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REVIEW ARTICLE
Long non-coding RNA (lncRNA): A potential
therapeutic target in acute lung injury
Almaz Zaki
b,1
, M. Shadab Ali
a,1
, Vijay Hadda
a,
*,
Syed Mansoor Ali
c,
**, Anita Chopra
d
, Tasneem Fatma
b
a
Department of Pulmonary, Critical Care and Sleep Medicine, All India Institute of Medical Sciences,
New Delhi, 110029, India
b
Department of Biosciences, Jamia Millia Islamia University, New Delhi, 110025, India
c
Department of Biotechnology, Jamia Millia Islamia University, New Delhi, 110025, India
d
Lab Oncology, Dr. BRA-IRCH, All India Institute of Medical Sciences, New Delhi, 110029, India
Received 18 March 2021; received in revised form 15 July 2021; accepted 17 July 2021
KEYWORDS
Acute lung injury;
Apoptosis;
Inflammation;
Long non-coding RNA
(lncRNA);
Macrophage
polarization
Abstract Acute Lung Injury (ALI) and its severe form Acute Respiratory Distress Syndrome
(ARDS) are the major cause of ICU death worldwide. ALI/ARDS is characterized by severe hyp-
oxemia and inflammation that leads to poor lung compliance. Despite many advances in under-
standing and management, ALI/ARDS is still causing significant morbidity and mortality. Long
non-coding RNA (lncRNA) is a fast-growing topic in lung inflammation and injury. lncRNA is a
class of non-coding RNA having a length of more than 200 nucleotides. It has been a center
of research for understanding the pathophysiology of various diseases in the past few years.
Multiple studies have shown that lncRNAs are abundant in acute lung injury/injuries in mouse
models and cell lines. By targeting these long non-coding RNAs, many investigators have
demonstrated the alleviation of ALI in various mouse models. Therefore, lncRNAs show great
promise as a therapeutic target in ALI. This review provides the current state of knowledge
about the relationship between lncRNAs in various biological processes in acute lung injury
and its use as a potential therapeutic target.
Copyright ª2021, Chongqing Medical University. Production and hosting by Elsevier B.V. This is
an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/
by-nc-nd/4.0/).
* Corresponding author. Room no. 8, Porta Cabin, New Private Ward, Department of Pulmonary, Critical Care and Sleep Medicine, AIIMS,
Ansari Nagar, New Delhi, 110029, India.
** Corresponding author. Room no. 509, Department of Biotechnology, Ramanujan Block, Jamia Millia Islamia University, Jamia Nagar, New
Delhi, 110025, India.
E-mail addresses: almazzaki1122@gmail.com (A. Zaki), ms1993ali@gmail.com (M.S. Ali), vijayhadda@yahoo.com (V. Hadda), smansoor@
jmi.ac.in (S.M. Ali), chopraanita2005@gmail.com (A. Chopra), tfatima@jmi.ac.in (T. Fatma).
Peer review under responsibility of Chongqing Medical University.
1
AZ and MSA have contributed equally and are joint first authors.
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Please cite this article as: A. Zaki, M.S. Ali, V. Hadda et al., Long non-coding RNA (lncRNA): A potential therapeutic target in acute lung
injury, Genes &Diseases, https://doi.org/10.1016/j.gendis.2021.07.004
https://doi.org/10.1016/j.gendis.2021.07.004
2352-3042/Copyright ª2021, Chongqing Medical University. Production and hosting by Elsevier B.V. This is an open access article under the
CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Available online at www.sciencedirect.com
ScienceDirect
journal homepage: http://ees.elsevier.com/gendis/default.asp
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Introduction
Acute lung injury (ALI) is a syndrome that comprises severe
hypoxemic respiratory failure along with bilateral lung in-
filtrates and is also linked with pulmonary as well as non-
pulmonary risk factors.
1
It is characterized by severe
inflammation that causes serious damage to the alveoli and
results in poor lung compliance.
2
ALI is associated with
significant morbidity and mortality, and its severe form,
i.e., acute respiratory distress syndrome (ARDS), has even
higher mortality rates. Globally, it affects around 3 million
people annually and is responsible for 10 percent of ICU
admissions.
3
Despite recent advancements in understand-
ing and management of the disease, patients suffering from
ALI/ARDS end up with a poor prognosis. Therefore, a new
approach for better understanding and effective treatment
strategies is urgently needed to mitigate the disease and
overcome the economic burden it causes.
Long non-coding RNA (lncRNA) is a fast-growing topic in
lung inflammation and injury.
