Noncoding RNAs in asthmatic airway smooth muscle cells

Bo Xiao, Liangxian Li, Dong Yao, Biwen Mo
European Respiratory Review 2023 32: 220184; DOI: 10.1183/16000617.0184-2022

Abstract

Asthma is a complex and heterogeneous airway disease caused by genetic, environmental and epigenetic factors treated with hormones and biologics. Irreversible pathological changes to airway smooth muscle cells (ASMCs) such as hyperplasia and hypertrophy can occur in asthmatic patients. Determining the mechanisms responsible is vital for preventing such changes. In recent years, noncoding RNAs (ncRNAs), especially microRNAs, long noncoding RNAs and circular RNAs, have been found to be associated with abnormalities of the ASMCs. This review highlights recent ncRNA research into ASMC pathologies. We present a schematic that illustrates the role of ncRNAs in pathophysiological changes to ASMCs that may be useful in future research in diagnostic and treatment strategies for patients with asthma.

Abstract

This review highlights findings concerning noncoding RNAs (ncRNAs) in asthmatic ASMCs so far and proposes a schematic diagram that helps us to better understand how ncRNAs are involved in pathophysiological behavioural changes in asthmatic ASMCs. https://bit.ly/3RUtVJz

Introduction

Asthma is a heterogeneous disease of the lower airways that affects nearly 400 million people worldwide [1]. Currently, mild asthma is well controlled but severe asthma is still a considerable burden on patients, families and healthcare systems [2]. Severe distortion of airway smooth muscle cells (ASMCs) is a common consequence of severe asthma [3]. Various studies have shown that asthmatic ASMCs are involved in hyperresponsiveness and the inflammatory and remodelling processes of severe asthma [4]. ASMC aberrations in asthmatics can cause hyperplasia, hypertrophy, inflammatory mediator secretions and extracellular matrix (ECM) protein secretions [3]. However, there is little that can be done for these ASMC distortions. The development of effective therapeutic approaches requires a solid understanding of the pathogenesis of the condition.

Many noncoding RNAs (ncRNAs) have been identified in asthmatic ASMCs in recent years [5]. Transcriptomic studies and microarrays revealed that many ncRNAs were found to be markedly and abnormally expressed among asthmatic ASMCs [6–13]. MicroRNAs (miRNAs) are the most altered subset of ncRNAs, followed by long noncoding RNAs (lncRNAs) and circular RNAs (circRNAs). However, research on this subject is fragmented and lacks a systematic analysis and functional validation. This is very unfavourable for the development of ncRNA-based diagnosis and treatment strategies for asthmatic ASMCs.

In this review, we systematically illustrate the role and relevance of ncRNAs in ASMCs. We summarise the pathophysiological regulatory processes of ncRNAs, especially miRNAs, lncRNAs and circRNAs, in hyperplasia, hypertrophy, ECM production and cytokine production in asthmatic ASMCs. We also discuss the huge potential of the ncRNA regulatory network as the basis for diagnosis and treatment of ASMC dysfunction. Together, this review evaluates the possibility of harnessing multiple ncRNAs to synergistically combat asthmatic ASMCs.

MiRNAs in asthmatic ASMCs

MiRNAs were identified as single-stranded ncRNAs with a length of approximately 22 nucleotides in 1993 [14]. Since then, they have been found to be involved in the regulation of cell proliferation, migration and apoptosis as important post-transcriptional regulatory factors [15]. MiRNA usually binds directly to the 3′-untranslated region (3′-UTR) of target gene mRNA through the RNA-induced silencing complex (RISC) [15, 16]. Subsequently, the RISC impedes translation of the target gene and the target gene mRNA is degraded by endonucleases [16].

