Abstract : Acute lung injury is a systemic inflammatory response
syndrome in the lungs, with a high incidence and fatality rate of
30%–40%. Despite the abundance of research on the pathogenesis of
lung injury and the great progress that has been achieved, the various
number of cells, cytokines and inflammatory response pathways involved
in the pathogenesis of acute lung injury (ALI) and their complex
relationships, which together constitute the cell network and
inflammatory factor network of ALI inflammatory response, demand more
attention. This study reviews the formation of this network in the
pathogenesis of acute lung injury.
Keywords : acute lung injury; inflammatory factor network; cell
network
Acute lung injury (ALI) is a primary disease caused by serious
non-cardiogenic pathogenic factors such as severe infection, shock,
trauma, disseminated intravascular coagulation, aspiration and so on.
The clinical manifestations are mainly acute progressive aggravated
dyspnoea and refractory hypoxemia. Numerous studies have investigated
the relationship between a single cell type, single cytokine, or cell
and molecule related to certain disease aspects; however, the study
based on a single research object cannot grasp disease occurrence and
development, affecting the therapeutic effects on the disease.
Therefore, this review of studies on cellular inflammatory cytokine
networks and cellular networks provides a more comprehensive
understanding of the pathogenesis of ALI and new research ideas.
1 Cytokine network
1.1 Tumour necrosis factor-α (TNF-α) and interleukin-1β (IL-1β)
TNF-α and IL-1β are considered promoters of the development of ALI/acute
respiratory distress syndrome[1][2]. TNF-α and
IL-1β in the plasma are often used to distinguish the severity of
systemic inflammation, increase the permeability of epithelial cells and
then lead to lung tissue injury and neutrophil aggregation, resulting in
pulmonary oedema. It also induces IL-8 production in alveolar
macrophages, type II epithelial cells and lung
fibroblasts[3][4][5]. TNF-α can also
promote the expressions of IL-6 and IL-1β in fibroblasts and the
differentiation of fibroblasts[6]. The
transcription of TNF-α and IL-1β is mediated by the nuclear factor (NF)-
κB, and the TNF-α promoter contains sites of NF-κB, which can stimulate
and activate NF-κB, thus forming a positive regulatory loop to amplify
and maintain inflammation[7].
TNF-α is secreted by activated monocytes and macrophages and can promote
cytokine production and neutrophil aggregation into the lungs, stimulate
fibroblast proliferation, lead to pleural septum thickening and increase
collagen production.[8][9][10] It can also
directly damage vascular endothelial cells and increase their
permeability. Moreover, it is a major cytokine that mediates early
inflammatory response and fibrosis. It is closely related to the
occurrence of lung injury[11][12][13].
TNF-α can interact with endothelial cells to induce lung endothelial
cell activation, increase the expression of vascular endothelial cell
surface adhesion molecules and stimulate leukocyte activation and
migration, both of which contribute to the aggregation of neutrophils to
the injured site, thus further activating monocytes, macrophages and T
lymphocytes and promoting the release of numerous pro-inflammatory
factors by inflammatory cells[14]. TNF-α also
regulates the expression of various pro-inflammatory factors (such as
IL-1, IL-6, platelet-activating factor, IL-8 and leukotriene) and
amplifies the inflammatory cascade reaction. TNF-α can also bind to
receptors on the surface of alveolar epithelial cells, causing changes
in cell metabolism, mediating epithelial cell apoptosis, shedding,
regeneration and ultimately, pulmonary
fibrosis[15][16].
IL-1β is secreted by mononuclear macrophages and is one of the major
inflammatory cytokines in pulmonary oedema fluid. IL-1β stimulates the
production of chemokines (e.g. IL-8), epithelial-derived neutrophil
chemokines ENA-78, monocyte chemokine peptide (MCP)-1, macrophage
inflammatory peptide-1 and the extracellular matrix produced by
fibroblasts. IL-6 and IL-1β are precursors of inflammation and
fibrosis[10][17][18][19][20][21].
1.2 IL-6
IL-6 is a water solubility mediator and is produced by dendritic cells
(DCs), mononuclear macrophages, B cells, activated T cell subsets,
fibroblasts, endothelial cells and
keratinocytes[5][22]. It is involved in the
acute-phase reaction during infection and can integrate the signals of
early inflammatory response. It is also an important inflammatory factor
in the early stage of inflammation and can promote the release of more
inflammatory factors. Sustained levels of IL-6 can inhibit inflammation
and coordinate anti-inflammatory activities required for inflammation
reduction[11][23][24]. In
lipopolysaccharide (LPS)-induced ALI, the formation of pulmonary oedema
in rats is highly correlated with IL-6, which is one of the main
inflammatory cytokines in pulmonary oedema fluid. IL-6 content can
reflect the severity of local reactions in the lungs and is used to
judge healing[25][26].