4
In human, less than 3% of
genome codes for proteins, while the rest of the genomic
part is consists of either introns or intergenic DNA.
5
Among
all the transcribed parts of the genome, most are tran-
scribed into non-coding RNA (ncRNA)
6
and are likely to be
non-functional.
7
However, a certain part of it plays a vital
role in gene regulation. ncRNA have been further divided
into multiple categories such as miRNA, snoRNA, piRNA, and
lncRNA based on their size/nucleotide length.
8
Long non-
coding RNA or lncRNA is the “non-coding RNA that ex-
ceeds 200 nucleotides in length”
9
and exhibits diverse roles
and functions in many important biological processes.
Earlier, lncRNAs were considered as a by-product of the
transcription process. However, with more research/study
focusing on the lncRNA, it became evident that these RNA
molecules play a crucial role in regulating many
physiological processes, including immunity,
10
inflamma-
tion, proliferation, cell differentiation, and cell sur-
vival.
11,12
In recent years, advances in next-generation
sequencing (NGS) technologies have prompted an eruption
of newly discovered lncRNAs, particularly in humans.
13
Long non-coding RNA regulates gene expression at
transcriptional, post-transcriptional, epigenetic, and chro-
matin levels and activates or constrains the expression of
target genes by directly binding to them or by recruiting
transcription factors (Fig. 1 showing lncRNA activity in
cellular environment).
14
Multiple studies suggest that dys-
regulation of lncRNA is associated with many human dis-
eases such as focal ischemia, cancer, neurodegenerative
diseases, and respiratory diseases.
15e18
Among respiratory
diseases, lncRNAs have been implicated in usual interstitial
pneumonia, chronic obstructive pulmonary diseases, lung
cancer, pulmonary arterial hypertension, and ALI.
19
The
scope of the present review will be limited to acute lung
injury/acute respiratory distress syndrome.
lncRNA in acute lung injury
lncRNA has provided new insights on the pathogenesis of
ALI. It will aid the investigators in developing a novel
therapeutic target for the treatment of acute lung injury.
So far, many studies have discovered the role of various
lncRNAs as a potential therapeutic target in acute lung
injury, such as MALAT1, NEAT1, TUG1, THRILL, etc. (see
Table 1). Some of the important lncRNAs are discussed
below.
MALAT1
MALAT1 (Metastasis Associated Lung Adenocarcinoma
Transcript 1) is 6.5 kb, abundant, evolutionary conserved,
and stable lncRNA that was found overexpressed in solid
Figure 1 General description of lncRNA activity in the regulation of cellular activities. (A) Expression of lncRNA in response to an
external stimulus. (B) It regulates the promoter and enhancer region, (C) lncRNA providing a platform for transcriptional activity.
(D) It also controls the chromatin remodeling; (E) alternate splicing via spliceosome, (F) translation and protein modification, and
(G) microRNA regulation in many cellular activities by lncRNA.
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Table 1 lncRNAs involved in ALI/ARDS.
lncRNAs Model and/or cells Expression Function Molecular targets References
TUG1 LPS-induced ALI Murine,
PMVECs
Decreased Alleviates inflammation and
apoptosis
miR-34 b-5p/GAB1
41
MALAT1 LPS-induced ALI in
HPMEC, Rat ALI/ARDS
model, sepsis patients
Increased Decreased apoptosis and
inflammation
miR-181a-5p,
ICAM-1, miR-425
42e44
CASC2 A549 cell line Decreased Increased viability, decreased
apoptosis, and inflammation
miR-27b/TAB2 axis
38
NEAT1 LPS-induced ALI mice
models and A549 cell line
Increased Enhanced cell viability and
reduced lactate dehydrogenase
release, apoptosis, and
caspase-3/9 activity.
Decreased inflammation
HMGB1/RAGE
signaling, miR-
944/TRIM37
32,36
THRIL Septic-induced ALI in
C57BL/6 mice model and
MPVECs.