In vitro cytokine stimulation studies

In 2010, Kuhn et al. [6] identified miRNAs in ASMCs exposed to interleukin (IL)-1β, tumour necrosis factor-α (TNF-α) and interferon (IFN)-γ by microarrays and found numerous miRNAs to be downregulated or upregulated. In addition, miR-25 inhibited the production of inflammatory mediators, ECM and contractile proteins [6]. Subsequently, next-generation sequencing identified miR-10a as the miRNA expressed most abundantly in primary human ASMCs [9]. MiR-10a inhibited cell proliferation by directly targeting the 3′-UTR of catalytic subunit α of phosphoinositide 3-kinase and played an important role in the phosphoinositide 3-kinase (PI3K) pathway [9]. Additionally, overexpression of miR-23b significantly inhibited cell proliferation and promoted apoptosis in transforming growth factor (TGF)-β-induced mouse ASMCs through negative regulation of the receptor type II of transforming growth factor β/p-mothers against decapentaplegic homologue 3 pathway [17]. As an inhibitor, miR-590–5p suppressed platelet-derived growth factor (PDGF)-mediated ASMC proliferation via the negative regulation of signal transducer and activator of transcription (STAT) 3 signalling [18]. In contrast, miR-30b-5p increased in PDGF-stimulated ASMCs and the overexpression of miR-30b-5p facilitated the proliferation and migration of ASMCs by directly targeting phosphatase and tensin homologue (PTEN) and activating the PI3K/Akt pathway [19]. Chen et al. [20] found an increase in miR-620 in TGF-β1-stimulated ASMCs. MiR-620 also targeted PTEN and promoted ASMC proliferation and suppressed ASMC apoptosis [20]. Similarly, Hou et al. [21] found that miRNA-19a targets PTEN and promotes the proliferation and migration of ASMCs. Moreover, miR-145 was highly expressed in ASMCs exposed to cytokine stimulation, while the suppression of miR-145 decreased ASMC proliferation and migration through negative regulation of Krüppel-like factor 4 [22]. Table 1 summarises all the abnormal expression and functions of miRNAs in ASMCs stimulated by various cytokines. This shows that the “miRNA-target” axis is a classic ASMC regulatory pattern in cellular asthma models. These data provide the foundation for further study of miRNAs in asthma animal models and patients.

View this table:
TABLE 1

Differentially expressed microRNAs (miRNAs) in cellular asthma models and their targets and functions in asthmatic airway smooth muscle cells (ASMCs)

In vivo studies using asthma animal models

A preclinical study showed that miR-192-5p is downregulated in asthmatic mice and the overexpression of miR-192-5p decreases airway remodelling by suppressing cell proliferation through targeting of matrix metalloproteinase-16 (MMP-16) and autophagy related 7 in the ASMCs of an asthma animal model [46]. Li et al. [47] showed that ovalbumin administration in mice or PDGF-BB treatment in ASMCs reduces the expression of miR-370, while overexpression of miR-370 attenuates airway remodelling by targeting fibroblast growth factor 1 (FGF1). Similarly, miR-200a exerted anti-asthma effects in mice by inhibiting the proliferation of ASMCs via the forkhead box C1/NF-κB pathway [48]. Additionally, miR-506-3p inhibited proliferation and promoted apoptosis of the ASMCs among asthmatic mice by targeting C-C motif chemokine ligand 2 and suppressing the activation of the Toll-like receptor 4/NF-κB signalling pathway [49]. In contrast, Issouf et al. [50] found that miR-221 is overexpressed in asthmatic equine airway smooth muscle and contributes to ASMC proliferation by regulating the cell cycle arrest genes (p53, p21 and p27). Moreover, miR-486-5p was overexpressed in TGF-β1-stimulated ASMCs and asthmatic mice and the promotion of proliferation and inhibition of apoptosis in asthmatic ASMCs were realised through the miR-486-5p/aquaporin-5 signal axis [51]. Table 2 summarises all the abnormal expression and functions of miRNAs in ASMCs from asthma animal model so far. The table shows the “miRNA-target” axis to be a classic ASMC regulatory pattern in asthma animal models. This research summary provides data that may be utilised in further research into miRNAs in ASMCs.

View this table:
TABLE 2

Differentially expressed microRNAs (miRNAs) in animal asthma models and their targets and functions in asthmatic airway smooth muscle cells (ASMCs)

