What can COPD genetics teach us about disease evolution?
Complex diseases such as COPD are not caused by single genetic variants; rather, they develop due to perturbations of biological networks consisting of genes and proteins. COPD genetics could provide critical information to build and refine these biological networks.
Are there any genetic analyses of COPD related phenotypes?
These genetic analyses in the COPDGene study were recently summarized by Ragland and colleagues (44) and are shown in Figure 3. In contrast to GWAS of COPD and lung function, the limited availability of these COPD-related phenotypes has led to smaller sample sizes and/or lack of available cohorts for replication.
Can GWAS be used to identify genetic determinants of COPD?
SEQUENCING-BASED APPROACHES TO IDENTIFY COPD GENETIC DETERMINANTS Although GWAS are highly effective at identifying common genetic determinants of complex diseases such as COPD, they are substantially less useful for the identification of rare genetic determinants.
Why study the biological pathways of asthma and allergy?
The continuing elucidation of the biological pathways underlying asthma and allergy will help identify new possible targets for intervention.
How does genetics affect asthma?
A person may have a genetic tendency toward asthma but never actually develop it. Genetics play less of a role in asthma development later in life, so adult-onset asthma and occupational asthma are less dependent on genes. A person can also develop asthma without any genetic predisposition for the condition.
How does treatment for COPD differ from treatment for asthma?
The essential difference is that the treatment of asthma is driven by the need to suppress the chronic inflammation, whereas in COPD, treatment is driven by the need to reduce symptoms. The treatment algorithm is based on severity for both asthma and COPD.
How does genetics contribute to COPD?
The only established genetic risk factor for COPD is homozygosity for the Z allele of the alpha1-antitrypsin gene. Heterozygotes for the Z allele may also be at increased risk. Other mutations affecting the structure of alpha1-antitrypsin or the regulation of gene expression have been identified as risk factors.
Is COPD genetically inherited?
Most of the time COPD isn't hereditary. It's usually caused by things you're exposed to, such as tobacco smoke or chemical fumes. Yet sometimes genes do play a role in the disease.
What is the best test to differentiate asthma from COPD?
Spirometry is the most commonly performed noninvasive test of lung function[50] and is considered the most practical and reliable tool for establishing the presence and severity of obstructive airway diseases, including asthma and COPD.
How does the pathophysiology of asthma differ from COPD?
Different pathophysiology Although asthma and COPD are both chronic inflammatory lung disorders, perhaps the most important difference between them is the nature of the inflammation that occurs. In asthma, inflammation is mainly caused by eosinophils, whereas in COPD neutrophils are involved.
Is asthma genetic?
It is a complex disease with both genetic and environmental risk factors. Asthma is caused by multiple interacting genes, some having a protective effect and others contributing to the disease pathogenesis, with each gene having its own tendency to be influenced by the environment.
Can asthma be hereditary?
Your inherited genetic makeup predisposes you to having asthma. In fact, it's thought that three-fifths of all asthma cases are hereditary. According to a CDC report, if a person has a parent with asthma, they are three to six times more likely to develop asthma than someone who does not have a parent with asthma.
Is COPD familial?
Intergenerational associations in chronic obstructive pulmonary disease (COPD) have been well recognized and may result from genetic, gene environment, or exposure to life course factors. Consequently, adult offspring of parents with COPD may be at a greater risk of developing COPD.
What is the genetic form of COPD called?
Because Alpha-1 is genetic, Alpha-1 lung disease is commonly called “genetic COPD.” People with Alpha-1 lung disease have two abnormal genes (one from each parent).
Is COPD acquired or congenital?
This form of COPD is caused by a genetic (inherited) condition that affects the body's ability to produce a protein (Alpha-1) that protects the lungs.
Can someone be born with COPD?
Some people are born with a rare condition called alpha1 antitrypsin deficiency (AAT deficiency). Having AAT deficiency causes a high risk of getting chronic obstructive pulmonary disease (COPD).
How many genes are associated with asthma?
Over a hundred different genes have been associated with asthma and the list is still growing. Asthma susceptibility genes fall mainly into three categories relating to 1) functioning of the immune system, 2) mucosal biology and function, and 3) lung function and disease expression (8, 9).