Increased Decreases the inflammation
and apoptosis
miR-424/ROCK2
25
SNHG5 LPS-induced mouse
model, A549 cell line
Decreased It inhibits inflammation and
promotes the cell viability
miR-205/COMMD1
45
PRNCR1 LPS-treated PVEC and
mouse model
Increased Attenuates expressions of
TLR4, NF-kB, and inflammatory
cytokines and increases cell
viability
miR-330-5p/TLR4
axis
46
Hsp4 LPS-induced MLE-12 cells Decreased Reduced apoptosis mTOR signaling,
miR-466 m-3p/
DNAjb6
47
lncRNA-5657 CLP-induced ALI mouse
model, patients with
sepsis-induced lung
injury, NR8383 cell line
Increased Alleviated inflammatory
response
spns2
48
CLMAT3 Monocytes isolated from
blood samples of healthy
controls and ALI
patients, U937
macrophage cell line,
C57BL/6 mice Model
Increased Alleviates pro-inflammatory
cytokines
CtBP2-p300-NF-kB
complex
49
MEG3 LPS-induced ALI mouse
alveolar and macrophage
NR8383 cells
Increased Improves inflammatory
response
microRNA-7b (miR-
7b)/NLR pyrin
domain containing
3 (NLRP3)
50
CASC9 LPS-induced HSAECs as
well sepsis-induced lung
injury mouse model
Decreased Increased the viability of
HSAECs
miR-195-5p/PDK4
axis
51
XIST Lung transplant patients,
PCI-induced rat model
Increased Alleviation of inflammation and
apoptosis, cessation of NET
formation
miR-21/IL-12 A
52
GAS5 LPS-induced murine
alveolar epithelial cell
line MLE-12
Decreased Decreased cell inflammatory
responses and apoptosis
miR-429/DUSP1
axis
53
SNGH14 LPS-induced ALI mouse
model
Increased Reduces the levels of pro-
inflammatory cytokines IL-18,
IL-1b, TNF-a, and IL-6 and
inhibits MH-S cell viability.
miR-34c-3p/WISP1
54
H19 LPS-induced ARDS in rats
and MH-S cells
Increased Pulmonary injury,
inflammation, and fibrosis
miR-423-5p/
FOXA1
55
Mirt2 LPS induced primary
cultured peritoneal
macrophages,
RAW264.7 cells
Increased Regulate macrophage
polarization and inflammation
TRAF6, NF-kB,
stat6 and MAPK
56
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tumors and associated with proliferation, progression,
metastasis, migration, invasion, survival, and acts as a
prognostic marker of cancers.
20
Investigation in LPS
treated macrophages showed upregulation of MALAT1,
while it was downregulated in IL4 treated cells and showed
contrasting expression in differentially treated macro-
phages. MALAT1 knockdown ameliorated LPS-induced M1
macrophage activation involved in lung injury and inflam-
mation, while IL-4 induced M2 macrophages activation was
enhanced in MALAT1 knockdown cells known for inflam-
mation resolution.
21,22
THRIL
TNF and HNRNPL related immunoregulatory long non-
coding RNA or THRIL have been previously reported as a
critical regulator in inflammatory diseases. The expression
level of THRIL increases in coronary heart disease patients
with systemic inflammation.
23
In a recent study, over-
expression of THRIL has been observed in sepsis patients.
More strikingly, it positively correlates with the increased
risk of ARDS, disease severity, inflammation, and high
mortality.
24
Chen et al reported overexpression of THRIL in
the tissues of sepsis-induced ALI mice, which was further
validated in the sepsis cell model. They also reported
attenuation in lung injury and increased survival when
THRIL was downregulated. It indicates that THRIL prompts
acute lung injury in sepsis.
25
THRIL binds to the promoter region of the TNF-aforming
RNA-protein complex with hnRPL, inducing the expression
of TNF-a, thus imposes an inflammatory response.
26
Chen
et al
25
reported a dramatic decrease in the protein level of
TNF-a, IL-1b, IL-6, and the number of macrophages and
neutrophils counts by silencing THRIL, indicating that inhi-
bition of THRIL relieved sepsis-induced inflammation and
ALI. Apoptosis is a crucial feature for inducing organ dam-
age.
27
Significant apoptosis occurs in sepsis-induced ALI,
and inhibition of THRIL can suppress the apoptosis and
further alleviate the ALI induced by sepsis.
25
Evidence
suggested that suppressed immune response may be linked
with sepsis-induced ALI. Downregulating the THRIL may
enhance immune response that can alleviate sepsis-induced
ALI as suggested by inhibition of alveolar macrophage
apoptosis.
28
Therefore, lncRNA THRIL can serve as a po-
tential therapeutic target for acute lung injury induced by
sepsis.
NEAT1
In recent years, the role of Nuclear Paraspeckle Assembly
Transcript 1 (NEAT1) has been vastly explored in multiple
diseases such as cancer and inflammatory diseases.
29
NEAT1
has also been implicated in inflammatory diseases. For
instance, it was found upregulated in rats having chronic
constriction injury, while knockdown of NEAT1 resulted in
suppression of neuroinflammation as well as neuropathic
pain behaviors.
