FUNDENI CLINICAL HOSPITAL
OF BUCHAREST
e-mail: popdociul@yahoo.com
Dr.ALINA HALPERN - PhD
The Lung Disease Hospital "Sf. Stefan", Bucharest
ABSTRACT.
THE
CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD)
is characterized by the progressive airways narrowing and air flow
limitation and related to an abnormal inflammatory process. In the
inflammatory process take part: the structural cells, cells of the
inherited and adaptive immunity: neutrophils, macrophages, T
lymphocytes with the predominance of the Tc1 cells. Under the action
of the etiologic factors multiple inflammatory mediators are released
with the help of the transcription factor NFkappaB. These play a key
role in orchestrating the chronic inflammation through their
chemotactic and proinflammatory action. The chronic inflammation
progresses in a very complex manner through the interaction of the
native and adaptive immunity cells with the inflammation cytokines
and mediators. The molecular basis of inflammation enlargement of is
not well known, but it is - in part - genetically determined.
COPD is a disease characterized by not fully reversible
airflow-limitation. That is usually progresive and associated with an
abnormal inflammatory response.The pattern of inflammation in airways
and lung parenchyma comprise cells of innate and adaptive immunity
such as macrophages. T lymphocytes with predominantly
CD8+{cito-toxic}T cells.
The
impact of ROS (reactive oxidative species) gives rise to a release of multiple inflammatory
mediators with the aid of the NF[kappa}B transcription factor. This
plays a key role in orchestrating the chronic inflammation by your
chemotactic and pro-inflammatory capacity. This chronic inflammation
progresses into a very complicated inflammation pattern of innate and
adaptive immunity interacting with cytokines and other mediators.The
molecular basis of inflammation is not yet understood but may be, at
least in part, genetically determined.
INTRODUCTION
1)
DEFINITION: is a disease characterised through the airflow limitation -
incompletely reversible, which is usually progressive and associated
with an abnormal inflammatory response of the lung to the action of
environment factors, gases, particles [3, 11, 1, 12]. The influence
raises with the worsening of the disease [3, 13] and aggravates the
airway obstruction.
2)
Both COPDand the Lung Cancer (LC) are
associated with smoking which, generating reactive oxidative species,
induce a state of inflammation in the lung. In both diseases is met
the activation of two transcription factors: NFkappaB and Activator
Protein-1 (AP-1) leading to the alteration of expression of a number
of genes.
The main characteristics IN LC and COPD[124]
- LCCOPD
Escape of apoptosis Raised apoptosisSelf-sufficient growthMatrix degradationInsensitivity to antigrowthInefficient tissue repairSustained agiogenesisLimited angiogenesisTissue invasionIntense immune inflamationLimited responses
It
is not yet precisely known for what reason the inflammatory response
is different in the two diseases. Perhaps this is due to the genetic
polymorphism, in cancer being the genes that regulate the genomic
integrity and in COPDit is the genes polymorphism that regulates the
immune response towards tissue destruction [2]
3)
THE CHRONIC INFLAMMATION
The
inflammatory model in COPDcomprises cells of the inherited and
adaptive immunity such as neutrophils, macrophages, T lymphocytes
with the prevalence of the Tc1 lymphocytes (CD + cytotoxic 8) in
particular in the small airways and in severe cases the increase of
neutrophils in the bronchial lumen [3, 13, 14].
In
COPD, the inflammatory mediators are raised and derive from the lung
inflammatory and structural cells [3, 15].
The
cigarette smoke may activate the surface macrophages and epithelial
bronchial cells that activate the chemotactic factors where
chemokines predominate, which play a key role in orchestrating the
chronic inflammation in COPD.
They
are the first inflammatory elements that occur in all smokers, but in
smokers with COPD this inflammation progresses into a very complex
that contribute to the elements of the inherited and adaptive
immunity, dendritic cells, T lymphocytes (Th1 and Tc1), to which it
is added a complicated interaction of cytokines and mediators.
The
molecular basis of the inflammation enlargement is not well known,
but in part is genetically determined [4]
THE
OXIDATIVE STRESS, SIGNALING FACTORS AND PATHWAYS
The
oxidative stress is an important characteristic in COPD [3, 16]. The
reactive oxidative species (ROS) can activate the NF-kappa B and
activator protein-1
(AP-1)transcription factors, which potentiate the inflammatory
response by activating several genes in COPD [3, 17].
Besides
the cigarette smoke [3, 18] there are also the structural and
inflammatory cells activated by tobacco in smokers lung and include
the neutrophils, eosinophils, macrophages, epithelial cells, which in
turn produce the ROS
The
increase of the response is activated:
-
either directly through the ROS activation on the target cells in the
airways and parenchyma (alveoli)
-
or indirectly through the pathways activation of transduction
signaling and the NF-kappa B transcription factor. This is activated
in airways and alveolar macrophages in patients with COPD and is also
activated in the COPD exacerbations [3, 19].
This
activation induces a neutrophilic inflammation by the raise of the
expression of CXC8 (IL-8) and other CXC-chemokines, TNF-alpha (a
cytokine) and MMP-9.
The
oxidants also activate the MAPK pathways
(mitogen-activated-protein-kinase), which regulates the expression of
inflammatory genes, their survival in some cells and some aspects of
the macrophage function [3, 20].
The
MAPK and PI3K are signaling pathways of the transduction altered by
ROS [1, 21, 22]. It was observed an increase of the p38MAPK
phosphorylated expressiveness (one of three major MAPK pathways) in
macrophages and alveolar wall of the COPD [1, 23].
The
p38MAPK inhibitor - named SD282 – reduces the inflammation caused
by tobacco, decreases the number of macrophages and neutrophils in
the lavage liquid, an effect not noticed in glucocorticoids [1, 24].
