Targeting Intra-Pulmonary P53-Dependent Long Non-Coding RNA Expression as a Therapeutic Intervention for Systemic Lupus Erythematosus-Associated Diffuse Alveolar Hemorrhage.
Yi-Cheng ChenYu-Chi ChouYu-Tung HsiehPin-Yu KuoMei-Lin YangHao-Earn ChongChao-Liang WuAi-Li ShiauChrong-Reen WangPublished in: International journal of molecular sciences (2021)
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.
Keyphrases
- poor prognosis
- long non coding rna
- systemic lupus erythematosus
- induced apoptosis
- pulmonary hypertension
- oxidative stress
- cell death
- cell proliferation
- cell cycle arrest
- end stage renal disease
- binding protein
- randomized controlled trial
- newly diagnosed
- chronic kidney disease
- disease activity
- ejection fraction
- endoplasmic reticulum stress
- cardiovascular disease
- long noncoding rna
- type diabetes
- skeletal muscle
- gene expression
- rheumatoid arthritis
- high grade
- small molecule
- prognostic factors
- patient reported outcomes
- endothelial cells
- signaling pathway
- drug induced
- patient reported
- peripheral blood