30
In brain injury, NEAT1 has anti-
inflammatory and anti-apoptotic functions.
31
Zhou et al
32
observed a very high level of NEAT1
expression in LPS induced ALI in mouse model. Huang et al
33
also reported remarkably high levels of NEAT1 in sepsis
patients, which was associated with augmented disease
severity and poor prognosis. Alveolar epithelial cells-II
(AECs) are the main injury sites in ALI/ARDS. It maintains
the alveolar-capillary barrier integrity and produces sur-
factant substances that decrease the pulmonary surface
tension. In ALI, this mechanism is impaired and results in
lower lung compliance. Therefore, protecting AECs from
injury represents a vital therapeutic strategy against ALI
induced by sepsis.
34,35
Zhou et al investigated the role of NEAT1 on the LPS-
exposed adenocarcinoma cell line. They discovered that
cessation of NEAT1 reduces the adverse function of LPS on
the availability of AECs. Additionally, NEAT1 inhibition
restrained apoptosis, caspase-3/9 activity, and release of
LDH in LPS-induced ALI, suggesting its protective roles in
ameliorating LPS induced AECs damage and apoptosis.
32
Inflammation and cytokine storm is the leading cause of
mortality and morbidity in ALI/ARDS. Controlling the in-
flammatory response could provide a vital therapeutic
target in sepsis-induced ALI. Suppression of NEAT1 signifi-
cantly reduces the pro-inflammatory cytokines IL-6, IL-1b,
and TNF-a.
32
Zhou et al
32
also reported that restoration of the
HMGB1-RAGE pathway, which is excessively activated in
sepsis models and patients, reverses the anti-inflammatory
and anti-injury efficacy of NEAT1 knockdown in AECs
exposed LPS. Evidence also suggested that NEAT1, like
other lncRNA, regulates the activities of specific down-
stream proteins such as TRIM37.
36,37
CASC2
Cancer susceptibility candidate 2 (CASC2) is located on
chromosome 10 and has been implicated as a crucial gene
involved in the pathogenesis of many types of malignancies,
including glioma and endometrial cancers.
38
Liu et al
39
discovered that CASC2 was downregulated in A549 cell
lines treated with LPS, while accumulation of CASC2
attenuated LPS-induced ALI in in vitro and in vivo condi-
tions. Ji L et al
40
established bronchopulmonary dysplasia
(BPD) model by giving 14 days of hyperoxia treatment to
neonates mice. Furthermore, lncRNA CASC2 has been found
reduced in murine lung tissue while CAV1 protein was found
elevated.
The mechanistic function of lncRNA in acute
lung injury
lncRNA-mediated cell signaling regulation and
acute lung injury
Cell signaling is vital in various cellular and physiological
processes. Many cell signaling pathways have been discov-
ered that play a pivotal role in various biological processes
and gene expression. A single signaling pathway often
consists of multiple signaling molecules that ultimately
affect gene expression by regulating the activity of tran-
scription factors directly or indirectly. Shreds of evidence
from recent studies suggest that lncRNAs are involved in
various cell signaling pathways in many diseases.
12,57
However, few studies are available that focus on the role
of these lncRNAs in acute lung injury. Here we have dis-
cussed some pathways that have been studied so far.
Study in the past demonstrated that MALAT1 could
worsen sepsis-induced inflammation and cardiac
A. Zaki, M.S. Ali, V. Hadda et al.
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insufficiency by regulating p38 MAPK/p65 NF-kB signaling
pathway.
58
Lin et al used three study groups in mice: the
control group, LPS group, and LPSþMALAT1 group, to
investigate the role of lncRNA MALAT1. They checked
various factors, including the expression level of p38MAPK/
P65 NF-kB signaling pathway-related protein in the lung
tissue and the BAL fluid of the mouse and reported that
knockdown of MALAT1 leads to reversal of the abnormal
increase in the phosphorylation of p38 MAPK and p65 NF-
kB
59
Likewise, Zhu et al
60
also demonstrated that MALAT1
via interaction with p65 blocks LPS-induced activation of
NF-kB and repressed LPS-induced inflammatory injury in
WI-38 cell line.
In a separate study on the mechanism of NEAT1 in ALI,
investigators corroborated the activation of HMGB1/RAGE
and NF-kB signaling in A549 cell lines treated with LPS.
Suppression of NEAT1 represses this pathway while reac-
tivates the HMGB1/RAGE signaling through HMGB1 over-
expression and dampened the anti-inflammatory/injury
effects of NEAT1 knockdown, implying it as a potential
therapeutic target for this condition.