What are the keywords for asthma?
Keywords: association analysis, asthma, epigenetics, genetics, genetic epidemiology, gene discovery, linkage analysis, pharmacogenetics. It has long been known that asthma runs in families and that children of asthmatic parents are at increased risk of asthma. However, asthma is not caused by a single mutation in one gene, ...
How much is the risk of asthma in children?
The recurrence risk of asthma in children with one affected parent is around 25%, whereas the risk if both parents are affected is around 50%. Twin studies also support asthma being much more likely to occur in an individual if that individual has a genetically close relative with the disease.
Is asthma genetic or environmental?
While it is obvious that the individual risk of asthma is dependent on familial background, the phenotypic expression of asthma may be modified by other genetic and environmental factors. It is deemed that a small number of genes set the individual background risk that is acted upon by another set of modifying genes and also environmental factors. For example, individuals with early-onset asthma more frequently have a family history of asthma than do those with later-onset asthma, suggesting that genes influence the age at onset of the disease (4). In addition, the severity of asthma as judged by symptom frequency, level of lung function, degree of airway responsiveness and airway inflammation, aggregates within families, which suggests that if a person has a positive family history of severe asthma, that person is more likely to develop severe asthma (5).
Is asthma a monogenic disease?
However, asthma is not caused by a single mutation in one gene, and therefore the transmission of the disease through generations does not follow simple Mendelian inheritance typical of classic monogenic diseases, such as Huntington's disease (autosomal dominant) or sickle-cell disease (autosomal recessive).
Is asthma a heritable trait?
Looking at the population gives clues about asthma being a heritable trait . First, there are large geographic and racial differences in disease occurrence. For example, the prevalence of asthma in many Western populations is high, up to 20%, whereas populations from the developing world exhibit much smaller prevalence rates, some as low as 1% or even lower (2). This is only indicative of a genetic causation in asthma, as different populations also have very different environmental circumstances. Second, offspring of asthmatic parents are at increased risk of asthma (Table 1). The recurrence risk of asthma in children with one affected parent is around 25%, whereas the risk if both parents are affected is around 50%. Twin studies also support asthma being much more likely to occur in an individual if that individual has a genetically close relative with the disease. For instance, the recurrence risk of asthma in monozygotic twins is much higher than in dizygotic twins, highlighting the role of genetic risk factors in asthma (3). Nevertheless, the fact that the concordance for asthma in monozygotic twins is not 100% – but around 75% – points to environmental risk factors also playing an important role.
How many genome-wide associations are there for COPD?
International COPD Genetics Consortium and UK Biobank genome-wide association studies for COPD. Manhattan plot demonstrating 82 genome-wide significant associations to COPD. Novel associations (not previously reported for COPD or lung function) are labeled with the nearest gene, and replication in the SpiroMeta cohort for lung function phenotypes is indicated. Adapted with permission from Reference 27.
How to understand COPD heterogeneity?
Studying genetic determinants of COPD-related phenotypes is one approach to understand COPD heterogeneity. An alternative is to define COPD subtypes using machine learning, imaging patterns, or other clinical features, and then to assess genetic associations to those subtypes. Castaldi and colleagues (50) used K-means clustering to define four COPD subtypes based on FEV1 (% predicted), emphysema at −950 HU, emphysema distribution (upper lung field/lower lung field), and segmental airway wall area. A cluster with mild upper lung–predominant emphysema was associated with an SNP near HHIP, while a severe emphysema cluster was most strongly associated with the chromosome 15q25 locus.
What is the long-range interaction between the COPD GWAS region and HHIPpromoter?
Chromosome conformation capture assay demonstrated a 7-kb region of interaction upstream from the HHIPgene with the HHIPpromoter. This upstream interacting genomic region is located within a frequently replicated COPD GWAS locus. Abbreviation: GWAS, genome-wide association study. Adapted with permission from Reference 29.
What are the phenotypes of chest CT?
