MiR-146a regulates PM1 -induced inflammation via NF-κB signaling pathway in BEAS-2B cells.

Exposure to particulate matter (PM) leads to kinds of cardiopulmonary diseases, such as asthma, COPD, arrhythmias, lung cancer, etc., which are related to PM-induced inflammation. We have found that PM2.5 (aerodynamics diameter <2.5 µm) exposure induces inflammatory response both in vivo and in vitro. Since the toxicity of PM is tightly associated with its size and components, PM1 (aerodynamics diameter <1.0 µm) is supposed to be more toxic than PM2.5 . However, the mechanism of PM1 -induced inflammation is not clear. Recently, emerging evidences prove that microRNAs play a vital role in regulating inflammation. Therefore, we studied the regulation of miR-146a in PM1 -induced inflammation in human lung bronchial epithelial BEAS-2B cells. The results show that PM1 induces the increase of IL-6 and IL-8 in BEAS-2B cells and up-regulates the miR-146a expression by activating NF-κB signaling pathway. Overexpressed miR-146a prevents the nuclear translocation of p65 through inhibiting the IRAK1/TRAF6 expression, and downregulates the expression of IL-6 and IL-8. Taken together, these results demonstrate that miR-146a can negatively feedback regulate PM1 -induced inflammation via NF-κB signaling pathway in BEAS-2B cells.

Transient Inhibition of the JNK Pathway Promotes Human Hematopoietic Stem Cell Quiescence and Engraftment.

The widespread clinical application of cord blood (CB) for hematopoietic stem cell (HSC) transplantation is limited mainly by the inadequate number of hematopoietic stem and progenitor cells (HSPCs) in single CB units, which results in unsuccessful or delayed engraftment in recipients. The identification of agents to promote CB HSPC engraftment has significant therapeutic value. Here, we found that transient inhibition of the JNK pathway increased the HSC frequency in CB CD34+ cells to 13.46-fold. Mechanistic studies showed that inhibition of the JNK pathway upregulated the expression of quiescence-associated and stemness genes in HSCs, preventing HSCs from entering the cell cycle, increasing glucose uptake and accumulating reactive oxygen species (ROS). Importantly, transient inhibition of the JNK pathway during CB CD34+ cell collection also enhanced long-term HSC (LT-HSC) recovery and engraftment efficiency. Collectively, these findings suggest that transient inhibition of the JNK pathway could promote a quiescent state in HSCs by preventing cell cycle entry and metabolic activation, thus enhancing the HSC number and engraftment potential. Together, these findings improve the understanding of the regulatory mechanisms governing HSC quiescence and stemness and have the potential to improve HSC collection and transplantation.

Indirect effect of PM1 on endothelial cells via inducing the release of respiratory inflammatory cytokines.

A large number of epidemiological studies have shown that increased cardiovascular morbidity and mortality are associated with exposure to high concentrations of PM2.5. One of the ways that PM2.5 affects the cardiovascular system is through systemic inflammation. Inflammatory cytokines such as TNF-α, IL-1ß, IL-6, and IL-8 stimulate endothelial cells, which leads to endothelial dysfunction. Compared with PM2.5, PM1 is smaller in size, has a larger surface area and absorbs more toxic substances such as heavy metals, organic compounds, and black carbon. However, the effect of PM1 on human health is less studied. Here, we used BEAS-2B cells and differentiated THP-1 cells to simulate epithelial cells and macrophages in the lung, respectively. The indirect effect of PM1 on endothelial cells was studied with a coculture model consisting of two cell lines (BEAS-2B cells and macrophages) in the top compartment and one cell line, human umbilical vein endothelial cells (EA.hy926), in the bottom compartment of a transwell plate. The results showed that PM1 could promote the release of inflammatory cytokines, including TNF-α and IL-6, from BEAS-2B cells and macrophages. In addition, PM1 upregulated ICAM-1 expression in EA.hy926 cells through TNF-α/NF-κB signaling pathways, promoting the adhesion of endothelial cells and monocytes, a key event in the initiation of atherosclerosis.

AMPKα2 deficiency exacerbates long-term PM2.5 exposure-induced lung injury and cardiac dysfunction.

Previous studies have demonstrated that long-term exposure to fine particulate matter (PM2.5) increases the risk of respiratory and cardiovascular diseases. As a metabolic sensor, AMP-activated protein kinase (AMPK) is a promising target for cardiovascular disease. However, the impact of AMPK on the adverse health effects of PM2.5 has not been investigated. In this study, we exposed wild-type (WT) and AMPKα2-/- mice to either airborne PM2.5 (mean daily concentration ~64 µg/m3) or filtered air for 6 months through a whole-body exposure system. After exposure, AMPKα2-/- mice developed severe lung injury and left ventricular dysfunction. In the PM2.5-exposed lungs and hearts, loss of AMPKα2 resulted in higher levels of fibrotic genes, more collagen deposition, lower levels of peroxiredoxin 5 (Prdx5), and greater induction of oxidative stress and inflammation than observed in the lungs and hearts of WT mice. In PM2.5-exposed BEAS-2B and H9C2 cells, inhibition of AMPK activity significantly decreased cell viability and Prdx5 expression, and increased the intracellular ROS and p-NF-κB levels. Collectively, our results provide the first direct evidence that AMPK has a marked protective effect on the adverse health effects induced by long-term PM2.5 exposure. Our findings suggest that strategies to increase AMPK activity may provide a novel approach to attenuate air pollution associated disease.