ROS
can also affect the antiproteases like alpha 1 antitrypsin and
"secretory leukocyte protease inhibitor" and accelerates
the elastin breaking in lung parenchyma [3, 25].
The
ROS and NO may affect various cellular functions. It may cause the
mitochondrial alterioration, breakings of the DNA chain and the
proteins structural and functional changes that have as result the
cell death [3, 26].
Such
alterations to the proteins can make them to become antigenic and
will result in the autoimmune response of T cells [3, 27].
This
may be a mechanism for the adaptive immune response observed in COPD.
The
oxidative stress plays a key role in the inflammatory process through
their role on the nuclear histones [3, 28]. The histone acetylation
plays a part in the nucleosome remodeling, which enables the access
to various inflammatory sites or other genes.
The
histone acetylation levels (HAT) correlate directly with the level of
gene transcription.
Backwards,
the spontaneous deacetylation through HDAC (histone deacetylase) or
through corticosteroids, changes the histone acetylation and prevents
the gene transcription and ends the inflammation cascade.
The
oxidative stress caused by tobacco plays an important role in raising
the level of acetylation (HAT) and decreasing the HDAC observed in
epithelial cells, macrophages and neutrophils in smokers [3, 21].
The
histone acetylation and HDAC inhibition are related to the increase
of the inflammatory genes activity (AP-1 and NF-kappaB) that forward
and maintain the inflammation [3, 21].
The
mechanism by which ROS enhances the NF-kappaB activation is
cellular-specific and different from the physiological activity.
Also, the oxidative stress may affect the enzyme activity that leads
to the NF-kappa B activatio [1, 29].
Along
with the raise in the COPD severity, the lung tissue shows a gradual
decrease in the HDAC activity (this is essential for the suppression
of inflammatory genes by corticosteroids) [1, 30, 31].
THE
EPITHELIAL CELLS
They
are the first line of defense and are able to release inflammatory
mediators. The epithelial response to cigarette smoke is an attempt
to protect and repair the injury [1-32]. The injury leads to the
development of squamous metaplasia, which means the temporary
replacement of columnar epithelium with squamous epithelium, an
effect which is correlated with the airways obstruction. The squamous
metaplasia affects the mucociliary clearance and raises the risk of
appearing both the lung cancer and the COPD.
The
airways squamous metaplasia increases along with the disease severity
in COPD [1]. It was also observed a small increase in the rate of
small airways proliferation in COPD [1, 34].
Epithelial
cells release inflammatory mediators such as TNF-alpha, Inter leukin
(IL)-1 beta, GM. CSF, CXCL8 (IL8), Leukotrien B4 [3, 35].
CXCL8
(IL-8) is a powerful chemo-attractant of the neutrophils.
The
epithelial cells release C-C chemokines such as :
CCL-5
(RANTES), Protein. 1 chemoattractant of the monocytes and CCL-11
(Eotaxin) with activity in macrophages and dendritic cells [3-35]
The
production and hypersecretion of mucus in the airways takes place
through the EGFR activation by TNF-alpha and neutrophil elastase,
probably mediated thourgh the protein kinase C [3, 35]. Tthey
contribute to the decrease of FEV-1.
The
epithelial cells can modulate the extracellular matrix by:
A)
the direct production of matrix proteins such as fibronectin and
collagen-mediated by TGF-alpha [3, 36].
B)
by fibroblast activity (recruitment and proliferation by producing
fibroblast growth factors of Type1and Type 2. To the airways
remodeling also contributes the high expression of MMP 9 in epithelia
[3, 37].
The
alveolar epithelial response to injuries is in many respects similar
to the response of the airway epithelium, but here the VEGF plays an
important role in regulating the vascular growth. In moderate COPD it
is notice an increase of the VEGF expression, but decreases in severe
COPD with emphysema, which is associated with the endothelial cell
apoptosis [3, 38].
The
VEGF is, at the same time, a pro-inflammatory cytokine that is
produced by the epithelial, endothelial, macrophages cells, activated
T-cells, that act through the enhancement of the endothelial
permeability on its way to be a chemoattractant of the monocyte. VEGF
is an intermediate between the cell-mediated immune inflammation and
angiogenic response associated [3-48].
THE
NEUTROPHILS
The
neutrophils are located particularly in the bronchial epithelium and
bronchial glands [1, 39] and in close apposition with the airway
smooth muscle fascicles [1, 40]. They are found in the bronchial
lumen and distinguish by sputum and BAL [3, 41].
The
neutrophils in sputum are increased in advanced COPD and are
accompanied by the airway obstruction and the decline of the
breathing function [1, 42, 43, 3, 44].
Smoking
leads to the alteration of the neutrophil phagocytic capacity through
suppressing the activity of caspase-3
in neutrophils. This results in a higher risk of over infections in
patients with COPD [1-24]. The activated neutrophils are found in
sputum and lavage fluid in COPD [3, 41].
The
neutrophil recruitment in COPD is performed by more chemotactic
signals. These derived from the epithelial cells, T-cells and
alveolar macrophages. They include the CXC chemokines such as CXCL-1
(GRO-ALFA), CXCL5 (ENA. 78) CXCL-8 (Il-8), which acts through the
CXCR-2 receptor, which are high in the COPD [3, 46].
The
neutrophils have the ability to also induce tissue alteration and
emphysema by releasing serine proteases, which include neutrophil
elastase (NE), cathepsin G, protease 3, MMP8 and MMP9.
Ii
is highly likely that the mucus hypersecretion is related to the
neutrophilia in the airways and their proteases [3, 47].
The
neutrophils, along with macrophages are effector cells.