Chest CT phenotypes are especially promising assessments to understand COPD heterogeneity, as the presence, severity, distribution, and pattern of emphysema can be determined. Manichaikul and colleagues (45) analyzed quantitative CT emphysema in a multiethnic general population sample of 7,914 subjects, the MESA (Multi-Ethnic Study of Atherosclerosis) Lung Study. They found genome-wide significant associations near SNRPFand PPT2. With additional fine mapping, the most strongly associated SNP in the PPT2region was located within an intron of the AGERgene. AGERencodes the sRAGE protein biomarker, which has been strongly associated with emphysema (46). Cho and colleagues (47) performed GWAS of chest CT phenotypes in the COPDGene, ECLIPSE, GenKOLS, and NETT studies. Five genome-wide significant associations with quantitative emphysema (percentage of low attenuation areas below −950 HU) were identified, including two previously identified COPD GWAS loci (HHIPand CHRNA3). The AGERregion, previously associated with lung function, was also associated with quantitative emphysema, and it was subsequently associated with COPD in the ICGC analysis (26). A region near the SERPINA1gene was also associated with emphysema, and it appeared to be driven by the Z allele; thus, with a highly specific phenotype (CT emphysema), even rare variants of large effect can be identified in genetic association studies. In addition, a region near DLC1, which has not been associated with lung function levels, was implicated in emphysema. Finding genetic determinants of CT airway wall phenotypes has been more challenging than emphysema phenotypes, potentially because only relatively large airways can be visualized due to the limits of CT resolution.
How many genes are in the GWAS region?
As shown in Figure 5, there are currently approximately 119 genes that demonstrate a COPD-related phenotype in a murine transgenic or knock-out model, and there are currently approximately 84 COPD and/or emphysema loci. The eight genes that are located within a COPD/emphysema GWAS locus and also show a murine COPD phenotype [HHIP(66), FAM13A(67), IREB2(68), AGER(69), MMP1(70), MMP12(71), SFTPD(72), and FBLN5] are likely COPD susceptibility genes that could provide valuable clues to COPD pathogenesis. Some of these biological pathways, such as protease-antiprotease balance (MMP1and MMP12) and extracellular matrix (FBLN5), have been known for decades. Studies of COPD GWAS genes have revealed novel roles in COPD-related processes, such as FAM13Ain WNT/β-catenin signaling (67). However, other biological processes, such as mitochondrial iron (related to IREB2) and hedgehog signaling (related to HHIP, although HHIPmay also have other biological functions) (66), were not widely studied before the COPD GWAS era. Surfactant protein D [encoded by SFTPD(73)] and sRAGE (encoded by AGER) are promising blood biomarkers that have been associated with COPD (46).
What can we expect to learn from large-scale whole genome sequencing studies of COPD?
Importantly, association of rare variants with COPD and COPD-related phenotypes will be enabled. In addition, these whole genome sequencing data will provide insights into genetic determinants of omics data types collected on the same subjects, which will empower systems and network-based analyses.
How do twin studies help to determine heritability?
Twin studies can be utilized to estimate heritability, the fraction of phenotypic variation due to genetic factors, by comparing disease prevalence in monozygotic (identical) twins who share all of their genes, and dizygotic (fraternal) twins who share approximately half of their genes. Ingebrigtsen and colleagues (7) studied 22,422 Danish and 27,668 Swedish twin pairs; they estimated COPD heritability to be approximately 60%.
What is the condition called when you are born with a high risk of getting COPD?
COPD and Genetics. Some people are born with a rare condition named alpha1 antitrypsin defici ency (called “AAT deficiency” for short). Having AAT deficiency causes a high risk of getting chronic obstructive pulmonary disease (COPD). Most people with AAT deficiency will get COPD if they smoke. People with AAT can also develop COPD ...
How to reduce the risk of developing emphysema?
Living a healthy lifestyle can reduce the risk of developing emphysema or COPD. Limiting alcohol, maintaining a healthy weight, and regular exercise can all help. Getting flu and pneumonia vaccines can also lower the risk of complications. 3
What is AAT deficiency?
