Macrophages are a heterogeneous population of phagocytic cells present in all tissues. Recently, several drugs that target the epigenetic machinery have emerged as attractive molecules for treating infection and inflammation by modulating macrophages. Treatment of lipopolysaccharide (LPS)-challenged macrophages with epigenetic modifiers leads to phenotype switching. This could provide stimulatory/destructive (M1) or suppressive/protective (M2) therapeutic strategies, which are crucial in the cytokine milieu in which the macrophages reside. In this review, we provide an overview of macrophage functional diversity during various diseases, including infection, as well as the current status in the development and clinical utility of epigenetic modifiers.

Myocardial infarction, atherosclerosis and hypertension are the most common heart-related diseases that affect both the heart and the blood vessels. Multiple independent risk factors have been shown to be responsible for cardiovascular diseases. The combination of a healthy diet, exercise and smoking cessation keeps these risk factors in check and helps maintain homeostasis. The dynamic monolayer endothelial cell integrity and cell-cell communication are the fundamental mechanisms in maintaining homeostasis. Recently, it has been revealed that small non-coding RNAs (ncRNAs) play a critical role in regulation of genes involved in either posttranscriptional or pretranslational modifications. They also control diverse biological functions like development, differentiation, growth, and metabolism. Among ncRNAs, the short interfering RNAs (siRNAs) and microRNAs (miRNAs) have been extensively studied, but their specific functions remain largely unknown. In recent years, miRNAs are efficiently studied as one of the important candidates for involvement in most biological processes and have been implicated in many human diseases. Thus, the identification and the respective targets of miRNAs may provide novel molecular insight and new therapeutic strategies to treat diseases. This review summarizes the recent developments and insight on the role of miRNAs in cardiovascular disease prognosis, diagnostic and clinical applications.

Introduction: Acute lung injury (ALI) during sepsis is characterized by bilateral alveolar infiltrates, lung edema, and respiratory failure. The exact molecular mechanism for ALI is poorly understood. Although chemical epigenetic modifiers can potentially limit lung inflammation, to date no study has examined the efficacy of DNA methyl transferase inhibitor 5-Aza 2-deoxycytidine (Aza) and histone deacetylase inhibitor Trichostatin A (TSA) combination therapy (Aza+TSA) on the polarization of macrophages. Hypothesis: We hypothesized that therapy with Aza+TSA would reduce inflammation in ALI and will stimulate the production of M2 macrophages. Methods and Results: In LPS-induced mouse ALI, post-treatment with a single dose of Aza+TSA showed a substantial attenuation of adverse lung inflammation and histopathological changes. Flow cytometry data showed a significant decrease in expression of CD14 and CD40, and increased expression of CD23 and CD124 in Aza+TSA-treated cells compared with untreated LPS-induced primary bone marrow derived macrophages (BMDMs) or LPS-induced BMDMs treated with either drug alone (Fig panel A). This was further confirmed by Western analysis for M1 marker NOS2 and M2 marker CD206. Our data showed lesser expression of NOS2 (Fig panel B) and higher expression of CD206 (Fig panel C) in LPS-challenged BMDMs treated with Aza+TSA than in the BMDMs treated with either Aza or TSA alone. These data support that Aza+TSA treatment promotes an M2 phenotype in LPS-stimulated macrophages, which secrete anti-inflammatory cytokines. Conclusions: This novel treatment with combined epigenetic modifiers has therapeutic potential for patients with sepsis-induced ALI by reducing inflammation and generation of alternatively activated M2 macrophages with more abilities of pathogen clearance.