THE
EOSINOPHILS
Their
role in COPD is uncertain. The presence of eosinophils in COPD
predict a response to corticosteroids and may indicate the
association of an asthma [3, 48. 1, 49, 50, 51].
The
presence of eosinophils in COPD makes obvious a COPD subgroup.
MAST-CELL
It
has been observed a raise of the Mast-Cell in the COPD airways [1,
52, 53]. They are seen in chronic bronchitis without obstruction and
are not observed in chronic bronchitis with obstructive component [1,
54].
The
airways smooth musculature
În
COPD it was noticed an increase in the airways smooth musculature
mici, even reaching 50% in stages III and IV [1, 55, 56].
The
development degree of the smooth musculature is reversely correlated
with the lung function [1, 55].
The
muscle cells have not only contractile properties. They are capable
of the expression and release of cytokines, chemokines, growth
factors, proteases and may participate in the inflammatory and
remodeling processes [1 57, 58].
The
cytokines and chemokines of interest in COPD released by the muscle
cells are the following: IL-6, CXCL-8 (IL-8) CCL-2 (MCP-1) CXCL1 (
(GRO_alpha) CXCL 10 (IP-10) and the factor stimulating the
macrophages and granulocytes-GM-CSF [1, 57, 59, 60, 61]
IL-1
beta proinflammatory cytokines, TNF-alpha, bradykinin induce the
release of CXCL-8 (IL-8), which in its turn is a powerful
chemoattractant and activator of the neutrophils, whereas IFN-gamma
and TNF-alpha induce the release of CXCL-10 (IP-10) which is
expressed in muscle cells of COPD [1, 59]. CXCL-10 (IP-10) is a
strong chemoattractant of the monocytes, neutrophils, T cells (Th-1
cells preferably). The smooth muscle is a source of the factors of
connective tissue growth such as CTGF and TGF-Beta (!). [62, 63]
THE
MONOCYTE MACROPHAGES
The
number of macrophages is 5-10 times higher in all lung compartments
[3p-532]. Macrophages are very important effector cells in COPD
through their potential of releasing ROS, extracellular matrix
proteins, lipid mediators, chemokines and matrix metalloproteinases
[1-64]. The macrophages number increases along with the COPD severity
[3-54] and the emphysema severity [3-65].
The
increasing number of macrophages in smokers is due to enhanced
expression of the BCL-X (B cells with anti-apoptotic activity) and
the increase in the cytoplasm of an inhibitor which regulates the
cell cycle - (Cyclin-dependent - cip/waf-1 p21 kinase inhibitor
[1-66] .This increase is characterized by the high expression of the
Ki-67 proliferation marker [1-67].
The
alveolar macrophages activated by the tobacco smoke release
inflammatory mediators such as:
TNF-alpha,
IL-1Beta, IL-6, IL+18, CXCL-8 (IL-8) and other CXC chemokines, CCL2
(monocyte chemoattractant protein-1). All these prove a cell that
links the smoking to the inflammation in COPD [3-68, 69]
Most
of the inflammatory proteins produced by macrophages are regulated by
the NF-kappa B transcription factor, which is activated in the
alveolar macrophages in patients with COPD, especially in
exacerbations [3-70].
The
lung macrophages in smokers with COPD have an extended life time
[3-66], probably due to IFN-gamma produced by theT cells.
The
lung macrophages also secrete elastolite enzymes, which include:
MMP-9,
MMP-2, MMP-12, K, L, and S cathepsins to which the neutrophil
elastase is added.
The
release of CXCL-1, TNF-alpha, and MMP is not inhibited by the
glucocorticoid steroids in COPD smokers, due to the activity
reduction in HDAC (hystone deacetylase), which does not happen in
normal smokers.
There
is an augmenting in the recruitment of circulating monocytes in
response to the action of chemokines for monocytes, such as CCL-2
which is high in sputum, lavage fluid and lung macrophages in COPD
[3-71].
Macrophages
in COPD have a lower ability to phagocyte the apoptotic neutrophils -
efferocytosis [1-72, 73]
THE
DENDRITIC CELLS
These
are a heterogeneous group of leukocytes, which have in common
morphological characters, secretory properties and the expression of
surface molecules.
The
dendritic cells are considered sentinels of the body. These are in
the first line of defense.
They
trigger one of the two types of immunity, having the ability to
stimulate the native T cells to and initiate an immune response. They
can migrate from the periphery to the lymphoid tissues where
stimulate and regulate the T cell function.
They
may trigger the massive proliferation of native interferon, either
specialises in cells that teach the immune system to recognize an
pathogen. The presence of an intruder stimulates the dendritic cells.
Further it is activated the pathway of PI3-kinase protein and the
immune response is triggered.
Then
in the core it is decided whether the native immunity can cope with
the pathogen. If it cannot, the adaptive immunity is activated [3 -
page 532].
They
may play the part of a connection between the innate immunity and
acquired immunity [10, 74.
]The
accumulation of dendritic cells in the epithelium and small airway
adventitia in COPD patients increases along with the disease severity
[1, 74, 75].
THE
IMMUNE RESPONSE
The
immune mechanism that leads to the inflammatory process in COPD is
mediated by various types of immune cells.
There
is an augmentation in the number of T lymphocytes in the lung
parenchyma and airways in patients with COPD [1-76], an increase
higher than CD + 8 than CD4 + [3-65, 75, 77].
Most
of T cells in the lung with COPD are the subtypes Th1 and TC1.
The
CD+4 and CD+8 cells from the lung with COPD show a high expression of
CXC3. This is a receptor activated by the chemokines CXCL 9 (MIG),
CXCL 10 (IP-10), CXCL 12 (I-TAC), which are increased in COPD [10,
78, 79]. This results in an accumulation of CD 4 and CD 8 cells.
