Acute lung injury (ALI) during sepsis is characterized by bilateral alveolar infiltrates, lung edema, and respiratory failure. Here, we examined the efficacy of DNA methyl transferase (DNMT) inhibitor Aza (5-Aza 2-deoxycytidine), histone deacetylase (HDAC) inhibitor TSA (Trichostatin A), and combination therapy (Aza+TSA) in protection of ALI. In LPS-induced mouse ALI, post-treatment with a single dose of Aza+TSA showed a substantial attenuation of adverse lung histopathological changes, and inflammations. Importantly, these protective effects were due to significant macrophage phenotypic changes observed in LPS-stimulated macrophages treated with Aza+TSA as compared with untreated LPS-induced macrophages or LPS-stimulated macrophages treated with either drug alone. Further, we observed significantly lower levels of pro-inflammatory molecules and higher levels of anti-inflammatory molecules in LPS-induced macrophages treated with Aza+TSA than in LPS-induced macrophages treated with either drug alone. The protection was ascribed to dual effects by an inhibition of MAPK-HuR-TNF and activation of STAT3-Bcl2 pathways. Combinatorial treatment with Aza+TSA reduces inflammation and promotes an anti-inflammatory M2 macrophage phenotype in ALI. This finding gives further evidence that the epigenetic treatment has a therapeutic potential for patients with sepsis.
Cardiovascular diseases are the number one cause of death globally with an estimated 7.4 million people dying from coronary heart disease. Studies have been conducted to identify the therapeutic utility of exosomes in many diseases, including cardiovascular diseases. It has been demonstrated that exosomes are immune modulators, can be used to treat cardiac ischemic injury, pulmonary hypertension and many other diseases, including cancers. Exosomes can be used as a biomarker for disease and cell-free drug delivery system for targeting the cells. Many studies suggest that exosomes can be used as a cell-free vaccine for many diseases. In this chapter, we explore the possibility of future therapeutic potential of exosomes in various cardiovascular diseases.
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