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Role of mi-RNAs in Respiratory Diseases

By March 6, 2019volume1-issue2
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Vimal Raj R et al.: Role of mi-RNAs in respiratory diseases

Review Article

Role of mi-RNAs in Respiratory Diseases

Vimal Raj R1 and Pajanivel R 2

1Assistant Professor, 2Professor & Head,
Department of Pulmonary Medicine, Mahatma Gandhi Medical College & Research Institute, Sri Balaji Vidyapeeth, Puducherry.

ABSTRACT:

Ever since the initial discovery in the early 1990s, microRNAs have become the focus of a multitude of conditions from basic biology to clinical applications in both diagnostic and prognostic strata. Previously they were believed to be of no biological relevance. Even in diseases of the lung, microRNAs have been analyzed in the pathophysiology, as drivers of disease, potential treatment targets, and serum biomarkers; however, much is yet to be understood about these non-coding RNAs for us to fully realize their potential therapeutic use. Here, we give a brief insight into their role in major respiratory diseases unearthed so far and the road ahead to better understand this potential biomarker.
Keywords: miRNA, biomarker, polymerase chain reaction

Corresponding Author: Dr. Vimal Raj R, Assistant Professor, Department of Pulmonary Medicine, Mahatma Gandhi Medical College & Research Institute, Sri Balaji Vidyapeeth, Puducherry.

How to cite this article: How to cite this article: Vimal Raj R and Pajanivel R, Role of mi-RNAs in Respiratory Diseases, JAPT 2018; 2:64-67

What are miRNAs?

Genomic studies revealed that numerous portions of the human genome do not encode conventional protein-coding genes but encode biologically active non-coding RNA species. With the rapid expansion of small RNA interference techniques over the past decade, it is now clear that many small RNA molecules could regulate gene and protein expression.

One class of such small non-coding RNAs is microRNAs (miRNAs), a group of regulatory RNAs of 19–22 nucleotides involved in control of gene expression at the post transcriptional level (1) thereby acting as RNA interfering (RNAi) molecule. While a well-known RNAi molecule, small interfering RNA (siRNA), is a small RNA that is artificially synthesized miRNA exists endogenously in the cell. miRNAs were first discovered in 1993 while studying Caenorhabditis elegans. After seven years (in 2000), let-7, the second miRNA was discovered, again in the C. elegans. In last decade, significant advances have been made in miRNA research leading to the discovery of more than 1,900 miRNAs that have been fully characterized (as per miRBase database viewed in Oct 2018).

Tuberculosis

miRNA spectrum in body fluids can reflect altered physiological and/or pathological conditions. Recent studies have shown that miRNAs are stably present in sputum (3,4) and unique miRNA signatures in sputum are altered in many lung diseases, such as lung cancer and chronic obstructive pulmonary disease (5,6).

Genome wide miRNA expression in sputum supernatant of patients with active pulmonary tuberculosis was also delineated in recent past (10). In this study by Yi Z et al, a total of 95 miRNAs were found to be expressed differentially by microarray and miR-3179, miR-147 overexpressed and miR-19b-2* suppressed in TB patient group compared with controls as observed in the validation cohort by real time polymerase chain reaction (RT-PCR).

Lv et al (7) showed that sputum and serum miRNA-144 expression levels showed significant response to treatment (decreased) after the initiation of treatment (one month after initiation of treatment). Their study involved 3 groups of patients and a fourth- control group. This study also showed a difference in the expression levels between sputum smear positive and smear negative patients (more in smear positive patients). These results indicate that sputum and serum miR-144 could be used as diagnostic indices for TB and even for TB severity. This suggestion is further rationalized by the ROC curve results, which showed both sputum and serum miR-144 to have relatively high sensitivity and specificity for the diagnosis of TB.

miR-144 was one of the microRNAs that were over expressed in active TB patients. Real-time RT- PCR analysis showed that miR-144 was mainly expressed in T cells. Transfection of T cells with miR-144 precursor demonstrated that miR-144 could inhibit TNF-α and IFN-γ production and T cell proliferation. miR-144 has been shown to directly inhibit the expression of autophagy-related gene Atg4a and to participate in the regulation of the autophagy process in M. tuberculosis infection (1). It is concluded that miR-144 might involve in regulation of anti-TB immunity through modification of cytokine production and cell proliferation of T cells.