When people have AAT deficiency, their livers do not make enough of an important protein called alpha1 antitrypsin. This protein protects the body’s tissue from being damaged. In someone with AAT deficiency, there is not enough AAT to protect the lungs, and they can become damaged. AAT deficiency can also cause liver damage. 2,3
Are there any other genetic causes of COPD?
Some studies have shown that close relatives of people with COPD are more likely to develop COPD, even if no one was AAT deficient. This is a sign that other genes may be involved in COPD. 1
Why is AAT deficiency dangerous?
AAT deficiency causes this risk because the person’s body does not have enough AAT proteins to protect the lungs. Without this protection, irritants like cigarette smoke can damage the lungs very badly. People with AAT deficiency who smoke often get emphysema at a young age – sometimes as early as their thirties.
Why is it important to diagnose AAT deficiency?
Early diagnosis can help people with AAT deficiency avoid risk factors, like smoking. It is important for people with AAT deficiency to avoid smoking themselves and even secondhand smoke. It is also recommended to avoid inhaling irritants like dust, fumes, or other toxins. 2,3
What is the treatment for AAT deficiency?
Oxygen therapy. Some people with AAT deficiency might also be treated with something called “augmentation therapy.”. In this kind of treatment, AAT proteins are delivered directly into the patient’s bloodstream to help protect the lungs from more damage.
What are the similarities between asthma and COPD?
However, both processes can have a pathogenic and pathophysiological basis easily differentiable in most cases.14The clinical characteristics shared by both diseases are based on the inflammation and obstruction of the airway, the latter being poorly reversible and progressive in COPD and variable and reversible in asthma. Likewise, the location of the inflammatory response among these pathologies also has differences, being the predominant involvement of COPD in peripheral airways and lung parenchyma, in contrast with the lack of lung parenchyma damage and the panfocal involvement of the airway in asthma. Moreover, the key cells and mediators in both process also differ, being neutrophils, CD8 + T-lymphocytes and macrophages with interleukin (IL)-8 and tumor necrosis factor-alpha (TNF-α), among others, playing a predominant role in the case of COPD. In asthma, eosinophils, mast cells, CD4 + T-lymphocytes and a smaller number of macrophages are the representative cells14with multiple inflammatory mediators involved in asthma15such as histamine, leukotrienes, IL-4, IL-5 and IL-13. The presence of high bronchodilator responsiveness as a read out of bronchial hyperresponsiveness (BHR), is characteristic of asthma and is partially correlated with the severity of the disease and with markers of inflammation. In COPD, as we will discuss later, the presence of BHR is not considered a predominant finding. However, when analyzing the behavior of BHR in people older than 65 years, smokers and nonsmokers, an association with excessive loss of lung function, measured through the forced expiratory volume in one second (FEV1), was found.16The consequence of the inflammatory cascade in both pathologies causes a progressive and scarcely reversible loss of lung function in COPD that is characterized by a bronchiolitis that evolves to fibrosis, where it is possible to observe areas of epithelial metaplasia of the mucus-producing cells. The remodeling of the airway present in asthma, due to the deposition of subepithelial collagen and the hypertrophy of the bronchial smooth muscle, may be responsible for the progression of the loss of lung function in persistent asthma. Conversely, in some patients the inflammatory profile of asthma and COPD could be similar, such as (1) neutrophilic asthma: a pattern of neutrophilic inflammation similar to that of COPD is found in smoking asthmatic patients, with predominance of neutrophils in the sputum, increased IL-8, TNF-α and oxidative stress, who also have a poor response to both inhaled and systemic corticosteroids;17(2) COPD with reversibility to bronchodilators may have increased eosinophils in the induced sputum, increased levels of exhaled nitric oxide (NO)4and better response to treatment with corticosteroids,17all characteristic of asthma; and (3) COPD with eosinophilia may show an underlying Th2 signature, expressed by high blood eosinophil counts that has been associated to a higher reversibility, and better response to ICSs.18Also, exacerbations of asthma and COPD can have common triggers (viruses, bacteria, environmental pollution, fumes). In both diseases exacerbations are associated with an increase in airway inflammation, an increase in the number of cells and higher concentrations of proinflammatory cytokines. Exacerbations of asthma show an increase in neutrophils and eosinophils, whereas exacerbations of COPD may present eosinophilia in the sputum.17
What is ACO in asthma?