CD+8
(Tc1) predominates to the CD + 4 (Th1) in the airways and parenchyma
in COPD. Tc1 secretes IFN-gamma, which expresses CXCR3, suggesting
that they are drawn into the lungs by the chemokines related to
CXCR3- [10, -80, 79]
In
the recruitment of T cells may also be involved the production of
CCL5 (RANTES), which attracts CD +4 and CD+8 via CCR5. This
production is increased in the COPD sputum compared to normal
[10-79].
Tc1
releases B granzimes and peforin, which are found high in the
patients sputum with COPD [10, 81]. They can induce the pneumocyte
type1apoptosis, contributing to the emphysema development [10, 82].
Tc1
and Th1 which lead to the inflammation may selfperpetuate due to
IFN-gamma, which stimulates the release of the CXCR3 ligand,
attracting more Th1şi Tc1 in the lung.
The
CD +8 cells enable important alterations in the lung. Besides the
cellular apoptosis and alveolar cells cytolysis, they also produce a
number of cytokines of type TNF-alpha, TNF-beta (lymphotoxin) and
IFN-gamma [3-69].
The
effector functions of the CD +4 are mediated by Th1-type cytokines,
which stimulate the higher migration of inflammatory cells (so-called
immune inflammation) [3-69]. The inflammatory process that conduces
to COPD result from a complex of inflammatory cells and immune cells,
mostly orchestrated by the T cells.
Thus
it was suggested that the COPD may also be regarded as an autoimmune
disease due to the antigens produced by the action of smoking on the
lung. [3-82, , 83, 84]
Fig. 1: Immune and inflamatory cells and those involved in COPD.
- The inhaled tobacco smoke and other irritants activate epithelial cells and macrophages to release chemotactic factors which attract inflammatory cells in the lungs, including: CCL2 acting on CCR2 for attracting monocytes, CXC – chemokine ligand (CXCL)1 and CXCL-8, which acts on CCR2 in order to draw in neutrophils and monocytes (which differentiate in macrophages in the lungs) and CXCL-9, CXCL-10 and CXCL-11 which act on CXCR-3 for attracting the Th1 and cytotoxic T type 1-cells (TC1). These cells, together with the macrophages and epithelial,cells release proteases such as, for example, matrix metalloproteinase (MMP) 9, which entails the elastin and emphizem degradation. Also, the neutrophil elastase conduces to the mucus hypersecretion. Epithelial cells and macrophages release the transforming growth factor (TGF)-β, which actuates the fibroblast proliferation leading to fibrosis in small airways.
Fig. 2: The T-CD+8 cells in COPD
Epithelial
cells and macrophages are stimulated by IFN-γ in order to release
the chemokines CXCL-9, CXCL-10 and CXCL-11 which together act on
CXCR-3 expressed on the Th1 and Tc1 cells for drawing them into the
lungs. The Tc1 cells through the release of perforin and granzyme B
induce the apoptosis of type 1 pneumocytes, contributing to the
formation of emphysema. The IFN-γ released by Th1 and TC1 prompts in
turn the release of CXCR-3 ligands, resulting in an of persistent
inflammatory activation.
With
the consent of Professor P.j.Barnes Breathe March 2011vol.7
no3:229-238
EMPHYSEMA
The
emphysema is characterized by the enlargement of alveolar spaces and
alveolar wall destruction, but without the evidence of fibrosis,
which may occur in the small airways.
There
are two theories on the emphysema pathogenesis [6]:
A}
Inflammation Theory. Tobacco smoke stimulates the inflammatory cells,
such that neutrophils, macrophages release proteases that entail the
breaking of the extracellular matrix (ECM) and basement membrane [6
85, 86, 87], the disequilibrium of protease-antiprotease balance,
prompting the MMP9 and MMP12, activation of proteases like the
neutrophil elastase and inactivation of alpha 1-antitrypsin. [1] We
also have the CD +8 cell activation for releasing perforin and
granzim.
The
inefficient clearance of the apoptotic cells by macrophages leads to
a decrease in the anti-inflammatory mechanism.
The
lung elastin distruction was suggested as the leading mechanism of
the lung alveoli damage and the release of neutrophil elastase and
metal proteinase in the inflammatory cells go beyond the defense
performed by the lung antiproteases and lead to parenchyma
damage.
Tobacco
smoke inhibits de novo synthesis and the tissue accumulation of
elastin and collagen [1-88]. The exposure to cigarette smoke also
inhibits the fibroblast proliferation ability [1-89, 90] and may
conduce to stopping the fibroblast cell cycle, mediated by the
activation of the p53 and p16 genes, which inhibits the cell cycle
leading to cell senescence [1-91] :
The
loss of telomerase activity, which is a marker for senescence is
observed in circulating lymphocytes from COPD [1-92].
In
COPD has been observed an increase in TGF-beta-1 with a reduction of
the type 1collagen expression [1-93]. The TGF-beta] increase with the
probable activation of MMP-12 may have elastolitic effects in lung
parenchyma, and fibrotic effects in small airways [1-93].
COL4A3
inhibits the neutrophil stimulation. COL4A3 may inhibit the
angiogenesis, leading to cell apoptosis [6, 94, 95].
The
effect of tobacco on the alveolar, epithelial cells induces all the
characteristics of the senescence (beta galactosidase activity,
changes in the cell morphology, the cell enlargement, increase in the
lysosome weight, accumulation of the lipofuscin, the definitive
growth stopping [1-96]
B]
Theory of apoptosis:
It
was observed an increase of the endothelial cell apoptosis. This is
correlated with the high caspase -3 and loss of anti-apoptotic Bcl-2
protein [1-97]. Caspase -3 is a marker of the apoptosis and oxidative
stress [1-98]
The
tobacco smoke diminishes the expression of VEGF and VEGFR 2 that
conduces to the apoptosis of epithelial and endothelial cells, with
the implicit loss of the ECM components (extracellular matrix) and
the alveolar units [6-99].