COPD

Few studies to date have examined the role for microRNAs in COPD. The majority of studies have focused on global patterns of microRNA expression. In two early studies, investigators evaluated the effects of cigarette smoke on microRNA expression in animal models. In the first study, rats were exposed to environmental cigarette smoke versus ambient air control over 4 weeks. Twenty-four microRNAs were significantly down-regulated between smoke-exposed and sham groups (10). In the second study, investigators evaluated the effects of smoke exposure on microRNA expression in mice. The majority of deregulated microRNAs in this study were also down-regulated (11).

Christenson and colleagues conducted a comprehensive analysis for microRNAs and mRNAs within different regions of the lung (12). They profiled eight separate regions within the lungs of eight individuals (six with COPD and two control subjects). Using this strategy, the authors were able to not only identify select deregulated microRNAs but also build and enrich for specific biological pathways. They identified 63 microRNAs that were deregulated in regions of emphysema. Of note, three of the deregulated microRNAs (miR- 638, miR-30c, and miR-181d) had an inverse relationship in expression to several of their predicted targets.

Muscle-specific miRNAs play a relevant role in the regulation of muscle development and repair after injury by targeting different pathways. In COPD, the inspiratory loads to which the respiratory muscle is continuously exposed may be a major player accounting for specific pattern of miRNA expression [13]. In the main inspiratory muscle (diaphragm) of patients with mild-to- moderate and severe COPD, expression of some muscle-specific miRNAs miR-1, miR-133, and miR- 206 is down-regulated. However, the expression of miR-486, miR-27a, miR-29b, and miR-181a does not differ between the patients and the controls [13].

Asthma

The inflammatory response is central to the progression and pathology of asthma and is manifested by a production of IgE and consistent recruitment of leukocytes, in particular eosinophils, together with Th2 cells and mast cells (14). MiR-21 is a microRNA that may be central to this process. Up-regulated in individuals with asthma, miR-21 targets IL-12, a potent cytokine responsible for Th1 cell activation.

Various asthma models were documented to have different expression of miRNAs. Wang et al. identified different expression of miR-145-5p, miR- 636, miR-338-3p, miR-4485, miR-1229-3p, miR-4707- 3p, and miR-3620-3p in the serum of patients with asthma, compared to patients with COPD [20]. A few studies demonstrated different expression of 11 miRNAs in the exhaled breath condensate (EBC) from patients with asthma compared to healthy individuals [21].

Targeting microRNAs may represent a novel potential therapeutic strategy in the treatment of asthma. By inhibiting expression of various microRNAs, such as miR-21, -106a, -126, -145, -155, and -221, abnormal cytokine expression and inflammation can potentially be mitigated.

Lung malignancy

MicroRNAs have been well studied in lung cancer with a multitude of cell, animal, and human studies demonstrating deregulation in lung tumors compared with uninvolved lung tissues (18). Specific microRNAs, although not lung cancer– specific, including let-7, miR-21, miR-29, miR-126, miR-155, and miR-17- 92, appear to be fundamental in tumor biology and thus ideal candidates as biomarkers in solid tumors (19-22). Sozzi and colleagues conducted an independent study demonstrating that a distinct panel of circulating microRNAs could be applied as diagnostic and prognostic biomarkers in lung cancer (17).

Conclusion

The role of microRNAs will be unearthed more and more in the years to come. Research outputs till date show that they will improve the diagnostic and prognostic accuracy of not only respiratory diseases but the entire disease conundrum. It is for us to understand their complex role in human physiology and disease processes. As far as pulmonologists are concerned, the role of individual microRNAs/ a panel of microRNAs in core respiratory diseases need to be analyzed in greater detail to make their usage in mainstream clinical practice a reality in the near future.

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