Studies comprising human asthmatic cells

While data from both in vitro and in vivo animal studies regarding the expression and function of miRNAs in ASMC changes are important, research using samples from asthma patients is particularly useful and informative. Davis et al. [62] identified multiple miRNAs in serum samples from asthmatic children using a TaqMan miRNA array. Further functional verification found that miR-16-5p inhibits human ASMC proliferation, whereas miR-30d-5p causes an increase in the average cell diameter of human ASMCs [62]. Feng et al. [63] found that miR-301a-3p decreases in the blood samples from asthma patients and miR-301a-3p directly targets the 3′-UTR region of STAT3, which suppresses the proliferation and migration of ASMCs, enhances ASMC apoptosis and decreases the inflammatory factor secretions of ASMCs. Similarly, miR-335-5p was found to be underexpressed in the plasma of asthmatic children and further results showed miR-335-5p reduces inflammation, airway fibrosis and autophagy in ASMCs [64]. In contrast, the expression of miR-21-5p was upregulated in ASMCs from asthma patients and a further study showed that miR-21-5p promotes ASMC remodelling, including mitochondrial activation, cell proliferation, cell hypertrophy, ECM production and cytokine production by targeting PTEN and enhancing PI3K signalling [65]. Additionally, the expression of miR-221 was also found to be upregulated in ASMCs from asthma patients and functional verification found that miR-221 induces hyperproliferation and IL-6 release [66]. Moreover, the expression of miR-378 was upregulated in the blood, lung tissue and ASMCs of asthmatic children and miR-378 aggravated airway remodelling by promoting proliferation, inhibiting apoptosis and increasing ECM secretion in ASMCs [67]. Table 3 summarises the findings from research to date on the abnormally expressed miRNAs in asthma patients and the function of these miRNAs in the pathophysiological changes of asthmatic ASMCs. The table also shows that the “miRNA–target” axis is a classic ASMC regulatory pattern in asthma patients. These data are important in the study of miRNAs in asthmatic ASMCs. More research using samples from asthma patients is needed to advance the application of these miRNAs in the diagnosis and treatment of asthmatic ASMCs.

View this table:
TABLE 3

Differentially expressed microRNAs (miRNAs) in asthma patients and their targets and functions in asthmatic airway smooth muscle cells (ASMCs)

The studies discussed in this section illustrated that miR-19a promotes the induction of pathophysiological processes by PDGF-BB in normal ASMCs [21]. However, they also showed that miR-19a plays a protective role in asthmatic ASMCs via the PDGF-BB−miR-19a−extracellular signal-regulated kinase 1/2−mitogen-activated protein kinase and STAT1 pathways [78]. These conflicting results from the in vitro and in vivo studies are problematic. Methods for the clinical application of miRNAs in the diagnosis and treatment of asthmatic ASMCs cannot be effectively developed unless in vitro, in vivo and clinical studies yield consistent results.

LncRNAs in asthmatic ASMCs

LncRNAs were originally considered the “noise” of genome transcription, by-products of RNA polymerase II transcription with no biological function [86]. In 1991, lncRNA Xist was the first identified regulator of X chromosome inactivation [87]. LncRNAs have gradually moved into the research spotlight over the last decade in the study of their role in ASMC alteration in asthma. Usually, most lncRNAs are involved in the remodelling of ASMCs through the indirect regulation of gene expression, which they achieve by targeting and binding to miRNAs [88, 89]. Therefore, the “lncRNA–miRNA–target” axis has become known as the classic regulatory pattern in the pathophysiology of asthmatic ASMCs.

LncRNAs are found to regulate the proliferation, migration, apoptosis, ECM production and inflammatory mediator secretion in ASMCs. Therefore, it is essential to summarise the effect of lncRNAs on asthmatic ASMCs (supplementary table 1).

Plasmacytoma variant translocation 1 (PVT1)

PVT1 is located on chromosome 8q24.21 [90], which is important to the functionality of ASMCs [89]. Yu et al. [91] found that PVT1 acts as a competing endogenous RNA (ceRNA) of miR-203a and induces the proliferation and migration of ASMCs through indirect regulation of the expression of E2F3. Subsequently, the comparison of lncRNA profiles in the ASMCs of nonsevere asthma patients, severe asthma patients and healthy controls identified a number of differentially expressed lncRNAs [7]. This includes PVT1, which was found to be upregulated in severe asthma patients, promoting ASMC proliferation and IL-6 release [7]. In addition, Wei et al. [92] confirmed that asthmatic mice carry higher PVT1 expression and thicker trachea/airway smooth muscle. They also showed that the PVT1–miR-29c-3p–PI3K–Akt–mammalian target of rapamycin axis promotes the proliferation of ASMCs [92]. Moreover, the expression of PVT1 was higher but the expression of miR-590-5p was lower in the serum of asthmatic children and the PVT1–miR-590-5p–follistatin-like 1 axis accelerated the proliferation and migration of ASMCs [93]. Therefore, PVT1 is a promising target for diagnosing and treating asthmatic ASMCs.

Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1)

MALAT1 is located on chromosome 11q13, first identified in predicting metastasis and survival in early-stage nonsmall cell lung cancer in 2003 [94]. In 2019, Lin et al. [95] demonstrated that MALAT1 is significantly upregulated in PDGF-BB-stimulated ASMCs and the knockdown of MALAT1 inhibits PDGF-BB-induced ASMC proliferation and migration. Analysis of the underlying molecular mechanisms showed that MALAT1, as a ceRNA for miR-150, reverses the suppression of eIF4E expression and activates Akt signalling, thereby being involved in PDGF-BB-induced ASMC proliferation and migration [95]. Subsequently, Yang et al. [96] found that MALAT1 level is significantly increased in the tracheal tissue of newborn asthmatic rats and the MALAT1–miR-133a–RyR2 axis plays an important role in inducing the secretion of inflammatory factors in ASMCs. MALAT1 was found to be upregulated and miR-216a was found to be downregulated in the serum in asthma patients and asthmatic rats [97]. Isolation of ASMCs showed that MALAT1 increases their proliferation, migration and invasion, and reduces their apoptosis, by binding to miR-216a [97]. Therefore, MALAT1 is worthy of further study in asthmatic ASMC research.

Taurine upregulated gene 1 (TUG1)

In 2005, TUG1 was first identified in genes upregulated in response to taurine treatment in developing mouse retinal cells [98]. Lin et al. [99] found that TUG1 is upregulated in ASMCs from asthmatic rats and the TUG1–miR-590-5p–FGF1 axis promotes the proliferation and migration in ASMCs and reduces the apoptosis in ASMCs. In addition, TUG1 was found to promote airway remodelling and mucus production in asthmatic mice and the TUG1–miR-181b–high mobility group box protein 1 axis was confirmed to work in mouse ASMCs [100]. Moreover, TUG1 expression was found to be increased in the airway tissue of asthmatic rats and TUG1 inhibition attenuated the viability and migration of the PDGF-BB-induced ASMCs [101]. The binding relationships between TUG1 and miR-138-5p and between E2F3 and miR-138-5p were confirmed in ASMCs [101]. In other words, the TUG1–miR-138-5p–E2F3 regulatory axis was critical to the acceleration of viability and migration of ASMCs [101]. Similarly, TUG1 level was also increased in asthmatic patients and PDGF-BB-stimulated human ASMCs; TUG1 promoted PDGF-BB-induced ASMC proliferation and migration via competitively adsorbing miR-216a-3p, directly targeting the miR-216a-3p-SMURF2 axis [102]. The above data offers novel insights into the role of TUG1 in asthmatic ASMCs and highlights its potential for use in treatment development.

Nuclear paraspeckle assembly transcript 1 (NEAT1)

In 2009, four groups independently discovered NEAT1 (also known as MENε/β), originally named nuclear enriched abundant transcript 1, which was subsequently changed to nuclear paraspeckle assembly transcript 1, an essential architectural component of paraspeckles [103–106]. In 2021, Zhu et al. [107] firstly identified that NEAT1 is increased but miR-139 is decreased in the ASMCs of asthma patients. Overexpression of NEAT1 was able to target miR-139 and activate the Janus kinase 3/STAT5 signalling pathway, which induced the production of inflammatory cytokines in ASMCs [107]. Subsequently, Wang et al. [108] found that NEAT1 combines with miR-9-5p and miR-9-5p combines with SLC26A2 to form the NEAT1–miR-9-5p–solute carrier family 26 member 2 axis, which facilitates PDGF-induced proliferation and inflammatory factor production in ASMCs. A recent study showed that the expression of NEAT1 is increased and that of miR-128 is decreased in the sputum of children with asthma [109]. NEAT1 was a ceRNA that boosted PDGF-BB-induced proliferation, migration, inflammatory cytokine secretion and ECM production in ASMCs [109]. However, as NEAT1 is a newly identified lncRNA in asthmatic ASMCs, more research is needed to elucidate its mechanisms.