Collagen
alpha-3 is a gene located in the 2q33. 3 2q37.2 region which may
inhibit the neutrophil activation, inhibits their production of
superoxide and secretion of proteinases [6-100, 101]. The collagenIV
alpha3 may also inhibit the endothelial cell proliferation and induce
the cell apoptosis [6-94, 102, 103]. Thus is suggested that
collagenIV alpha3may be involved in the COPD pathogenesis, modulating
the inflammatory response and alveolar wall apoptosis [6-86].
The
CCL5 gene has an 28G- allela (single nucleotide polimorphism) which
predisposes to a degree of protection against emphysema development.
It was observed an inverse correlation between the functional
28G-allela and emphysema severity [7-p. 37].
EXACERBATIONS
WITHIN THE COPD
AMPLIFICATION
OF THE LUNG INFLAMMATION
In
advanced COPD we have exacerbations through viral and bacterial
infections [1, 104, 105]. These lead to the amplification of the
inflammatory response, by activating the immune and inflammatory
cells existing in the airways.
The
macrophages low efficiency to phagocyte both bacteria and apoptosis
neutrophils or epithelial cells enhances the activation of
inflammation leading to necrosis and release of products that
alterate the tissues [1, 106].
The
viral infections are associated with exacerbations in COPD [7. 107,
108, 109].
The
viral and bacterial infections may affect the NFkappaB. MMP8 lead in
turn to the release of inflammatory mediators and cytokines [1, 110].
During
exacerbations it is observed an activation of NF kappa B in pulmonary
macrophages [1, 111]
During
exacerbations it is noticed a raise in the plasmatic level of the
IL-6, CXCL8 (IL-8) and leukotrienes B [1, 112, 1].
In
COPD exacerbations with neutrophilic in bronchiolar epithelium, there
has been seen an increase of the genes expression CXCL5 (ENA-78) and
CXCL8 (IL-8) and CXCR2 receptor [1. 209]. Both CXCL5 (ENA-78) and
CXCR2 receptor shows a chemoattraction for neutrophils. Exacerbations
in light COPD are corresponding to CCL5 overregulation, both in
inflammatory cells and epithelial of the bronchial mucous[1, 3, 7]
CCL5
may be involved in the pathogenesis of epithelial remodeling and the
chronic hyper reactivity in response to viral infections.
CCL5
is a genetic risk factor in chronic inflammatory diseases of the
airways (asthma, COPD) [7].
Within
the regulator area of the CCL5 gene have been identified 3 SNPs
(single nucleotide polimorphisms) with functional activity. These
SNPs have been related to an increased level of CCL5 [7, 117, 118]
and high values of the blood eosinophils [7, 119]
The
genetic variations may explain the substantial variation in the
frequency of exacerbations in patients with COPD and similar
breathing function [10, 120, 121]
The
SNP of the B surfactant protein (SFTPB) termed Ro-302479 showed an
association with the exacerbations in COPD and with a susceptibility
for COPD. This SNP of the SFTPB is a proof of its presence in the
COPD physiological pathogenesis.
Microsatellite
instability (MSI) is found 50% in COPD and is not noticed in
non-smoking and healthy people [8, p612] . In patients with MSI and
COPD it has been seen an increase in exacerbations. Three markers
have shown a link with the exacerbations are: G-29802, D-13S71,
D-14S-580.
Relating
MSI to the COPD exacerbations indicates that somatic mutations may be
involved in the pathogenesis and natural history of the disease.
The
MSI has been correlated with a high rate of mutations and is
corresponding to a defective defense system. Detecting MSI in the
COPD sputum is a marker that shows a genomic instability in COPD. The
microsatellite instability alters the DNA defense ability [8-122,
123]. The relatively high frequency of COPD exacerbations with
genetic instability proves the link between the DNA repair activity
and oxidative stress due to the frequency of COPD exacerbations and
vice versa [10].
CONCLUSIONS
1)
THE OXIDATIVE STRESS acts either directly on the target cells in the
lungs, or indirectly by activating the transcription factor NFkappaB.
This activation induces a neutrophil inflammation through the
expression enhancement of the CXCL8 (IL-8), TNF-alpha and MMP9.
Reactive
oxidative species (ROS) also affect the antiproteases (alpha 1
anti-trypsin) and accelerate the elastin breaking in the lung
parenchyma.
The
oxidative stress entails a histone acetylation build up and inhibits
the histone deacetylase from the epithelial and inflamatory cells.
Thus it is also facilitated and maintained the inflammation.
2)
EPITHELIAL CELLS. Being the first line of defense - under the action
of the etiological factors it is produced the squamous metaplasia
that affects the mucociliary clearance and this grows along with the
disease severity.
The
epithelial cells release inflammatory mediators such as TNF-alpha
cytokines, CXCL8 (IL8), GM-CSF, B leukotriene.
Epithelial
cells also release C-C chemokines, such as: CCL5 (RANTES),
chemoattractant protein 1 of the monocytes and Eotaxin.
The
mucus production and hyper secretion is produced through the EGFR
action by TNF-alpha and neutrophil elastase.
Epithelial
cells may remodel the airways by produccing matrix proteins and by
producing fibroblast growth factors.
Within
the alveolar epithelium, in response to injury, plays an important
role in the high VEGF expression, which regulates the vascular
growth. VEGF is simultaneously a proinflammatory cytokine.