32
lncRNA sponging miRNA in acute lung injury
miRNA is 18e22 nucleotides small non-coding RNA that
regulate gene expression post-transcriptionally, typically
binding at 30UTR of target messenger RNA (mRNA). On
account of acute lung injury, miRNA act as a potential
biomarker in the diagnosis and severity of the acute lung
injury disease.
61
In brief, biogenesis of miRNA begins in the
nucleus where RNA polymerase II transcribes pri-miRNA
(2000 bp long, double-stranded, capped, and poly-
adenylated) as a precursor of miRNA, which is further
cleaved and processed by RNase III-like endonuclease,
drosha, and transported as pre-miRNA to the cytoplasm
through exportin-5. In the cytoplasm, pre-miRNA is further
processed, producing 25 nucleotides miRNA duplex (miR-
NAemiRNA*) by the action of cytoplasmic RNase III Dicer.
One strand of miRNA duplex is degraded, and the remaining
one gets accommodated into an RNA-induced silencing
complex (RISC) incorporated with Argonaut protein. miRNA
loaded with RISC-Ago complex has seed region which
complementarily binds to 30or 50UTR regions of target
mRNA for its degradation resulting negative regulation.
62,63
It is estimated that approximately 60% of human genes are
targeted and regulated by miRNA, and they can serve as a
therapeutic target in various diseases.
64
The developing
horizon of research identified and reported that lncRNA is
an endogenous sponge to miRNAs that can control the
expression of genes by targeting miRNAs in acute lung
injury. In a study, downregulation of miR-34 b-5p by over-
expressed TUG1 was protective in sepsis-induced acute
lung injury in mice model.
41
Elevated MALAT1 was found to
be associated with acute lung injury that downregulated
miR-181a-5p expression.
42
Similarly, increased level of
THRIL downregulated miR-424 in sepsis-induced lung injury
where knockdown of THRIL potentially enhanced miR-424
and markedly increased the survival rate of septic mice.
25
LPS treated A549 cell lines showed a decreased amount of
lnc-CASC2 with a raised level of miR-27 b. Overexpression
of lnc-CASC2 further downregulated miR-27 b, preventing
LPS induced acute lung injury.
38
Jinyuan et al
54
performed
in vivo and in vitro studies and found aggravated expression
of lncRNA SNHG14 adversely influenced microRNA-34c-3p
expression in LPS induced acute lung injury models. It is
well established that lncRNA regulates miRNA by acting as
an agonist or antagomir. Furthermore, miRNA processing,
their transport to mRNA, and even outside the cell could be
controlled by lncRNA.
65e67
Role of lncRNA in different biological processes
in acute lung injury
Pyroptosis
Pyroptosis is a newly discovered cell death process stimu-
lated by both infectious and non-infectious sources,
including factors produced in the host during myocardial
infarction.
68
It is distinct from other forms of cell death
both morphologically and mechanistically. The defining
feature of pyroptosis is its dependency on Caspase 1, which
mediates this type of cell death. It is not involved in
apoptosis, and neither its degradation ceases apoptosis.
69
In recent decades lncRNAs were found to be associated
with pyroptosis. Pyroptosis plays a key role in the inflam-
matory resolution of acute lung inflammation. Guo
et al demonstrated that inflammasomes activation and
inflammasome-dependent pyroptosis is associated with
acute lung inflammation.
70
Several lncRNAs have been
recognized as a key regulator in acute lung inflammation,
either by modulating miRNAs/downstream molecules or by
directly regulating pyroptosis.
71,72
Luo et al investigated
the molecular mechanism and also looked for the candidate
lncRNA and mRNA involved in pyroptosis in LPS induced
acute lung injury. They found 1503 differentially expressed
lncRNA and observed that lncRNA4344 sponged miR-138-5p
and promoted pyroptosis in inflammatory responses by
targeting NLRP3 in LPS-induced ALI.
73
MALAT1 and NEAT1 have been the most widely reported
lncRNAs in acute lung injury, and it is also associated with
pyroptosis (See Fig. 2). Apart from these lncRNAs, many
other lncRNAs are associated with pyroptosis regulation,
and still, many more are being identified. Targeting these
lncRNAs associated with pyroptosis could provide a poten-
tial therapeutic target.
Apoptosis
Apoptosis is a highly conserved “programmed cell death”
found across all metazoans and is crucial for the develop-
ment, maintenance of tissue homeostasis, and prevention
of cancer.