Other lncRNAs

Other lncRNAs have been studied and found to be upregulated or downregulated in asthmatic ASMCs (supplementary table 1). Serval studies showed that some lncRNAs promote pathophysiological changes in asthmatic ASMCs, such as H19 imprinted maternally expressed transcript (H19) [110], brain cytoplasmic RNA 1 (BCYRN1) [111, 112], transcription factor 7 [113], growth arrest specific 5 [114, 115], CDKN2B antisense RNA 1 (ANRIL) [116], colorectal neoplasia differentially expressed (CRNDE) [117], FTX [118], RNA component of mitochondrial RNA processing endoribonuclease [119] and 00882 [120]. In contrast, multiple studies showed that some lncRNAs play a protective role and inhibit the changes in asthmatic ASMCs, such as cancer susceptibility (CASC) 2 [121], CASC7 [122], H19 [123], long intergenic nonprotein coding RNA–p53-induced transcript (LINC-PINT) [124] and RP5-857K21.7 [125]. All the regulatory mechanisms are summarised in detail in supplementary table 1. However, these lncRNAs are not extensively studied. More in vitro and in vivo experiments are needed to distinguish their exact functions.

CircRNAs in asthmatic ASMCs

CircRNAs were first discovered in the 1970s in plant viroids and, subsequently, in the cytoplasm of eukaryotic cells [126]. Numerous circRNAs have been successfully identified in different cell lines and species with the advent of high-throughput sequencing [127]. However, only a few studies have addressed the role of circRNAs in the pathophysiological changes in asthmatic ASMCs so far. These circRNAs, which serve as ceRNAs, were described in facilitating the abnormality of asthmatic ASMCs (supplementary table 2). Therefore, the “circRNA–miRNA–target” axis is a classic regulatory pattern in the pathology of asthmatic ASMCs. Lin et al. [128] and Jiang et al. [129] both confirmed that circular homeodomain interacting protein kinase 3 (circHIPK3) is significantly upregulated in PDGF-induced ASMCs. Lin et al. [128] first found that the circHIPK3–miR-326–stromal interaction molecule 1 axis promotes PDGF-induced ASMC proliferation and migration and reduces ASMC apoptosis. Subsequently, Jiang et al. [129] identified the circHIPK3–miR-375–MMP-16 axis, which promotes PDGF-induced proliferation, invasion and migration in ASMCs. Additionally, elevated levels of erb-b2 receptor tyrosine kinase 2 (ERBB2), casein kinase 1 epsilon (CSNK1E) and 0002594 were found in asthmatic patients and PDGF-induced ASMCs [10, 130, 131]. Inhibition of ERBB2 reduced the PDGF-induced proliferation, migration and inflammatory cytokine secretion in ASMCs and promoted ASMC apoptosis [130]. ERBB2, as a ceRNA, targeted the miR-98-5p– insulin like growth factor 1 receptor signal to realise the above functions [130]. The CSNK1E–miRNA-34a-5p–vesicle associated membrane protein 2 axis and the 0002594–miR-139-5p–tripartite motif 8 axis both promoted PDGF-induced ASMC proliferation, migration and inflammatory factor secretion through similar interactions to those of ERBB2 [10, 131].

In short, circRNA have a complex range of functions in asthmatic ASMCs that have not been fully explored. Only a few studies have shown that circRNAs mainly act as ceRNAs of miRNAs to disinhibit the effect of miRNAs on target genes, thereby promoting the pathophysiological changes in asthmatic ASMCs. Hence, more studies are needed to clarify the role of circRNAs in asthma ASMCs.

The ncRNA regulatory network in asthmatic ASMCs

The study of ncRNAs in ASMCs has focused on three core regulatory axes, the “miRNA–mRNA axis”, the “lncRNA–miRNA–mRNA axis” and the “circRNA–miRNA–mRNA axis”. However, the more comprehensive ncRNA regulatory network is underinvestigated. MiRNA and mRNA are especially important in the above three core regulatory axes. Therefore, the construction of a wider regulatory network based on miRNA or mRNA would enhance our understanding of ncRNAs and help us to find ncRNA-based synergies that might be used to inhibit the changes in asthmatic ASMCs.

