SIRT6 ameliorates LPS-induced apoptosis and tight junction injury in ARDS through the ERK1/2 pathway and autophagy

by Selleckchem | Oct 21 2023

Sirtuin6 (SIRT6) has been demonstrated to be involved in a range of physiological processes and diseases, while its role in acute respiratory distress syndrome (ARDS) remains unclear. Therefore, this study focused on the role and underlying mechanism of SIRT6 in ARDS with the aim of identifying potential therapeutic targets. In this study, we found that SIRT6 was significantly decreased in lipopolysaccharide (LPS)-induced A549 cells and a murine model. In vitro overexpression of SIRT6 restored the expression of tight junction proteins (ZO-1 and occludin) and alleviated cell apoptosis and inflammation, while knockdown of SIRT6 aggravated the loss of tight junction proteins (ZO-1 and occludin) and promoted cell apoptosis and inflammation in LPS-induced A549 cells. Furthermore, the overexpression of SIRT6 enhanced autophagy and inhibited the ERK1/2 pathway, while the knockdown of SIRT6 inhibited autophagy and activated the ERK1/2 pathway. The autophagy activator rapamycin and the ERK1/2 inhibitor PD98059 rescued the effects of SIRT6 knockdown on tight junction proteins, apoptosis, and inflammation. Mechanistically, SIRT6 deacetylated histone 3 at Lys9 to negatively regulate the ERK1/2 pathway. In vivo, the SIRT6-specific inhibitor OSS_128167 also significantly accelerated LPS-induced loss of tight junction proteins, lung inflammation, and apoptosis. Meanwhile, the SIRT6-specific inhibitor OSS_128167 also activated the ERK1/2 pathway and inhibited lung autophagy. These results suggested that SIRT6 could ameliorate the loss of tight junction proteins, inflammation, and apoptosis in LPS-induced ARDS by inhibiting the ERK1/ 2 pathway and enhancing autophagy, indicating that SIRT6 plays a beneficial role in ARDS and might be a potential therapeutic target for ARDS.

Comments:

The study you mentioned focuses on investigating the role of SIRT6 (sirtuin 6) in acute respiratory distress syndrome (ARDS) and identifying potential therapeutic targets. Here's a breakdown of the key findings:

1. SIRT6 levels: The study observed a significant decrease in SIRT6 levels in lipopolysaccharide (LPS)-induced A549 cells (a human lung carcinoma cell line commonly used to study lung diseases) and a murine model of ARDS.

2. Overexpression and knockdown of SIRT6: In vitro experiments showed that overexpression of SIRT6 restored the expression of tight junction proteins (ZO-1 and occludin) and reduced cell apoptosis and inflammation in LPS-induced A549 cells. On the other hand, knockdown of SIRT6 exacerbated the loss of tight junction proteins and increased cell apoptosis and inflammation.

3. Autophagy and ERK1/2 pathway: Overexpression of SIRT6 enhanced autophagy (a cellular process involved in the degradation of damaged proteins and organelles) and inhibited the ERK1/2 pathway (a signaling pathway associated with inflammation and cell survival). Conversely, knockdown of SIRT6 inhibited autophagy and activated the ERK1/2 pathway.

4. Rescue experiments: Treating SIRT6 knockdown cells with an autophagy activator (rapamycin) or an ERK1/2 inhibitor (PD98059) restored the effects of SIRT6 knockdown on tight junction proteins, apoptosis, and inflammation. This suggests that autophagy activation and ERK1/2 inhibition are involved in the protective effects of SIRT6.

5. Mechanism: The study found that SIRT6 deacetylated histone 3 at Lys9, which negatively regulated the ERK1/2 pathway. This suggests that SIRT6 modulates the activity of the ERK1/2 pathway through epigenetic modifications.

6. In vivo validation: Using a specific SIRT6 inhibitor (OSS_128167), the study demonstrated that inhibiting SIRT6 accelerated the loss of tight junction proteins, increased lung inflammation, and apoptosis in an LPS-induced ARDS mouse model. Additionally, the inhibitor also activated the ERK1/2 pathway and inhibited lung autophagy.

Overall, the findings suggest that SIRT6 plays a beneficial role in ARDS by preserving tight junction proteins, reducing inflammation and apoptosis, and that it may serve as a potential therapeutic target for ARDS. The study also indicates that SIRT6 exerts its effects by inhibiting the ERK1/2 pathway and enhancing autophagy. However, further research is needed to validate these findings and explore the clinical implications.