Mivebresib alleviates systemic lupus erythematosus-associated diffuse alveolar hemorrhage via inhibiting infiltration of monocytes and M1 polarization of macrophages

by Selleckchem | Aug 01 2023

Background: Diffuse alveolar hemorrhage (DAH) is a serious complication that can arise from systemic lupus erythematosus (SLE) and other autoimmune diseases. While current treatments for DAH have limitations and adverse side effects, recent evidence suggests that inflammatory macrophages play a crucial role in the development of DAH. In this study, we investigated Mivebresib, a BET protein-bromodomain-containing protein 4 (BRD4) inhibitor, as a potential treatment for DAH.

Results: Our findings show that Mivebresib effectively protected C57BL/6J mice against pristane-induced DAH by inhibiting the migration and polarization of monocytes and macrophages, as well as pathogenic B and T cells. Specifically, Mivebresib modified the distribution of leukocytes, impeded the polarization of inflammatory macrophages, and reduced the frequency of CD19 + CD5 + B cells in the lungs of pristane-treated mice. Furthermore, in vitro experiments demonstrated that Mivebresib inhibited LPS-induced M1 polarization of macrophages and the expression of pro-inflammatory cytokines, M1 marker genes, and chemokines-chemokine receptors while thwarting the secretion of IL-6 and TNF-α. Transcriptomic analysis suggested and experiments comfimed that Mivebresib inhibits M1 polarization via interrupting the p300/BRD4/HIF1A axis.

Conclusions: Our study demonstrates that Mivebresib has therapeutic potential for the life-threatening complication of DAH caused by SLE. By inhibiting macrophage polarization and the infiltration of inflammatory cells, Mivebresib may offer a promising treatment option for patients suffering from this disease.

Comments:

That's an interesting study! The results suggest that Mivebresib, a BET protein-bromodomain-containing protein 4 (BRD4) inhibitor, shows promise as a potential treatment for diffuse alveolar hemorrhage (DAH) associated with systemic lupus erythematosus (SLE) and other autoimmune diseases. Here's a summary of the key findings:

1. In a mouse model of pristane-induced DAH, Mivebresib effectively protected the mice by inhibiting the migration and polarization of monocytes and macrophages, as well as pathogenic B and T cells.
2. Mivebresib altered the distribution of leukocytes, hindered the polarization of inflammatory macrophages, and reduced the frequency of CD19+CD5+ B cells in the lungs of the mice.
3. In vitro experiments demonstrated that Mivebresib inhibited the M1 polarization of macrophages induced by LPS (lipopolysaccharide), resulting in reduced expression of pro-inflammatory cytokines, M1 marker genes, and chemokines-chemokine receptors. It also inhibited the secretion of IL-6 and TNF-α.
4. Transcriptomic analysis suggested that Mivebresib inhibits M1 polarization by interrupting the p300/BRD4/HIF1A axis.

Based on these findings, the study concludes that Mivebresib has therapeutic potential for treating DAH caused by SLE. By inhibiting macrophage polarization and the infiltration of inflammatory cells, Mivebresib may offer a promising treatment option for patients with this life-threatening complication.

It's worth noting that this study appears to be preclinical, conducted in a mouse model and in vitro experiments. Further research, including clinical trials, will be necessary to evaluate the safety and efficacy of Mivebresib in human patients with DAH associated with SLE or other autoimmune diseases.