ACO is the coexistence of two bronchial inflammatory disorders in the same individual. Given the fact that COPD and asthma can present with a variety of clinicopathological features, it should come as no surprise that ACO lacks a universally applicable definition and a precise set of diagnostic criteria. In this context, the Spanish Respiratory Society’s algorithm represents a practical and easy-to-implement solution, because it allows to identify those patients with bronchial chronic obstruction who can benefit from treatment with ICSs, and, in a hypothetical near future, from biological drugs. One pragmatic way to account for the heterogeneity of ACO is to adopt a strategy of defining specific and measurable therapeutic objectives for every single patient and identifying the traits that can be treated to achieve those objectives. Nevertheless, more studies are needed in order to clarify several important issues with regard to ACO, such as the molecular pathways and underlying mechanisms, the identification of possible specific biomarkers for diagnosis and targeted treatment, the prognosis and, finally, the optimal therapeutic interventions for this entity.
Does tiotropium help with asthma?
It has been demonstrated that tiotropium reduces exacerbations by 21% and improves pulmonary function and symptoms when given as an add-on therapy in asthma patients who remain uncontrolled despite been treated with a combination of ICSs and long-acting β adrenoceptor agonists (LABAs)52and remarkably, an exploratory subgroup analysis of four large randomized trials suggests that the results are independent of a type 2 phenotype.53Since tiotropium seems to be well tolerated for asthma patients, it would be almost mandatory to recommend triple inhaled therapy for severe asthma patients with persistent bronchial obstruction.
Does IL-5 block e-COPD?
Theoretically, blocking the pathway activated by IL-5 may have a beneficial impact in e-COPD patients. To date, only data on benralizumab and mepolizumab are available. A phase IIa clinical trial showed that numerical, albeit nonsignificant, improvement in COPD exacerbations, quality of life and FEV1 were greater in benralizumab-treated patients with high baseline blood eosinophil concentrations compared with placebo.48In addition, mepolizumab at a dose of 100 mg was associated with a lower annual rate of exacerbations than placebo among patients with COPD and an eosinophilic phenotype.49Further research is needed to clarify whether anti-IL-5 drugs should be employed in specific COPD subpopulations characterized by ‘type 2-high’ inflammation.
Is asthma a chronic disease?
Asthma and chronic obstructive pulmonary disease (COPD) are two inflammatory diseases characterized by airflow obstruction that have different pathogenic mechanisms and different degrees of response to anti-inflammatory treatment. Given the fact that both are highly prevalent conditions, it is very likely that they overlap in some individuals. In the last decade there has been increasing interest in this entity that is now known as asthma–COPD overlap (ACO). However, this interest is not new, and was already addressed by Burrows and colleagues in 1987, describing a group of patients who had a clinical evolution and a prognosis that was between asthma and COPD,1at that time labelled as ‘asthmatiform bronchitis’, supporting the view of a common origin of asthma and COPD, the so-called Dutch hypothesis.2Recent studies of lung function trajectories in COPD also support the influence of early childhood asthma in lung development.3The reason for this renewed interest has to do, on the one hand, with the proposal of identification of phenotypes with different prognosis and response to therapy in COPD and, on the other, with the warning provoked by the indiscriminate use of inhaled corticosteroids (ICSs) in patients with COPD that led to an increased signal of pneumonia in some clinical trials.
Is asthma a disease of adulthood?
Smoking habits later in life might lead to the development of fixed airflow limitation and COPD in many of these patients. A second potential pathway recognizes patients with a lifetime smoking history, subsequent COPD and late-onset features of asthma (adult-onset eosinophilic as thma) or COPD with eosinophilic inflammation. Since both asthma and COPD are inflammatory diseases that affect the bronchial tree, the overlap of both diseases should show some evidence of a Th1 inflammatory pattern (characteristic of COPD) and some evidence of a Th2 (characteristic of asthma). However, there is a lack of evidence about the biology of ACO, with very few studies supporting this intuitive hypothesis.18,19
Is asthma a COPD?
