microRNA profiling in lung tissue and bronchoalveolar lavage of cigarette smoke-exposed mice and in COPD patients: a translational approach

Abstract

Chronic obstructive pulmonary disease (COPD) is characterized by a progressive airflow limitation and is associated with a chronic inflammatory response in both airways and lungs. microRNAs (miRNAs) are often highly conserved between species and have an intricate role within homeostatic conditions and immune responses. Also, miRNAs are dysregulated in smoking-associated diseases. We investigated the miRNA profile of 523 miRNAs by stem-loop RT-qPCR in lung tissue and cell-free bronchoalveolar lavage (BAL) supernatant of mice exposed to air or cigarette smoke (CS) for 4 or 24 weeks. After 24 weeks of CS exposure, 31 miRNAs were differentially expressed in lung tissue and 78 in BAL supernatant. Next, we correlated the miRNA profiling data to inflammation in BAL and lung, obtained by flow cytometry or ELISA. In addition, we surveyed for overlap with newly assessed miRNA profiles in bronchial biopsies and with previously assessed miRNA profiles in lung tissue and induced sputum supernatant of smokers with COPD. Several miRNAs showed concordant differential expression between both species including miR-31*, miR-155, miR-218 and let-7c. Thus, investigating miRNA profiling data in different compartments and both species provided accumulating insights in miRNAs that may be relevant in CS-induced inflammation and the pathogenesis of COPD.

Gene Expression and Epigenetic Changes in Mice Following Inhalation of Copper(II) Oxide Nanoparticles

“…Specifically, the expression of mmu-miR-21a-5p, mmu-miR-147-3p, mmu-miR-449a-5p, and mmu-miR-703 was deregulated in the lungs of mice exposed to multi-walled carbon nanotubes [24] and mmu-miR-342-3p in mice exposed to nano-TiO2 particles [25]. The deregulation of the miRNAs observed in our study was further found in the lungs of mice after cigarette smoke exposure (mmu-miR-21a-5p, mmu-miR-135b-5p, mmu-miR-146a-5p, mmu-miR-146b-5p, mmu-miR-155-5p, mmu-miR-342-3p, mmu-miR-449a-5p, mmu-miR-489-3p, and mmu-miR-672-5p) [26], in mice with cigarette smoke induced atherosclerosis (mmu-miR-21a-5p and mmu-miR-155-5p) [27], in the lungs of mice after radon inhalation (mmu-miR-21a-3p, mmu-miR-135b-5p, mmu-miR-146b-5p, mmu-miR-1298-5p, mmu-miR-6972-5p, and mmu-miR-703) [28], in mice with lung tumors (mmu-miR-135b-5p, mmu-miR-146b-5p, mmu-miR-223-3p, and mmu-miR-1298-5p) [29][30][31], in an ovalbumin-induced asthma mouse model (mmu-miR-21a-5p, mmu-miR-135b-5p, mmu-miR-146a-5p, mmu-miR-155-5p, mmu-miR-223-3p, and mmu-miR-451a) [32], and in mice with pneumonia and influenza infections (mmu-miR-21a-5p, mmu-miR-144-5p, mmu-miR-155-5p, and mmu-miR-223-3p) [33][34][35]. This overall suggests that the inhalation of CuO NPs induces a similar response as the above-mentioned adverse conditions and therefore likely has negative effects on the organism.…”

Oxidative stress, autophagy and airway ion transport

“…Increased expression resulted from Nrf-2 displacement of repressive factors [BTB and CNC homology 1, basic leucine zipper transcription factor (Bach1) and v-Maf avian musculoaponeurotic fibrosarcoma oncogene homolog K (MafK) heterodimers] binding to an upstream antioxidant response element, resulting in increased CFTR transcription (248). However, over time, CFTR mRNA stability decreased due to upregulation of specific oxidative stress-induced mi-croRNAs (e.g., miR-223, miR-155, and miR-21) targeting CFTR transcripts (15,34,96,214).…”

Environmental Influencers, MicroRNA, and Multiple Sclerosis

“…113,114,138,147 miR-218 and miR-22 were elevated in MS and EAE to levels similar to those found in cigarette smokers. 116,117,129,153 Survivin expressions in MS (4.5-fold) could not be attributed to cigarette smoking only (1.79-fold). 125,144 Levels of Let-7c in MS did not correlate with those found in cigarette smokers (-1.45-fold).…”

“…170 Furthermore, as detailed previously, miR-155 was associated with MS and MS environmental stimuli (Table 2). 108,110,116,121,130,145,235 Likewise, Ehtesham et al demonstrated that IFN-β can restore the expression levels of the previously described MS-or EAE-associated miRNAs: miR-145 and miR-20a (Tables 2 and 5). 24,122,138,171,234,241,260 Similarly, Manna et al studied 16 differentially expressed miRNAs in IFN-β treated RRMS patients vs naive patients.…”

“…125,144 Levels of Let-7c in MS did not correlate with those found in cigarette smokers (-1.45-fold). 116,138 miR-342 was upregulated by 3.2-fold in MS patients, half of it could be attributed to cigarette smoking (1.51-folds increase). 118,127 Nonconclusive results of miR-31 in EAE models make it hard to correlate to the results of cigarette smoke.…”