3)SMOOTH
MUSCULATURE OF THE AIRWAYS
Smooth
musculature increases up to 50% in COPD conducing to the lowering of
the lung function. They also release cytokines, chemokines, growth
factors, proteases.
Proinflammatory
cytokines such as IL. 1 beta, TNF-alpha, bradykinin induce the
release of CXCL8 (IL-8), which is a powerful neutrophil
chemoattractant.
The
IFN-gamma and TNF-alpha cytokines induce the release of CXCL10 (IP
10), which is well-expressed in the cell muscle in COPD.
Smooth
muscle is a growth factor source of the connective tissue (CTGF and
TGF-beta).
4)
NEUTROPHILS. Are high in COPD and cause the airway obstruction and
the decrease of the pulmonary function.
They
have a low phagocytic capacity, through the suppression of the
Caspase-1 activity.
The
neutrophil recruitment is performed by multiple chemotactic signals.
They include the CXC chemokines: CXC-1 (GRO-alpha), CXCL5 (ENA78) and
CXCL8 (IL8), which are high in COPD.
They
induce alveolar alterations and emphysema through releasing serine
proteases such as the neutrophil-elastase, cathepsin G and MMP9 MMP8.
The
mucus hypersecretion is related to the neutrophils in the airways and
their proteases.
5)
MONOCYTES MACROPHAGES. Their number is 5-10 times higher in COPD.
This increase is owed to the grown expression of (BCL) X that has an
antiapoptotic action.
The
macrophages activated by the tobacco smoke release inflammatory
mediators such as TNF-alpha IL-6, IL-I beta, IL-12, CXCL8 (IL8) and
CCL2 (monocyte chemoattractant) and other CXC chemokine (CXCL-I). All
these inflammatory proteins produced by macrophages are regulated by
the NFkappaB transcription factor, which is active in patients with
COPD.
Macrophages
in COPD have a extended life, very likely due to the IFN-gamma
produced by T lymphocytes.
Macrophages
also secrete elastolitic enzymes: MMP-9, MMP-12, MMP-2, cathepsin K,
L, S to which is also added the neutrophil elastase.
The
release of CXCL-1, TNF-alpha and MMP is not inhibited by
glucocorticoids in smokers with COPD, due to the decrease of the HDAC
activity, which is not seen in normal persons.
There
is an increase in the recruitment of circulating monocytes due to the
selective action for monocytes of the C-C chemokine CCL-2, which is
increased in COPD.
The
macrophages in COPD have a low phagocytic capacity of apoptotic
neutrophils.
6)
IMMUNE RESPONSE.
The
immune mechanism, resulting in the inflammatory process in COPD is
mediated by different types of immune cells .
There
is an increase in the number of T lymphocytes in COPD. Moat of
T-cells in the lung in patients with COPD are the subtypes Th1 [CD4
+} and Tc1 [CD 8 +}
Tc1
predominate compared to Th1 in COPD.
Tc1
secretes IFN-gamma, which expresses CXCR3, suggesting that they are
drawn into the lungs by the chemokines related to CXCR3.
CD4
and CD8 in the lungs with COPD indicate a high expression of CXCR3.
This is a receptor activated by the chemokines CXCL9, CXCL10, CXCL11,
which are grown in COPD. The high expression of CXCL10 by the
bronchiolar epithelium lead to an accumulation of Th1 and Tc1 cells,
expressing CXCR3.
In
COPD we have an increase in chemokine CCL5 (RANTES). This attracts
and recruits Th1 and Tc1 via CCR5.
Th1
and Tc1 conducing the inflammation may self-perpetuate since
IFN-gamma stimulates the release of CXCR3, which attracts more Tc1
and Th1 cells in the lung.
The
energised Tc1 produce apoptosis and cytolysis of the alveolar cells,
resulting a number of TNF-alpha, TNF-beta and IFN gamma type
cytokines.
The
inflammatory process leading to COPD results from a complex of
inflammatory cells and immune cells, most of them orchestrated by
theT cells.
COPD
may also be considered an immune disease due to antigens produced by
the lung injury under the action of smoking.
Tc1
release granzimes and perforin which induce apoptosis of the type 1
pneumocyte, contributing to the emphysema development.
7)
EMPHYSEMA.
There
are two theories on its pathogenesis.
a)
Inflammatory Theory. Tobacco stimulates the inflammatory cells, which
release proteases leading to the breaking of extracellular matrix
(EMC) and basement membrane. The lung elastin destruction has been
suggested as the leading mechanism of alveolar destruction which
release the neutrophil elastase and proteases from the inflammatory
cells which exceed the antiprotease defense of the lungs (alpha1
antitrypsin) and lead to destruction.
The
lung repair is inhibited by tobacco smoke. Is inhibited by the
fibroblast proliferation capacity. It is also inhibited de novo
synthesis and accumulation of elastin and collagen. In COPD has been
noticed an increase of the TGF-beta1 and CTGF with a decrease in the
production of type 1collagen. The raise in TGF-beta1 with a probable
activation of the MMP12 can lead to elastolitic effects in parenchyma
and fibrotic effects in small airway cells.
Also
it is observed a loss in the telomerase activity (senescence marker)
in circulating lymphocytes from COPD.
b)
Apoptosis Theory
We
have an apoptosis growth through the decrease in VEGF signalling.
This is correlated with the high Caspase3 activation and loss of the
antiapoptotic protein (BCL2)X. The tobacco smoke decreases the VEGF
and VEGFR2 expression that leads to the apoptosis of endothelial,
epithelial cells, with the implicit loss of the extracellular matrix
components (EMC) and alveolar units. The VEGF level drops in the
sputum of patients suffering of COPD together with the desease
aggravation.