Asthma and chronic obstructive pulmonary disease (COPD) are both highly prevalent conditions that can coexist in the same individual: the so-called ‘asthma -COPD overlap’ (ACO). Its prevalence and prognosis vary widely depending on how ACO is defined in each publication, the severity of bronchial obstruction of patients included and the treatment they are receiving. Although there is a lack of evidence about the biology of ACO, the overlap of both diseases should express a mixture of a Th1 inflammatory pattern (characteristic of COPD) and a Th2 signature (characteristic of asthma). In this review we support a novel algorithm for ACO diagnosis proposed by the Spanish Respiratory Society (SEPAR), based on a sequential evaluation that considers: (a) the presence of chronic airflow limitation in a smoker or ex-smoker patient ⩾35 years old; (b) a current diagnosis of asthma; and (c) the existence of a very positive bronchodilator test (PBT; ⩾15% and ⩾400 ml) or the presence of eosinophilia in blood (⩾300 eosinophils/μl). This algorithm can identify those patients who may benefit from a treatment with inhaled corticosteroids (ICSs) and maybe from biological drugs in a near future. In addition, it is easily applicable in clinical practice. The major disadvantage is that it groups patients with very different characteristics under the ACO’s umbrella. In view of this heterogeneity, we recommend a strategy of defining specific and measurable therapeutic objectives for every single patient and identifying the traits that can be treated to achieve those objectives.
Why is breathing harder and harder with COPD?
As COPD gets worse, breathing gets harder and harder. This may be partially due to the changes in the alveoli of the lungs as emphysema progresses . Consider the main components of COPD again: asthma, chronic bronchitis and emphysema. Of these three, emphysema is often the most serious.
Is asthma the same as COPD?
As you can see, asthma and COPD have similar symptoms. They both make it hard to breathe. Asthma and COPD also have similar treatments. Let's talk about that for a moment. Then we'll add a couple of treatments that are particular to COPD.
What are the causes of COPD?
Infections of the respiratory tract contribute to the pathogenesis and course of COPD in at least two different ways: (i) viral and bacterial infections are the most important cause of acute COPD exacerbations and (ii) bacterial colonization and chronic infection of the airways amplify and perpetuate chronic inflammation in stable COPD [96]. Bacteria such as H. Influenza, S. pneumoniaand Moraxella catarrhalisare detected in 25% of patients with stable COPD and more than 50% of patients during exacerbation [97] while a severe COPD exacerbation can be caused by. It is increasingly recognized that the human host is colonized by diverse, site-specific microbial communities that constitute the human microbiome [98–100]. New evidence indicates that the composition of airway microbiota differs in states of health and disease and with severity of disease [101], or the use of inhaled corticosteroids and inhaled bronchodilators [102], and that the microbiota, as a collective entity, may contribute to pathophysiologic processes associated with chronic airway disease [101–106]. Using microarray analysis, airway specimens have been analyzed from COPD patients who were being managed for severe respiratory exacerbations [104]. Therefore, a diverse bacterial community is documented to be present during pulmonary exacerbation in the setting of antibiotic administration [105]. Viral infections are detected in 10–15% of sputum sample in stable COPD patients and in 30–60% of patients with COPD exacerbation (62) with rhinoviruses and influenza viruses being most frequently associated with the exacerbations [106].
What is COPD in a lung?
Chronic obstructive pulmonary disease (COPD) is an inflammatory disease of the airways, mainly associated with cigarette smoke (CS) exposure. The disease is characterised by a progressive and irreversible decline in lung function caused by airflow obstruction, destruction of parenchyma, and emphysema [1, 2].
What is the innate immune system?