IL-6 regulates cell growth and
differentiation[26]. It can promote the phenotype
transformation of macrophages, induce macrophages to differentiate into
M2 type, stimulate macrophages to secrete MCP-1, promote
atherosclerosis, increase the expression of cell adhesion molecules,
stimulate the proliferation and migration of vascular smooth muscle
cells, regulate infection, or promote the accumulation of neutrophils at
the wound site. IL-6 also delays polymorphonuclear cell (PMN) apoptosis,
inhibits DC formation and NF-κB activation in these cells and the
expression of chemotactic factor CCR7 and promotes keratinocyte
proliferation or gliosis in dermal
fibroblasts[23][24].
IL-6 signal transduction can be classified into classical activation and
transactivation. Classical IL-6 receptor signalling controls both
intracentric stabilisation processes and immune outcomes. IL-6
trans-signal transduction plays an important role in leukocyte
recruitment and apoptosis, maintenance of T cell effector function and
inflammatory activation of interstitial tissue and regulates the
expression of adhesion molecules intercellular adhesion molecule
(ICAM)-1 and vascular cell adhesion molecule
1[23]. The IL-6 trans-signal transduction
mechanism ensures an effective defence mechanism, prevents excessive
tissue damage and drives the transition from neutrophil recruitment to
monocyte recruitment[23].
1.3 IL-8
IL-8 is mainly produced by alveolar macrophages, type II epithelial
cells and lung fibroblasts[5][27]. IL-8 is the
main chemokine of neutrophils and plays a chemotactic role mainly by
binding to CXCL1, a homologous receptor on
neutrophils[18]. In endotoxaemia models and acid
inhalation models, IL-8 monoclonal antibody binds to IL-8 and prevents
binding to CXC chemokine receptors on PMN, significantly reducing lung
injury and PMN migration[18].
1.4 High mobility group 1 protein (HGMB-1)
HGMB-1 is a highly conserved eukaryotic protein isolated from chromosome
protein and is a transcription factor[28]. It can
be passively released from damaged and necrotic cells and actively
secreted by immune cells stimulated by cytokines and endotoxins (DCs and
macrophages)[29]. In ALI, NF-κB activation
increased HMBG-1 secretion. Extracellular HGMB-1 can be used as a
cytokine to mediate nonspecific inflammatory response or as an
endogenous danger signal to initiate and enhance specific immune
response, induce neutrophilic inflammatory pulmonary oedema, stimulate
macrophages to secrete TNF-α, further promote macrophages to express
HGMB-1 and maintain the inflammatory
response[29][30]. Moreover, HGMB-1 is an
inhibitor of the Bcl-2 family member Bak, resulting in neutrophil
apoptosis inhibition and aggravation of neutrophil accumulation.
Anti-HGMB-1 antibodies can reduce the migration of neutrophils to the
site of lung injury[29][31].
1.5 Interferon-γ (IFN-γ)
IFN-γ is derived from the glycoprotein of activated T lymphocytes. It
activates defence cells and promotes the release of IL-1β, IL-6 and
TNF-α, thereby further amplifying the inflammatory response. It also
mediates endothelial cell damage, increases vascular permeability,
promotes neutrophils to enter the alveoli and mediates lung damage.
1.6 Haeme oxygenase-1 (HO-1)
HO-1 is a stress protein stimulated by inflammatory cytokines, heat
shock, heavy metals and oxidants, which can degrade haem into Fe2+,
biliverdin BV and CO[29][32]. The downstream
product CO can regulate inflammation, reduce inflammatory cell
production and interact through the MAPK pathway to increase the
production of anti-inflammatory cytokines. Therefore, HO-1 has
anti-inflammatory, antioxidant, anti-apoptotic and anti-proliferative
effects. Moreover, an interaction was found between inducible nitric
oxide synthase (iNOS) and HO-1. NO is a strong inducer of HO-1, and the
expression of HO-1 can inhibit iNOS expression and
activity[33][34]. Therefore, HO-1 and CO have
protective effects on ALI, inducing HO-1 expression and inhibiting
LPS-induced lung injury, iNOS expression and NO
production[33]. The overexpression of HO-1 also
significantly decreased the total number of cells, neutrophils, W/D
ratio and EBA exudation in the bronchoalveolar lavage fluid and
significantly inhibited the increase in TNF-α concentration and HMGB1
expression[29].