74
Inadequate apoptosis may result in autoim-
munity or cancer. On the other hand, augmented or
heightened apoptosis may lead to degenerative diseases.
75
Blebbing, cell shrinking, nuclear fragmentation, and
apoptotic body formation are some of the characteristic
morphological changes during apoptosis.
76
Our lung is a
complex structure made up of various types of cells, such as
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endothelial cells, epithelial cells, fibroblasts, and different
leukocytes. Apoptosis of these cells can either exacerbate
or ameliorate lung injury subject to cell types involved.
77
In
the lungs of ALI patients, apoptosis of neutrophils is
delayed, and various soluble factors, including GM-CSF,
mediate this effect. In contrast, epithelial apoptosis is
likely to be mediated by sFasL.
77
The role of lncRNAs in acute lung injury and apoptosis
has been studied by many researchers in the last few years.
The results obtained by Liu et al
42
demonstrated that
downregulation of lncRNA MALAT1 significantly decreased
the Fas level and apoptosis in the HPMEC cell line and ALI
mouse model. Li et al
38
showed that accumulation of
lncRNA CASC2 attenuated the increased apoptosis in LPS
induced A549 cells. Ji et al
47
in a similar study found that
overexpression of Hsp4 lncRNA significantly reverted LPS
induced apoptosis in MLE12 cell lines. Together, these
outcomes clearly show that regulation of lncRNAs could
reduce ALI-induced apoptosis in cell lines and mouse
models.
Until now, studies have primarily focused on the role of
lncRNAs in apoptosis during ALI in general. There are two
different apoptosis pathways: intrinsic (mitochondrial-
dependent pathway) and extrinsic (death receptor-
dependent pathway).
78
The Bcl-2 family proteins regulate
the intrinsic pathway in addition to pro-apoptotic proteins
and anti-apoptotic proteins. This pathway is ignited by
the mitochondrial damage that induces the secretion of
cytochrome-c that activates the Caspase-3, which is the
ultimate factor responsible for apoptosis. On the other
hand, the extrinsic pathway is initiated by the interaction
of Fas ligand with Fas receptor and TNF-ligand with TNF-
receptor that activates the Caspase-8 culminating with
the activation of Caspase-3 and initiation of apoptosis.
79
Therefore, the apoptotic pathway associated with the ef-
fects of lncRNAs on ALI remains enigmatic, and further
studies are needed to find out more about its role.
Autophagy
In different forms of stress, including nutrient scarcity,
growth factor deprivation, infectious condition, and hyp-
oxia, cells degrade themselves to recycle nutrients essen-
tial for cellular functions by an intracellular catabolic
process known as autophagy. Autophagy initiates with the
formation of double-membrane vesicles, the autophago-
some, that encapsulates or engulfs damaged organelles,
distorted macromolecules, and different cytoplasmic
debris and ends up with the fusion with lysosomes, termed
as autolysosome, for degradation.
80,81
The autophagic flux
is the measure of cargo delivery by autophagosomes to
autolysosomes.
82
The main purpose of autophagy is to
provide cellular essentials for cell thriving. Poorly regulated
autophagy processes are linked with various diseases,
including acute lung injury. Although the role of autophagy
in the context of acute lung injury is still indefinite and
remains uncertain. However, increased pro-inflammatory
cytokines in LPS treated mice manifested acute lung
Figure 2 The roles of lncRNAs involved in the various biological process during acute lung injury. lncRNAs act via targeting their
downstream molecules, such as miRNA/proteins. TUG1 act via regulating their downstream target miR-34 b-5p/GAB1. MALAT1 has
more than one downstream target molecules including miR-181a-5p, ICAM-1, miR-425. CASC2 acts via regulating miR-27b/TAB2
axis. NEAT1 has HMGB1/RAGE signaling as its downstream target. THRIL regulates the activity of miR-424/ROCK2 for functional
effects. Mirt2 controls TRAF6, NF-kB, stat6 and MAPK signaling pathways. The target of PRNCR1 is miR-330-5p/TLR4 axis. In
contrast, XIST acts via regulating the activity of miR-21/IL-12 A.
A. Zaki, M.S. Ali, V. Hadda et al.
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injury. Alveolar epithelial cells of LPS treated mice showed
a significant increase in the expression of autophagy marker
LC3B. In addition, administration of autophagy inhibitors 3-
methyladenine (3-MA) and chloroquine (CLQ) potentially
decreased total protein in BALF and lung injury score, thus
alleviating lung injury.
