Airway inflammation is a hallmark of asthma, and suggests a dysregulation of homeostatic mechanisms. MicroRNAs (miRNAs) are key regulators of gene expression necessary for the proper function of cellular processes. We tested the hypothesis that differences between healthy and asthmatic subjects may be a result of distinct miRNA cellular profiles that lead to differential regulation of inflammatory genes. We collected human bronchial epithelial cells from seven healthy donors and seven patients with asthma, and profiled miRNA expression, using the Affymetrix (Santa Clara, CA) miRNA array platform. Results were confirmed according to quantitative RT-PCR on RNA isolated from 16 healthy and 16 asthmatic donors. We identified 66 miRNAs that were significantly different (≥ 1.5-fold; P ≤ 0.05) between the two groups, and validated three of them in epithelial cells from 16 asthmatic and 16 healthy subjects. Molecular network analysis indicated that putative targets were principally involved in regulating the expression of inflammatory pathway genes (P ≤ 10(-4)). Our analysis confirmed the prediction that the expression of IL-8, Cox2, and TNF-α was up-regulated in asthmatic cells, whereas the expression of IL-6 was lower compared with that in healthy control subjects. Network analysis was also used to identify a novel asthma-associated gene. The top-ranked predicted target of the highly down-regulated miRNA-203 in asthmatic cells was the aquaporin gene AQP4. Its expression was confirmed to be significantly higher in cells from patients with asthma. Overall, these data suggest that the heightened inflammatory pathway activation observed in patients with asthma may be attributed to underlying aberrant miRNA expression.

Epidemiologic studies have demonstrated increased human morbidity and mortality with elevations in the concentration of ambient air particulate matter (PM). Fugitive fly ash from the combustion of oil and residual fuel oil significantly contributes to the ambient air particle burden. Residual oil fly ash (ROFA) is remarkable in the capacity to provoke injury in experimental systems. The unique composition of this emission source particle makes it particularly useful as a surrogate for ambient air PM in studies of biologic effects testing the hypothesis that metals mediate the biologic effects of air pollution particles. A majority of the in vitro and animal model investigations support the postulate that transition metals present in ROFA (especially vanadium) participate in Fenton-like chemical reactions to produce reactive oxygen species. This is associated with tyrosine phosphorylation, nuclear factor kappa B and other transcription factor activation, induction of inflammatory mediator expression, and inflammatory lung injury. It is also evident that vanadium accounts for a significant portion of the biologic activity of ROFA. The extrapolation of this body of investigation on ROFA to the field of ambient air PM is difficult, as particles in numerous environments have such small amounts of vanadium.

No abstract