1.7 IL-10
IL-10 is an important anti-inflammatory factor in inflammatory injury
response. It is secreted by mononuclear macrophages and can downregulate
the secretions of T-cofactors, MHCII antigens and co-stimulatory
molecules on macrophages and inhibit neutrophil rolling, adhesion and
transepithelial migration and the release of inflammatory factors such
as TNF-α, IFN-γ, IL-1 and IL-8. IL-10 can also block cytokine-induced
chemotactic and oxidative burst, reduce recruitment of neutrophils,
interfere with neutrophil-mediated tissue damage, inhibit Th1-mediated
immune response and enhance the body’s anti-infection
ability[35][36][37].
2 Cell network
2.1 Macrophages
Macrophages are a type of white blood cell that develops when monocytes
migrate into the lung tissue. Macrophages are widely distributed and can
be divided into alveolar macrophages (AM), interstitial macrophages
(IM), bronchial macrophages, pulmonary intravascular macrophages and DCs
after entering the lung tissue. These cells constitute the first line of
defence for removing foreign
bodies[38][39][40].
In the absence of inflammation, macrophages are in an immune resting
state and can secrete large amounts of prostaglandins, which reduce the
release of cytokines and inhibit cytokines from stimulating collagen
synthesis[16][38]. When external substances
enter the body, AM, as an important target cell, is polarised in an
activated state, which has certain biological effects: it produces
numerous free radicals and secretes inflammatory factors, thus
activating other inflammatory reactions enzyme, and LTs can increase the
expression of adhesion molecules in vascular endothelial cells at
inflammatory response sites, making PMNs easy to adhere
to[38][40][41]. IM promotes the removal of
PMNs from the lung and secretes IL-1, IL-6, reactive oxygen species
(ROS) and iNOS after
stimulation[26][38][42][43]. Moreover,
it can present specific antigens to T cells, induce T cell
differentiation, mediate Th1 and Th17 cell immune response in Th cells
and promote inflammation[47]. In a complex
inflammatory environment, macrophages are simultaneously regulated by
different molecular events and signalling pathways involving JAK-STAT,
TLR-NF-κB, MAPK, hypoxia-dependent signalling pathways and differential
TLR expression[40][44][45][46].
Macrophages can be classified into classically activated macrophages
(M1) and selectively activated macrophages (M2) according to metabolic
pathways, types of cytokines secreted and surface
markers[26]. M1 are induced by bacteria, and their
products, such as LPS, or cytokine IFN-γ, promote inflammation and
cytotoxicity, high expression of iNOS, ROI and production of TNF-α,
IL-1β, IL-6, CXCL-3, CXCL-5 and CXCL-8. Induced by IL-4, IL-10 and
glucocorticoids, M2 promote damage repair and tissue regeneration while
maintaining mild and continuous anti-inflammation, high expression of
Arg1 (arginine) and IL-10 production[45][51].
Therefore, macrophages have both pro-inflammatory and anti-inflammatory
effects and phagocytic and secretory
functions[51]. They can phagocytise not only cell
debris but also apoptotic polymorphonuclear leukocytes while producing
numerous free radical ROS, secreting inflammatory factors and being the
main source of cellular inflammatory factors TNF-α, IL-1β and IL-6 and
finally initiating the inflammatory
cascade[39][51].
2.2 PMNs
PMNs are mainly neutrophils, including a small number of eosinophils and
basophils. PMNS are one of the main effector cells of ALI. They remove
foreign bodies mainly by producing ROS and antibacterial proteins. PMNs
can be activated by TNF-α, IL and chemokines produced by macrophages,
and migratory recruitment occurs. Moreover, various proteases and oxygen
free radicals are released, causing the inflammatory
storm[47]. When PMNs are inhibited by apoptosis,
excessive and prolonged activation occurs, resulting in basement
membrane destruction and increased capillary barrier permeability. When
neutrophil transepithelial migration occurs, it will further destroy the
alveoli and damage the lungs[19].
2.3 Endothelial cells
The integrity of pulmonary microvascular endothelial cells is critical
in the initiation of lung inflammation, preventing protein-rich fluid
from flowing into the interstitial lung tissue and alveoli from plasma
and inflammatory cells, reducing the range of inflammatory effects and
reducing pulmonary oedema. Among them, cadherin (VE) and
adhesive-junctional proteins play a key role in the maintenance of
endothelial barrier integrity[48][49].