Figure 1a shows a regulatory network constructed with PTEN as the core. Overexpression of CASC7, H19 and LINC-PINT and inhibition of miR-19a, miR-21, miR-620, miR-30b-5p, miR-26a-5p and miR-181a should exert synergistic anti-asthmatic ASMC effects. Figure 1b shows a regulatory network constructed with miR-590-5p as the core. Synergistic inhibition of TUG1, PVT1 and FTX should accelerate the accumulation of miR-590-5p, exerting a stronger anti-asthmatic ASMC proliferation. This suggests that the study of the progression of ncRNAs in diseases using the wider regulatory networks can overcome many obstacles; for example, the targeting one single ncRNA to achieve diagnostic and therapeutic effects.

FIGURE 1
FIGURE 1

Noncoding RNA (ncRNA) regulatory networks constructed with phosphatase and tensin homologue (PTEN) and microRNA (miR)-590-5p as cores, respectively. a) This network, including the “miR-181a/miR-19a/miR-620/miR-30-5p-PTEN”, “long noncoding RNA (lncRNA) CAS7/H19-miR-21-PTEN” and “lncRNA long intergenic nonprotein coding RNA–p53-induced transcript (LINC-PINT)-miR-26a-5p-PTEN” axes, regulates proliferation, cytokine secretion, extracellular matrix (ECM) secretion and corticosteroid sensitivity in airway smooth muscle cells (ASMCs). b) This network, including the “lncRNA taurine upregulated gene 1 (TUG1)/plasmacytoma variant translocation 1 (PVT1)/FTX-miR-590-5P- fibroblast growth factor 1 (FGF1)/follistatin-like 1 (FSTL1)/Janus kinase 2 (JAK2)” and “miR-590-5P-signal transducer and activator of transcription 3 (STAT3)” axes, regulates the proliferation in ASMCs. UTR: untranslated region.

Supplementary tables 3 and 4 summarise other ncRNAs that synergistically inhibit the pathophysiological changes in asthmatic ASMCs with miRNAs or mRNAs as the cores. Although these ncRNAs cannot form a broad regulatory network in previous studies, they also deserve our attention nonetheless. Figure 2 is a schematic diagram of a broader regulatory network that has been created to facilitate an understanding of the mechanisms behind the involvement of ncRNAs in asthmatic ASMCs. With an increasing body of research, this regulatory network map will become more complete over time and our strategies for the diagnosis and treatment of asthmatic ASMCs based on ncRNAs will also become more refined.

FIGURE 2
FIGURE 2

Schematic diagram of the noncoding RNA (ncRNA) regulatory network in asthmatic airway smooth muscle cells (ASMCs). First, the three independent regulatory axes on the left, “microRNA (miRNA)–mRNA”, “long noncoding RNA (lncRNA)–miRNA–mRNA” and “circular RNA (circRNA)–miRNA–mRNA”, regulate hyperplasia, hypertrophy, inflammatory mediators secretion and extracellular matrix (ECM) secretion in asthmatic ASMCs. Then, intertwined ncRNA regulatory network of lncRNA, circRNA and miRNA on the right regulates hyperplasia, hypertrophy, inflammatory mediator secretion and ECM secretion in asthmatic ASMCs. UTR: untranslated region.

Discussion

Research on the roles of ncRNAs in ASMCs and their clinical relevance is still in the development stage. While transcriptomic studies and ncRNA microarrays provide us with many abnormally expressed ncRNAs, only a few ncRNAs have been fully verified [6–13]. Therefore, verification of the functions of these ncRNAs will significantly expand the breadth of ncRNA research in ASMCs.

A more complete ncRNA regulatory network will become possible as more ncRNAs in ASMCs are identified. This network will provide a more complete understanding of ncRNAs in ASMCs and will help us to formulate synergistic ncRNA-based asthmatic ASMC diagnostic and treatment strategies.

In addition, we offer three suggestions for future research on the role of ncRNAs in asthmatic ASMCs. First, the lncRNA MALAT1 was found to induce human ASMC apoptosis [96], but inhibit ASMC apoptosis in rat ASMCs [97]. In addition, lncRNA H19 also produced contradictory results in two studies. Yu et al. [123] showed that H19 inhibits proliferation and migration in human ASMCs, while Xiang et al. [110] showed that H19 promotes proliferation and migration in human ASMCs. In these similar cases, more studies are needed to determine the functions of these ncRNAs. Second, we suggest research that aims to establish whether the ncRNAs working in asthmatic inflammatory cells and other airway structural cells contribute to the pathophysiological changes in asthmatic ASMCs. Third, studies could focus on the regulatory role of circRNAs in asthmatic ASMCs. All these works together would facilitate the formation of a huge, intertwined, ncRNA-based asthmatic ASMC regulatory network and contribute to the development of diagnostic and therapeutic strategies for asthmatic ASMCs.

