Altered microRNA profiles in bronchoalveolar lavage fluid exosomes in asthmatic patients

Abstract

Background Asthma is characterized by increased airway narrowing in response to nonspecific stimuli. The disorder is influenced by both environmental and genetic factors. Exosomes are nanosized vesicles of endosomal origin released from inflammatory and epithelial cells that have been implicated in asthma. In this study we characterized the microRNA (miRNA) content of exosomes in healthy control subjects and patients with mild intermittent asthma both at unprovoked baseline and in response to environmental challenge. Objective To investigate alterations in bronchoalveolar lavage fluid (BALF) exosomal miRNA profiles due to asthma, and following subway air exposure. Methods Exosomes were isolated from BALF from healthy control subjects (n = 10) and patients with mild intermittent asthma (n = 10) after subway and control exposures. Exosomal RNA was analyzed by using microarrays containing probes for 894 human miRNAs, and selected findings were validated with quantitative RT-PCR. Results were analyzed by using multivariate modeling. Results The presence of miRNAs was confirmed in exosomes from BALF of both asthmatic patients and healthy control subjects. Significant differences in BALF exosomal miRNA was detected for 24 miRNAs with a subset of 16 miRNAs, including members of the let-7 and miRNA-200 families, providing robust classification of patients with mild nonsymptomatic asthma from healthy subjects with 72% cross-validated predictive power (Q2 = 0.72). In contrast, subway exposure did not cause any significant alterations in miRNA profiles. Conclusion These studies demonstrate substantial differences in exosomal miRNA profiles between healthy subjects and patients with unprovoked, mild, stable asthma. These changes might be important in the inflammatory response leading to bronchial hyperresponsiveness and asthma.

Extracellular vesicles released in response to respiratory exposures: implications for chronic disease

“…The same CSE-EV were less potent inducers of monocyte adhesion to endothelial cells than EV secreted by unexposed cells , questioning a role of CSE-induced EV in immune cell recruitment. Several human and animal studies that assessed in vivo effects of respiratory exposures were not able to link changes in circulating EV to alterations in inflammatory markers (Emmerechts et al 2012a(Emmerechts et al , 2012bLevanen et al 2013;Mobarrez et al 2014). Several investigators even found that smokers displayed decreased concentrations of circulating PS + EV compared to nonsmokers (Badrnya, Baumgartner, and Assinger 2014;Enjeti et al 2017;Grant et al 2011).…”

“…Several investigators even found that smokers displayed decreased concentrations of circulating PS + EV compared to nonsmokers (Badrnya, Baumgartner, and Assinger 2014;Enjeti et al 2017;Grant et al 2011). In part, the failure to detect proinflammatory changes in EV in response to respiratory toxicants in vivo may be due to (1) use of relatively mild and acute exposures (Levanen et al 2013;Mobarrez et al 2014) or (2) the fact that current methods are not sensitive enough to detect subtle changes in EV and inflammatory mediators in study populations without clinical disease.…”

Subtypes of Asthma Defined by Epithelial Cell Expression of Messenger RNA and MicroRNA

“…There are at least three ways that miRNAs are protected from RNases. First, miRNAs can be contained within membrane-bound vesicles termed "exosomes" (40). Second, miRNAs can be bound by proteins such as Argonaute (41).…”

Let-7a is differentially expressed in bronchial biopsies of patients with severe asthma

“…The variability in treatment response is based on large asthma clinical heterogeneity, and understanding the pattern of airway inflammation and molecular factors regulating those processes could be helpful in defining asthma endotypes and understanding why therapy is not effective in all patients 6 . MicroRNAs (miRNAs), 19-25 nucleotides long non-coding small RNAs involved in regulation of gene expression through a process known as RNA interference 729 , may play a role in orchestrating the phenotypic programming of immune and airway epithelial cells to enhance the production of cytokines and other mediators that result in the inflammation that characterizes asthma 3,4,[10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25] . Therefore, miRNAs may contribute to asthma pathology.…”