+PM_(2.5)低染毒组、哮喘+PM_(2.5)中染毒组及哮喘+PM_(2.5)...[目的]观察不同浓度大气PM_(2.5)对哮喘大鼠的影响,并初步探索PM_(2.5)诱导大鼠哮喘加重过程中miR155、STAT6、IL-13的变化。[方法]将50只SD大鼠随机分为:对照组,哮喘组,哮喘+PM_(2.5)低染毒组、哮喘+PM_(2.5)中染毒组及哮喘+PM_(2.5)高染毒组。对照组和哮喘组均给予生理盐水1.5 m L/kg(以每千克体重计,下同),哮喘+低、中、高染毒组分别给予PM_(2.5)生理盐水混悬液1.5、6.0、24.0 mg/kg。通过腹腔注射卵清蛋白(OVA)致敏,雾化吸入OVA构建大鼠哮喘模型,第25、28、31、34天予以PM_(2.5)气管滴注染毒。第36天处死大鼠后,观察肺脏HE染色病理切片,比较各组大鼠支气管肺灌洗液(BALF)中细胞总数及分类计数;通过RT-PCR检测大鼠肺组织中miR155、STAT6(信号转导和转录激活因子6)、IL-13的基因表达水平;ELISA检测大鼠BALF中IL-13蛋白水平。[结果]哮喘组大鼠BALF中嗜酸粒细胞百分比高于对照组,哮喘+PM_(2.5)中、高染毒组高于对照组及哮喘组,差异均有统计学意义(P<0.05);哮喘+PM_(2.5)中、高染毒组大鼠肺组织miR155及STAT6基因表达水平高于对照组,差异均有统计学意义(P<0.05);大鼠肺组织miR155与STAT6基因表达呈明显正相关(r=0.843,P<0.001);5组大鼠肺组织IL-13基因及BALF中IL-13蛋白表达水平间的差异无统计学意义(P>0.05)。[结论]miR155及STAT6可能在PM_(2.5)加重哮喘过程中起作用,并且miR155与STAT6之间存在关联。展开更多
基金supported by grants from the National Natural Science Foundation of China(Grant Nos.82473601 to Y.L.,82404234 to W.S.,and 82073518 to C.N.)the Foundation of Chongqing Key Laboratory of Prevention and Treatment for Occupational Diseases and Poisoning(Grant No.2022-2023ZYBKF04 to C.N.)。
文摘Silicosis is an occupational lung disease caused by prolonged exposure to silica dust in the workplace.It has a complex pathogenesis and currently lacks effective treatments.Homoharringtonine(HHT)is a natural compound approved for the treatment of acute myeloid leukemia,but its effects on silicosis remain unclear.In the present study,we constructed a mouse model of silica(SiO_(2))-induced pulmonary fibrosis and evaluated the preventive and therapeutic effects of HHT.The results showed that HHT significantly attenuated the progression of SiO_(2)-induced pulmonary fibrosis in mice.We then used MRC-5,a human lung fibroblast cell line,to explore the mechanisms underlying HHT's inhibitory effects in vitro and found that HHT significantly inhibited the activation and migratory capacity of MRC-5 cells.Mechanistically,these effects were mediated by enhanced ubiquitination and degradation of the CCR1 protein.Furthermore,HHT exhibited favorable biocompatibility in vivo,and its preventive and therapeutic effects were validated in SiO_(2)-treated mice.Collectively,the current study demonstrates that HHT shows significant potential as a therapeutic agent for silicosis by targeting CCR1 and the PI3K/AKT/m TOR signaling pathway,highlighting it as a promising candidate for clinical translation for silicosis treatment.
文摘[目的]观察不同浓度大气PM_(2.5)对哮喘大鼠的影响,并初步探索PM_(2.5)诱导大鼠哮喘加重过程中miR155、STAT6、IL-13的变化。[方法]将50只SD大鼠随机分为:对照组,哮喘组,哮喘+PM_(2.5)低染毒组、哮喘+PM_(2.5)中染毒组及哮喘+PM_(2.5)高染毒组。对照组和哮喘组均给予生理盐水1.5 m L/kg(以每千克体重计,下同),哮喘+低、中、高染毒组分别给予PM_(2.5)生理盐水混悬液1.5、6.0、24.0 mg/kg。通过腹腔注射卵清蛋白(OVA)致敏,雾化吸入OVA构建大鼠哮喘模型,第25、28、31、34天予以PM_(2.5)气管滴注染毒。第36天处死大鼠后,观察肺脏HE染色病理切片,比较各组大鼠支气管肺灌洗液(BALF)中细胞总数及分类计数;通过RT-PCR检测大鼠肺组织中miR155、STAT6(信号转导和转录激活因子6)、IL-13的基因表达水平;ELISA检测大鼠BALF中IL-13蛋白水平。[结果]哮喘组大鼠BALF中嗜酸粒细胞百分比高于对照组,哮喘+PM_(2.5)中、高染毒组高于对照组及哮喘组,差异均有统计学意义(P<0.05);哮喘+PM_(2.5)中、高染毒组大鼠肺组织miR155及STAT6基因表达水平高于对照组,差异均有统计学意义(P<0.05);大鼠肺组织miR155与STAT6基因表达呈明显正相关(r=0.843,P<0.001);5组大鼠肺组织IL-13基因及BALF中IL-13蛋白表达水平间的差异无统计学意义(P>0.05)。[结论]miR155及STAT6可能在PM_(2.5)加重哮喘过程中起作用,并且miR155与STAT6之间存在关联。