Moreover, the three independent regulatory axes in figure 2 are the classic pathophysiological behavioural regulatory patterns of ncRNAs in asthmatic ASMCs. However, Zhang et al. [112] presented that there are 11 direct combination sites between miR-150 and lncRNA BCYRN1. As an upstream signal, miR-150 inhibited ASMC proliferation and migration through the negative regulation of BCYRN1 in IgE-induced ASMC pathology [112]. Subsequently, another group found that CRNDE directly combines with transforming growth factor-β-activated kinase 1 in ASMCs to activate the NF-κB pathway by enhancing inhibitor of nuclear factor-κB kinase phosphorylation and promotes ASMC proliferation and migration [117]. Such studies add new regulatory mechanisms to those seen in the three classic regulatory axes, further elucidating the involvement of ncRNAs in the regulation of the ASMC pathophysiology.

Conclusions

This review is the first to summarise the mechanisms by which ncRNAs regulate asthmatic ASMCs. We propose building an ncRNA regulatory network based on three classic regulatory patterns to help us better understand ncRNAs in ASMCs. This will facilitate the construction of ncRNA-based diagnostic and therapeutic strategies for asthmatic ASMCs. Finally, we must be aware that such an ncRNA regulatory network can also be constructed in other diseases, such as cancer. It is hoped that this review will deepen research understanding of the involvement of ncRNAs in the occurrence and development of various diseases and contribute to the formulation of more accurate and effective diagnostic and treatment strategies.

Questions for future research

  • What other ncRNA functions contribute to the regulation of pathophysiological changes in asthmatic ASMCs that have not been identified in the tables outlined in this review?

  • What other direct targets of ncRNAs contribute to the regulation of pathophysiological changes in asthmatic ASMCs that have not been identified in the tables outlined in this review?

  • What are the functions and targets of abnormally expressed ncRNAs, as determined by transcriptomic studies and microarrays?

  • Are the functions and direct targets of the ncRNAs listed in tables in this review consistent in in vitro, in vivo and patient studies?

  • Are many ncRNAs involved in noncanonical regulatory patterns in asthmatic ASMCs?

  • How can ncRNAs with synergistic effects be utilised in clinical research based on the schematic diagram in figure 2?

  • Do the ncRNAs found in asthmatic ASMCs also effect the function of other cells in the lungs?

Supplementary material

Supplementary Material

Please note: supplementary material is not edited by the Editorial Office, and is uploaded as it has been supplied by the author.

Supplementary table 1 ERR-0184-2022.SUPPLEMENT1

Supplementary table 2 ERR-0184-2022.SUPPLEMENT2

Supplementary table 3 ERR-0184-2022.SUPPLEMENT3

Supplementary table 4 ERR-0184-2022.SUPPLEMENT4

Footnotes

  • Provenance: submitted article, peer reviewed.

  • Author contributions: B. Xiao and L. Li wrote the manuscript; B. Xiao and D. Yao edited the manuscript; B. Xiao and B. Mo revised and finalised the manuscript. All authors approved the final version.

  • Conflicts of interest: B. Xiao reports no conflicts of interest.

  • Conflicts of interest: L. Li reports no conflicts of interest.

  • Conflicts of interest: D. Yao reports no conflicts of interest.

  • Conflicts of interest: B. Mo reports no conflicts of interest.

  • Support statement: This work was supported by the National Natural Science Foundation of China (81560005, 81760007, 81760008, 81960007, 82060006 and 82160008), and the High Level of Innovation Team and Outstanding Scholars Program in Colleges and Universities in Guangxi, China. Funding information for this article has been deposited with the Crossref Funder Registry.

  • Received September 30, 2022.
  • Accepted February 7, 2023.
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Noncoding RNAs in asthmatic airway smooth muscle cells
Bo Xiao, Liangxian Li, Dong Yao, Biwen Mo
European Respiratory Review Jun 2023, 32 (168) 220184; DOI: 10.1183/16000617.0184-2022
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