Abstract 21057: Combined Administration of DNMT and HDAC6 Inhibitors Suppress Endotoxemia Induced Macrophages Pro-Inflammatory Signaling Pathway
| Autor: | Zhigang Zhou, Saheli Samanta, Sheeja Rajasingh, Bahar Barani, Nicholas Drosos, Rui-Lan Wang, Buddhadeb Dawn, Johnson Rajasingh |
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| Rok vydání: | 2017 |
| Předmět: | |
| Zdroj: | Circulation. 136 |
| ISSN: | 1524-4539 0009-7322 |
| Popis: | Background: Acute lung injury (ALI) is an common inflammatory disease that affects millions of people worldwide. Therapies based on a new understanding of disease pathogenesis are needed. Studies have shown that treatment with a single drug is not effective in controlling the pro-inflammatory response caused by ALI. Hypothesis: The combinatorial epigenetic treatment with 5-Aza-2’-deoxycytidine (Aza, a DNMT inhibitor) and Tubastatin-A (TBSA, a HDAC6 inhibitor) after LPS-induced ALI would mitigates the pro-inflammatory P38-MAPK signaling and rescues animal from ALI-induced death. Methods: Acute lung injury was induced in C57BL mice by intraperitoneal injection of LPS (10mg/kg). One hour later, the mice received either vehicle, Aza (1mg/kg), TBSA (0.25mg/kg), or Aza+TBSA. After 12 hours, the mice were sacrificed for further biochemical and histological analyses. To delineate the signaling mechanism, we have used macrophage cell line (RAW 264.7). For this, macrophages were treated with vehicle, LPS (1ug/ml), Aza (50nM), TBSA (750nM), or with combined treatment for 30 min and 24 hours for Western and qRT-PCR analyses. Results: We observed that all mice treated with LPS and LPS+Aza died within 24 hrs. The mice treated with LPS+TBSA exhibited 20% survival rate whereas the LPS+Aza+TBSA- treated group displayed 80% survival rate. Our results revealed that LPS significantly increases the expression of inflammatory cytokines such as iNOS, IL-6 and TNF-α in macrophages. However, the increased mRNA expression was significantly reduced after treatment with Aza+TBSA (Fig. A) . We also found that Aza+TBSA suppressed the LPS-induced P38-MAPK signaling pathway (Fig. B) . Conclusion: We report for the first time that Aza+TBSA together reverses the outcome of ALI induced by endotoxemia. |
| Databáze: | OpenAIRE |
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