Targeting Intra-Pulmonary P53-Dependent Long Non-Coding RNA Expression as a Therapeutic Intervention for Systemic Lupus Erythematosus-Associated Diffuse Alveolar Hemorrhage

被引:9
|
作者
Chen, Yi-Cheng [1 ,2 ,3 ]
Chou, Yu-Chi [4 ]
Hsieh, Yu-Tung [5 ]
Kuo, Pin-Yu [5 ]
Yang, Mei-Lin [5 ]
Chong, Hao-Earn [1 ]
Wu, Chao-Liang [3 ]
Shiau, Ai-Li [5 ]
Wang, Chrong-Reen [1 ,5 ]
机构
[1] Natl Cheng Kung Univ, Dept Internal Med, Med Coll & Hosp, Tainan 70403, Taiwan
[2] Ditmanson Med Fdn, Chiayi Christian Hosp, Dept Med Res, Chiayi 600566, Taiwan
[3] Natl Cheng Kung Univ, Dept Biochem & Mol Biol, Med Coll, Tainan 70403, Taiwan
[4] Acad Sinica, Biomed Translat Res Ctr, Taipei 11529, Taiwan
[5] Natl Cheng Kung Univ, Dept Microbiol & Immunol, Med Coll, Tainan 70403, Taiwan
关键词
systemic lupus erythematosus-associated diffuse alveolar hemorrhage; p53-dependent apoptosis; long non-coding RNA; short hairpin RNA; intra-pulmonary delivery; COLLAGEN-INDUCED ARTHRITIS; CELL-DEATH; PRISTANE; P53; AMELIORATION; PATHOGENESIS; INFLAMMATION; INDUCTION; MORTALITY; APOPTOSIS;
D O I
10.3390/ijms22136948
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Diffuse alveolar hemorrhage (DAH) in systemic lupus erythematosus (SLE) is associated with significant mortality, requiring a thorough understanding of its complex mechanisms to develop novel therapeutics for disease control. Activated p53-dependent apoptosis with dysregulated long non-coding RNA (lncRNA) expression is involved in the SLE pathogenesis and correlated with clinical activity. We examined the expression of apoptosis-related p53-dependent lncRNA, including H19, HOTAIR and lincRNA-p21 in SLE-associated DAH patients. Increased lincRNA-p21 levels were detected in circulating mononuclear cells, mainly in CD4+ and CD14+ cells. Higher expression of p53, lincRNA-p21 and cell apoptosis was identified in lung tissues. Lentivirus-based short hairpin RNA (shRNA)-transduced stable transfectants were created for examining the targeting efficacy in lncRNA. Under pristane stimulation, alveolar epithelial cells had increased p53, lincRNA-p21 and downstream Bax levels with elevated apoptotic ratios. After pristane injection, C57/BL6 mice developed DAH with increased pulmonary expression of p53, lincRNA-p21 and cell apoptosis. Intra-pulmonary delivery of shRNA targeting lincRNA-p21 reduced hemorrhage frequencies and improved anemia status through decreasing Bax expression and cell apoptosis. Our findings demonstrate increased p53-dependent lncRNA expression with accelerated cell apoptosis in the lungs of SLE-associated DAH patients, and show the therapeutic potential of targeting intra-pulmonary lncRNA expression in a pristane-induced model of DAH.
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页数:20
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