83
Stimulation of WI-38 human lung
fibroblasts with LPS triggers the expression of the lncRNA
HAGLROS and thereby causing cell injury.
Furthermore, downregulation of HAGLROS assuaged LPS
induced cellular injury by increasing cell viability and
curbing autophagy.
39
lncRNAs regulating autophagy in acute
lung injury are not fully characterized. Therefore, elabo-
rated research is needed to elucidate the role of lncRNA in
autophagy linked with ALI.
Inflammation
Inflammation is the sequential response by the body’s im-
mune system against harmful stimuli, including invading
infectious agents, toxic substances, damaged cells, or
irradiation, consequently eliminating noxious substances
and initiation of the healing process by the body. There-
fore, inflammation is categorized as a protective mecha-
nism essential for health.
84,85
Inflammation is known to play
an essential role in the pathophysiology of ALI. Various re-
ports have exhibited that lncRNA exerts an essential func-
tion in inflammatory processes. Excessive inflammation
could initiate a cascade to exacerbate further lung damage
leading to macrophage activation and polarization, neu-
trophils recruitment, and release of pro-inflammatory cy-
tokines such as TNF-a, IL-1b, IL-6, and ICAM1.
86
lncRNA-
5657 gets upregulated in LPS treated alveolar macrophage
cell lines and in lung tissue of CLP rats.
Furthermore, substantially overexpressed lncRNA-5657
results in the production of pro-inflammatory cytokines
including TNF-a, IL-1b, and IL-6, whereas the reverse was
noticed after silencing of lncRNA-5657.
48
In a study,
knockdown of lncRNA MALAT1 improved LPS induced acute
lung injury in mice by decreasing the level of inflammatory
cytokines. In addition, the number of neutrophils and
macrophages in BALF was found to be reduced.
59
Mice with
acute lung injury showed decreased expression of lncRNA
CASC2, AQP1, and increased miR-144-3p proportional to
inflammation in lung tissue. Alternatively, overexpression
of CASC2 by transfection in LPS treated A549 cell lines
restored AQP1 protein and ameliorated acute lung injury.
87
Zhiming et al reported upregulation of lncRNA SNHG16 and
pro-inflammatory cytokines such as (IL-6, IL-1b, and TNF-a)
in WI-38 cells after treatment with LPS. Downregulation of
SNHG16 significantly increased cell viability and propor-
tionally reduced the expression of IL-6, IL-1b, and TNF-a.
88
lncRNA effect on macrophage polarization in acute
lung injury
Macrophages are versatile and multifaceted innate immune
cells involved in the first line of defense. Their ability to
detect, engulf and eliminate intruding pathogens make
them prominent in an inflammatory response
89
However,
they can be subdivided into two functional categories (M1
and M2 macrophages) depending on specific external
stimuli and signals. M1 macrophages are the classically
activated subtype of macrophages that are involved in pro-
inflammatory response, on the other hand, alternatively
activated M2 macrophages are responsible for the anti-
inflammatory and angiogenic properties
90
. M1 macro-
phages are characterized by their ability to express pro-
inflammatory cytokines, including TNF-a and IL-1band
iNOS (inducible NO synthase).
91
Besides, M2 macrophages
release anti-inflammatory cytokines such as IL-10 and TGF-
b, including characteristic markers (Arg-1, Ym1, Fizz1)
expression.
92
Macrophage polarization plays a crucial role in the eti-
ology of many multifactorial diseases such as atheroscle-
rosis, sepsis, autoimmune diseases, cancer, tissue injury
and repair.
93
Differentially expressed lncRNA in polarized
macrophages (M1 and M2) provide a conspicuous result in
their involvement in inflammation and regulation.
94
In a
study, overexpression of MALAT1 in LPS treated mouse
BMDM was reported. Further studies also reported similar
observations in human monocytic THP-1 and human pe-
ripheral blood mononuclear cell-derived macrophages.
MALAT1 demonstrated its role in regulating clec16a (C-type
lectin domain family 16 member A) protein known for its
role in activating pro-inflammatory macrophages. MALAT1
knockdown cells were observed with substantially
decreased clec16a transcript. Extending work showed that
clec16a knockdown proportionally decreased in MALAT1
knockout mice that distinctly showed the role of MALAT1 in
macrophage activation and inflammation.