During inflammation, selectin on the surface of endothelial cells
interacts with ligands on the surface of neutrophils to mediate immune
cascade reactions such as capture, rolling and adhesion of
neutrophils[48][49]. In the resting state, the
expression level of ICAM-1 in vascular endothelial cells is low, which
plays an important role in stabilising cell–cell interaction and
promoting the migration of leukocyte endothelial cells. In the presence
of inflammatory stimulators such as TNF-α and LPS, endothelial cells
highly express surface p-selectin and
E-selectin[48]. The expression of p-selectin on
the surface of endothelial cells activates endothelial cells and
interacts with leukocyte receptors, which mediates the rolling of
leukocytes on activated endothelial cells, and E-selectin further
mediates adhesion, makes leukocytes approach the cytokines and
chemokines secreted and expressed on endothelial cells, activates
leukocytes to express β2 integrin and bind to their
receptors[49][50]. It can enhance the adhesion
between leukocytes, inflammatory cells and endothelial cells, promote
neutrophil recruitment and endothelial cell activation and destroy the
integrity of endothelial cells, making it easier for them to penetrate
the endothelium[48][51]. Furthermore,
endothelial cells can synthesise and release vasoactive substances,
prostaglandins, PGI2, NO and inflammatory mediators TNF- α, IL-1 β and
IL-8 that are involved in the occurrence and development of
inflammation[39].
2.4 Epithelial cells
Alveolar epithelial cells are divided into type I epithelial cells and
type II epithelial cells. Type I epithelial cells express
globulin-transmembrane immune advanced glycation end product receptor,
and type II epithelial cells secrete surfactant D, which has
anti-inflammatory effects and participates in pathogen phagocytosis and
neutrophil recruitment. Type I and II alveolar epithelia are closely
connected and selectively regulate the epithelial
barrier[19][52].
When alveolar epithelial cells are activated by AM products such as
oxygen free radicals, IL-1, TNF-α and other inflammatory mediators,
diffuse damage occurs and integrity is destroyed, leading to loss of
surfactant activity and decreased secretion and barrier
function[19]. More monocytes will be recruited to
the inflammatory site, macrophages by secreting TNF-α, IL-8, IL-6,
IL-1β, cytokines and other induction of recruitment of various cells,
including neutrophils, lymphocytes and
eosinophils[53]. When PMNs enter the alveoli, they
stimulate the epithelium to release vascular growth factors,
pro-inflammatory cytokines, acute-phase proteins (C-reactive protein and
protease inhibitors) and chemokines to participate in the inflammatory
response[5].
2.5 Lymphocytes.
In indirect ALI, in addition to neutrophils and macrophages, lymphocytes
CD4+, CD25+ and Foxp3+T are specifically recruited into the lungs. In
the immune response, Th cells that play a role are differentiation
antigen4+, T cells (CD4+, T cells), which are differentiated into Th1,
Th2, Th17 and Treg cells[36]. Th1 mediates
cellular immune response, secretes IL-2, IFN-γ, TNF-α, IFN-γ and IL-12
to initiate Th1 cell differentiation, promote T lymphocyte
differentiation, maturation and proliferation, enhance macrophage
phagocytosis and regulate alveolar inflammation, which are necessary to
remove intracellular pathogens[22]. Th2 mediates
humoral immune response and secretes IL-4, IL-5, IL-6, IL-10 and IL-13,
which are the key for host cells to defend against extracellular
pathogens and help B cells produce antibodies. IL-4 can induce Th2 cell
differentiation[22]. Th17 secretes
pro-inflammatory factors IL-17A, IL-17F and IL-22, which can
cooperatively induce tissue inflammation[22]. Treg
cells secrete cytokines such as IL-10 and TGF- β, which mediates immune
response. In the early stage of inflammation, effector T lymphocytes
(Th1 cells) are activated; with disease progression, Th2 cell
transformation occurs when the effector T cells enter the stage of
fibrosis[42].
In summary, the pathogenesis of ALI involves the accumulation of various
key effector cells, multiple physiological and pathological changes and
activation and release of various inflammatory cytokines, and all levels
influence each other, forming a complex cell network and cytokine
network. This will provide a new scheme for the clinical treatment of
ALI for a more comprehensive and in-depth understanding of the role of
inflammation and changes in the inflammatory microenvironment in the
pathogenesis of ALI.
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