Page 41 - JCTR-11-2

Journal of Clinical and
Translational Research miRNA in pneumonia and pulmonary fibrosis

in the pathophysiology of IPF. In recent years, miRNA various human disorders, including IPF. For instance, miR-
mimics and inhibitors have been explored as potential 199a-5p, let-7d, and miR-21 have been identified to play
therapeutic tools for a wide range of human disorders. critical roles in pulmonary fibrosis. The importance of
57
In the context of lung pathology, many miRNAs have dysregulation of miRNAs in the pathology of both silica- and
been identified as promising diagnostic biomarkers. For bleomycin-associated lung fibrosis was demonstrated in
instance, miRNA-320e and miRNA-320c were recognized a study, where the authors discovered a unique miRNA
as candidate biomarkers for diagnosing patients with profile for the disease. In mouse fibrotic lung tissues,
58
chronic obstructive pulmonary disease (COPD) at risk of miR-21, miR-3107, miR-151-3p, miR-455, and miR-486-5p
developing lung carcinoma. Moreover, desensitization of showed differential expression. Furthermore, lung tissue
miRNA-339-5p and upregulation of miRNA-21 in plasma and serum samples of patients with silicosis or IPF showed
have shown diagnostic potential for early-stage lung lower levels of miR-486-5p expression compared to healthy
adenocarcinoma. In cases of silica-induced pulmonary donors. Thus, miR-486-5p might be a key pathogenic
59
fibrosis (SPF), miRNA-19a downregulation can be a factor underpinning the emergence of lung fibrosis. miR-
useful indicator. The functional variant of miRNA-4508 486-5p is produced by processing the intronic RNA derived
(rs6576457) may exert a major role in the emergence of SPF from the ANK1 gene. Based on the cell and tissue types,
and act as a possible marker for diagnosis. However, the this gene produces either a short (enriched in skeletal and
molecular mechanisms by which these miRNAs influence heart muscle) or a long (enriched in erythroid) variant
disease progression remain to be fully elucidated. In of the acute respiratory distress protein that connects the
50
smoking-related pulmonary fibrosis, several circulating cytoskeleton to the plasma membrane. Although ANK1
60
miRNAs – miR-125b-5p, miR-20b, miR-128, and miR- is conserved across vertebrates, miR-486-5p is highly
30e – were significantly altered in both pulmonary tissue conserved among mammals but absent in non-mammalian
and plasma of mouse models. Forced vital capacity and species such as birds and fish. Located on chromosome
radiologic tests showed an upregulation of blood miR- 8p11, a region frequently deleted in various cancers, miR-
21 levels in IPF patients compared to controls and it was 486-5p and its counterpart miR-486-3p are involved in
linked to severe tissue damage. Reduced miR-30a-5p tumor suppression. Reduced miR-486-5p expression
51
60
levels in BALF EXOs may serve as a potential biomarker has been observed in lung, colorectal, melanoma, and
for IPF diagnosis, while artificially boosting their levels gastrointestinal cancers, whereas miR-486-3p dysregulation
may serve as a potential IPF management strategy. 52 has been reported in pancreatic and esophageal cancers. 61
In addition, few plasma miRNAs were found to be In both animal models and clinical samples,
prospective indicators of COPD. Given the significance decreased miR-486-5p expression has been associated
of miRNAs in IPF, the utilization of miRNAs as possible with pathogenic induction of pulmonary fibrosis. Silica
markers for early disease detection will facilitate the and BLM-associated pulmonary fibrosis animal models
identification and validation of additional circulating showed decreased miR-486-5p expression, similar to the
miRNAs. Recent studies have even identified miRNA tissue samples from silicosis and IPF patients. Notably,
53
62
signatures in sputum-derived EXOs that are associated the higher miR-486-5p expression inhibits the TGF-1-
with disease severity in IPF. These composite signatures, associated fibrogenesis in NIH/3T3 cells and reduces
comprising several miRNAs, offer promising avenues pulmonary fibrosis in mice. These results show that miR-
for non-invasive diagnosis with high specificity and 486-5p has a potent anti-fibrotic effect in lung tissues and
sensitivity. 54 therefore represents a novel pharmacotherapeutic target
for the management of pulmonary fibrosis. 59
12. miRNA in the treatment of IPF
Another miRNA of interest is miR-770-5p, which has
Targeting specific miRNAs offers promising therapeutic been found to be significantly downregulated in both
potential for the treatment of IPF. Theoretically, molecular silicosis patients and mice exposed to silica. miR-770-5p
targeted therapies, such as miRNA-based treatments, can exhibited in vivo anti-fibrotic effects and in vitro inhibition of
effectively minimize damage to healthy tissue by precisely fibroblast activation via suppression of TGF-β1 signaling. 63
targeting affected cells. However, before the introduction Specifically, it targets TGFBR1, a key receptor in the TGF-β/
of miRNA-based treatment for IPF, numerous issues, Smad pathway, thereby interfering with fibroblast activation
including their reported flaws, must be resolved. 55,56 and extracellular matrix deposition. These findings identify

Advances in genome-wide miRNA profiling have the miR-770-5p/TGFBR1/Smads axis as a novel regulatory
provided critical insights into the pathophysiology, mechanism in silica-associated pulmonary fibrosis, providing
prognosis, and potential therapeutic interventions for a scientific basis for multi-target therapeutic development.

Volume 11 Issue 2 (2025) 35 doi: 10.36922/JCTR025080009