21
LPS stimulated
primary cultured peritoneal macrophages (PCPM) showed
Mirt2 lncRNA upregulation, whereas the opposite was
observed in IL-4 treated cells. Knockdown of inflammatory
pathways downstream signaling proteins such as MyD88 and
TRIF partially inhibited Mirt2 expression. Immunoprecipi-
tation assays revealed Mirt2 interaction with TRAF6 that
regulates inflammatory response. Mirt2 also regulates M2
polarization via PPARgand STAT-6 independent pathway
56
The horizon of lncRNAs can be exploited to evaluate their
intricate role in macrophage polarization and their thera-
peutic potential in acute lung injury.
Ferroptosis
Ferroptosis is a type of cell death induced by a small
molecule called erastin; it inhibits the import of cystine,
leading to depletion of glutathione and inactivation of
phospholipid peroxidase glutathione peroxidase 4 (GPX4).
95
Cell death induced by erastin in ferroptosis is distinct from
other forms of cell death such as apoptosis, necrosis, and
autophagy based on morphological, biochemical, and ge-
netic characteristics.
95
Many diseases have been reported
to be associated with ferroptosis. Recently, the role of
ferroptosis in lung diseases have also been reported.
96,97
Liu et al
98
demonstrated that Fer-1 (ferroptosis inhibitor)
alleviates the LPS-induced ALI as well as the inflammatory
responses in vivo efficiently by regulating ferroptosis.
lncRNA seems to play an essential role in the regulation
of ferroptosis. Interaction between many lncRNAs and
various cancer cells has been demonstrated, including lung
cancer cells.
99
However, the role of lncRNA in the regula-
tion of ferroptosis during acute lung injury has not been
Genes &Diseases xxx (xxxx) xxx
+MODEL
7
explored. Exploring the role of lncRNA in this area could
provide better therapeutic targets to manage ALI patients.
Efferocytosis
Efferocytosis is a process in which apoptotic cells are
cleared by the phagocytic cells. It is vital for normal
development, tissue repair and homeostatic cell turnover.
Apoptotic cells comprise many potential autoantigens and
alarmins like adenosine, HSP proteins, HMG box-1 proteins.
Secretion of these molecules during necrosis leads to mor-
tality in the appropriate sepsis model, and their long-term
persistence can also induce autoimmunity.
100
Dysfunctional
efferocytosis has been reported in many lung diseases such
as asthma, COPD, and cystic fibrosis; This led to the pro-
posal that promoting efferocytosis might arrest the pro-
gression of the disease.
101
Dysfunctional efferocytosis affects the prognosis in
ALI/ARDS murine model. During gut ischemia-reperfusion
in mice, the concentration of MFG-E8, an efferocytotic
opsonin, decreases significantly while intraperitoneal
administration of the same decrease inflammatory cyto-
kines in the lung and also alleviates lung injury leading to
increased survival.
102
In the LPS-induced ALI model, mice
lacking MFG-E8 showed enhanced neutrophil infiltration,
inflammatory cytokines, and reduced survival.
103
The role of lncRNAs in efferocytosis has not been well
studied. However, a recent study by Simion et al showed the
role of macrophage-specific lncRNA MAARS in atherosclerosis
and demonstrated that knockdown of MAARS is associated
with increased expression of MerTK, a crucial receptor for
efferocytosis, both in vivo and in bone marrow-derived
macrophages (BMDMs). Additionally, silencing of MAARS
increased the expression of mRNA SIRT1, an anti-apoptotic
HuR target gene known to increase the macrophage-
dependent efferocytosis.
104
Conclusion and future perspective
Acute lung injury is one of the major causes of ICU death
around the world. The current treatment strategy is not
effective enough to mitigate disease morbidity and mor-
tality. New therapeutic targets are needed urgently that
can effectively reduce the disease burden. In the last few
decades, lncRNAs provided a new dimension to researchers.
Studies have successfully demonstrated these molecules as
novel potential targets in acute lung injury/ARDS/sepsis.
These RNAs are involved in various pathophysiological pro-
cesses such as apoptosis, inflammation, cell signaling
pathways etc. However, the mechanisms underlying these
processes are still needed to be explored extensively.
Moreover, most of these studies are based on mouse models
and cell lines, and only a few are based on patient’s sam-
ples. Therefore, the role of these lncRNAs is needed to be
established in a larger sample size and to find its role as a
therapeutic target in human subjects.
Conflict of Interests
The authors declare that there is no conflict of interests.
Acknowledgements
We would like to thank All India Institute of Medical Sci-
ences and Jamia Millia Islamia, New Delhi for providing
infrastructure, journal access, and internet facilities. We
acknowledge the Indian Council of Medical Research (ICMR)
for providing fellowship to AZ and MSA.
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