8)
EXACERBATIONS WITHIN THE COPD
In
advanced COPD we have an increase of the bacterial and viral
infections that trigger NFkappaB and the MAPK pathway leading to the
release of inflammatory mediators and cytokines.
During
exacerbations, the plasma levels of the IL-6, CXCL8 (IL8), B
leukotriene increases.
In
exacerbations it is observed a high expression of the genes CXCL5,
CXCL8 and the CXCR2 receptor expressing an attraction to neutrophils.
In
exacerbations from COPD is also involved the CCL5 (RANTES) chemokine.
It is a risk factor COPD, asthma.
In
the regulating area of the CCL5 gene have been identified 3 SNPs
(single nucleotide polimorphism), which have been associated with an
increased level of the CCL5.
The
SNP of the SFTPB (surfactant protein B) termed Ro-302 479 has
indicated an association with the exacerbations in the COPD and with
a susceptibility for COPD.
The
microsatellite instability (MSI) is seen in 50% of the patients with
COPD and not noticed in healthy smokers.
Patients
with COPD and MSI have shown an increase in the exacerbations. The
factors which are related to exacerbations are the three markers: G
29802, D13S71 and D14S580.
The
MSI association with the COPD exacerbations indicates that the
somatic mutations are involved in the pathogenesis and natural
history of the disease
Figures
1 and 2 were obtained by the kind permission of Mr. Prof. Peter
Barnes (National Hearth and Lung Institute, Imperial College -
London, UK), to whom I would like to thank on this way.
- DEFINITIONS
CYTOKINES.
Signaling proteins, messengers which:
a)
initiate and amplify the inflammatory and immune responses by
recruiting and activating the cells.
b)
regulate the activation and differentiation of the T and B
lymphocytes whose functions are crucial in the immunity mediated by
the specific cell.
c)
initiate and regulate the local repair processes until solving the
immune responses.
CXC
and CC chemokines are cytokines of smaller dimensions.
CATHEPSIN
G is a proteinase which participates in the cell autolysis and self
digestion. is It is encoded by the CTSG gene.
CATHEPSIN
K is a protease which has the ability to catabolize the elastin,
collagen, gelatin. This leads to the loss of lung elasticity
(emphysema).
Transduction.
The transfer of information to the genes from one cell to another by
means of a vector.
Transcript.
Stage of expressing a gene within which the information contained in
the DNA sequence is copied in the form of an mRNA sequence.
TRANSLATION.
Translating the mRNA information into protein-constituent
information.
C
protein kinase.
Mediates the immune response, regulates the cell growth. At the
bronchial level it produces broncho-constriction by acting on the
smooth musculature. Neutrophil elastase.
It is a serine protease belonging to the family of chemotripsine.The
high expression entails the emphysema or emphysematous changes.
GALACTIN-1. It is a protein with affinity for galactoside. It has
polyvalent functions and a wide biological acivity. Is involved in
the immune response, in the survival of T cells. in inflammation and
allergy.
ACTVATOR
PROTEIN1 (AP-1). This is a transcription factor. The AP-1 activity is
induced by growth factors, cytokines, and oncoproteins. AP-1 induces
the transcription of a variety of genes involved in multiple cellular
functions (proliferation, differentiation, transformation,
surviving).
ALPHA
1 ANTITRYPSINE. Is a protein that defends the lung.
Its
deficiency is inherited and causes emphysema.
CTGF
(conective tissue growth factor). Acts on the endothelial and
epithelial cells. Increases the DNA synthesis induced by the
fibroblast growth factor. It is a major chemotactic and mitogenic
factor for the connective tissue cells.
CYCLIN-DEPENDENT
KINASE. It regulates the cell cycle, cell division, induces the
apoptosis of the neutrophils that mediate inflammation. The CDKN2A
gene is located in the 9p. 21 area. It is a tumor-suppressor gene.
Has an inhibitor: p16INK4A.
NF
kappa B acts as a transcription factor. It has key role in regulating
the immune response.
Leukotrienes.
Are lipid mediators responsible for the inflammatory effects. They
are produced from the arachidonic acid through the 5-lipo-oxygenase
enzyme.
Proteinase
3 is a serine protease which is expressed in neutrophils. It is not
known its role in neutrophils.
MAPK-ERK
PATHWAY. Is a way of signaling the transduction.
It
couples the intracellular responses to the growth factors on cell
surface receptors. The MAPK pathway transduces a variety of external
signals leading to broad cellular responses such as growth,
differentiation, inflammation and apoptosis. In mammals there are
three major ways : MAPK-ERK, SAPK-INK, and p38MAPK.
SD-282
is an inhibitor of the p38MAPK-inase. It reduces the inflammatory
response in those exposed to tobacco, while dexamethasone is
ineffective. It decreases the growth of COX-2 and reduces the IL-6
levels.
PI3K
(phosphatidil-inositol-3 kinase). It has a crucial role to the cell
growth and survival. It is a signaling pathway of the transduction
altered by ROS (reactive-oxidative species). It stimulates cancer
cell proliferation and survival.
P21-CIP-WAF-1
is a universal inhibitor of the cyclin-dependent kinase.
-
CYTOKINES and RECEPTORS
TNF-alpha
(TNFalpha R1 and R2). Strong proinflammatory mediator, inducing both
the direct and indirect inflammation. The TNF receptors induce the
production and release and of a number of inflammatory mediators,
which in turn increases the inflammation.
INTERLEUKIN-1
(IL-1 alpha and beta and IL-1R alpha receptor). A proinflammatory
cytokine that initiates and maintains the inflammation, activates
endothelial and epithelial cells. They are produced by macrophages,
monocytes and dendritic cells.
TGF-BETA1.
It is a cytokine with multiple functions, control of growth, cell
proliferation, cell differentiation and apoptosis. TNF-1beta may
inhibit the secretion and activity of some cytokines such as
TNFalpha, IFN-gamma and other leukines. Advances the proliferation of
mature T cells.
INTERLEUKIN-6
(IL6 Ralfa). It is a multifunctional cytokine related to
inflammation, vascular permeability and cell proliferation
INTER-LEUKIN-10
is known as an anti-inflammatory cytokine known as „human cytokine
sinthesis inhibitory factor”. It is produced by monocytes, T cells,
dendritic cells and epithelial cells. Inhibits the proinflammatory
cytokines such as IFN-gamma, IL-2 IL3, TNF-alpha GM -CSF.
INTERLEUKIN18
(IL18 R-alfa). It is a cytokine produced by macrophages. IL18 along
with IL12 contributes to the cell-mediated immunity. Following the
IL18-stimulation of NK cells and some T cells induce a release of
IFN-gamma (which is also a cytokine) which in turn activates
macrophages and other cells. IL18 is a severe proinflammatory
cytokine.
-
GAMA INTERFERON and INFGR1, INFGR2 receptors
It
is a cytokine. It was also called a factor of macrophages activating.
It is secreted by Th1, Tc, cells, dendritic cells, NK cells. It has
antiviral, immune-regulatory and antitumor characteristics. Acts and
increases the lysosomal activity in macrophages. It forwards the
adhesion and setting necessary for the leukocytes migration. The
IFNGR deficiency is related to the high susceptibility to infections.
IFNgama is a main cytokine of the Th1cell.
GM-CSF
(CSF2) şi G-CSF (CSF3). These are proteins secreted by macrophages,
Tcells, mast-cell, endothelial cells and fibroblasts. The genes are
located in the area 5q31 and resepctively 17q11. 2 -q12. They are
factors important in the proliferation and survival of neutrophils
and macrophages. They induce the increase in expression of
proinflammatory cytokines and amplifies the inflammatory response.
-
CXC CHEMOKINE
CXCL1
(GRO-ALFA=growth-related oncogene) şi receptorul CXCR2. The gene is
located on the chromosome 4. It presents neutrophil chemotaxis,
regulates the endothelial cell function (angiogenesis).
CXCL2
and the CXCR2 receptor present neutrophil chemotaxis and regulates
the endothelial cell function.
CXCL-5
(ENA78, epithelial-derived neutrophil-activating peptide). Stimulates
the neutrophil chemotaxis, has angiogenic properties. Intreacts with
the CXCR2cell surface receptor.
CXCL8
(IL8). Interacts with the CXCR1 and CXCR2 receptors. It is
chemoattractant for neutrophils, CD8 + T cell, regulates the
endothelial cell function
CXCL9
(CXCR3). It is a chemoattractant of the T cells which is induced by
INFgama. Is closely related in activity to CXCl10 and CXCL11. They
are located on the chromosome 4. Their chemotactic function is
performed with CXCR3.
CXCL10
(IP10) (CXCR3) The gene is located on the chromosome 4. It is a
chemoattractant of macrophages, monocytes, dendritic cells, NK cells.
Inhibits the colonies formation in bone marrow, inhibits angiogenesis
and has antitumor activity.
CXCL12
(pre B cell growth-stimulating factor). It is a chemoattractant of
the T lymphocytes T, monocytes, but not also neutrophils. The gene is
located on the chromosome 10.
CXCR3.
It is expressed in neutrophils, the activated T lymphocytes, and NK
cells, some epithelial cells and endothelial cells. It regulates the
leukocyte traffic. Interacts with
CXCL9,
CXCL10, CXCL11, attracts the Th1 cells, activates the MAPK pathway.
-
CC-CHEMOKINES
CCL2
belongs to the CC-chemokines family. It is also named monocyte
chemoattractive protein1 (MCP-1). It recruits monocytes, memory T
cells and dendritic cells at the place of injury or infection.
CCL5
(RANTES= regulated on activation normal T cell expressed and
secreted). Is a risk factor in the chronic inflammatory diseases. The
exacerbations in COBP are associated with CCL5 over-regulating. It is
a chemokine for Th1, monocytes and NK cells. It acts through CCR5,
CCR3. CCR1.
CCL11
(, EOTAXIN). A CCR3 receptor. Is a chemokine for Th1, for neutrophils
and eosinophils. The gene is located on the chromosome 17.
-
MATRIX METALLOPROTEINASES
MMP2
Matrix-metallopeptidase 2. Intervenes in breaking the extracellular
matrix (embryonic period, reproduction, development, but also
metastasis)
MATRIX
METALLOPEPTIDASE 8 (neutrophil collagenase). Interfers in breaking
the extracellular matrix. It has the function of type I, II and III
collagen degradation.
MATRIX
METALLOPEPTIDASE 9. Intervenes in breaking the extracellular matrix.
Interferes in the physiological processes (embryonic development,
reproduction, tissue remodeling, but also metastasis. Is the key
effector in remodeling the extracellular matrix.
MATRIX
METALLOPEPTIDASE 12 (MMP 12). It is secreted by the inflamatory
macrophages (human macrophage elastase). It plays a major role in the
occurrence of lung emphysema in smokers.
GRANZYME.
Is a series protein released by the cytoplasmic granules within the
CD8 + (Tc1) and NK cells. It activates along with perforin and other
cytotoxic mediators in order to induce the death of target cell by
apoptosis.
PERFORIN-1
Is a cytotoxic protein existing in the cytoplasmic granules of CD8
and NK cells.
BIBLIOGRAPHY
IN DEFINITIONS
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G. B. Toews.
Cytokines
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Toshinori Yoshida and Rubin M. Tudor
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