The innate immune system is the first line of defence against microbial infections. Several humoral factors and cells (neutrophils, macrophages, dendritic cells, natural killer cells, monocytes, and mast cells) that participate in innate immunity are recruited in order to control pathogen invasion. Recently, there has been growing evidence to implicate the NLRP3 inflammasome and its products in the inflammation observed in COPD patients [29, 30]. The NLRP3 inflammasome is a multimeric protein complex important in stimulating caspase-1 activation and subsequently the release of the mature form of the inflammatory cytokines IL-1βand IL-18 [29]. (Figure 1) The primary role of the inflammasome and its products, as part of the innate immune system, is that they can be triggered to assist in defence against invading pathogens. Invading pathogens drive an increase in reactive oxygen species (ROS) leading to the activation of the inflammasome, both directly and indirectly [31] to produce inflammasome-associated procytokines, after their recognition by a family of receptors through pathogen-associated molecular patterns (PAMPs) [32]. This recognition is achieved by several families of pattern recognition receptors (PRRs) expressed in alveolar macrophages, dendritic cells, and epithelial cells, which first contact microbial pathogens. The PRRs include Toll-like receptors (TLRs), nucleotide-binding domain leucine-rich repeat-containing receptors (NLRs), C-type lectin receptors (CLRs), and RIG-I-like receptors (RLRs) [33]. TLRs are known to recognize PAMPs on the cell surface, whereas NLRs sense microbial molecules in the cytosol of the host cell [34]. A number of groups have shown that the TLR4 is central to the inflammatory response in murine models of COPD [35–37]. Mice that have been genetically altered so that the TLR4 is not functional fail to develop the inflammation after cigarette smoke challenge that is observed in wild-type mice. Activation of the TLR4 alone, in vitro at least, is not thought to lead to marked activation of the inflammasome. In lung tissues collected from clinically indicated resections it was demonstrated that the percentage of CD8+ T cells expressing TLR1, TLR2, TLR4, TLR6, and TLR2/1 were significantly increased in COPD subjects relative to those without COPD. In contrast, from the same subjects, only TLR2/1 and TLR2 on lung CD4+ T cells and CD8+ NKT cells, respectively, showed a significant increase in COPD and there was no difference in TLR expression on lung CD56+ NK cells. Production of the Tc1 cytokines IFN-γand TNF-αby lung CD8+ T cells was significantly increased via costimulation by Pam3CSK4, a specific TLR2/1 ligand, but not by other agonists. Furthermore, this increase in cytokine production was specific to lung CD8+ T cells from patients with COPD as compared to lung CD8+ T cells from smokers without COPD. These data suggest that as lung function worsens in COPD, the autoaggressive behavior of lung CD8+ T cells could increase in response to microbial TLR ligands, specifically ligands against TLR2/1 [37].
What are the inflammatory mediators in COPD?
Several inflammatory cells and their mediators participate in the inflammatory response in COPD. Exposure to cigarette smoke, noxious particles, or gases can activate an inflammatory cascade in the airways resulting in the production of a number of potent cytokines and chemokines which play a critical role in the induction of chronic inflammation and subsequent tissue destruction [14]. Epithelial cells are activated to produce inflammatory mediators, including tumour necrosis factor (TNF-) a, interleukin (IL-) 1b, granulocyte-macrophage colony-stimulating factor (GM-CSF), and CXCL8 (IL-8) [14, 15]. Furthermore, epithelial cells in small airways may be an important source of transforming growth factor (TGF-) b, which then induces local fibrosis [14]. Comer et al. [16] showed that cigarette smoke extract (CSE) pretreatment of primary bronchial epithelial cells (PBECs) followed by P. aeruginosaLPS stimulation reduced IL-8 release from COPD PBECs but increased it from cells of smokers without airflow obstruction and nonsmokers. TLR-4 expression, MAPK, and NF-κB activation in COPD cultures were reduced after CSE treatment, but not in the smokers without airflow obstruction or nonsmoking groups, which was associated with increased apoptosis.
What are the effects of bacteria on the airway?
Bacterial exacerbations lead to increased airway and systemic inflammation as a result of direct effects of bacteria and of the host response [96]. Several PAMPs of bacteria are recognised by specific PRRs on epithelial cells and innate immune cells, triggering the NFκB pathway and other signal transduction pathways resulting in the production of proinflammatory cytokines and chemokines [107]. Sputum and bronchoalveolar lavage analyses have shown increased concentrations of neutrophils, CXCL8, TNF-α, and proteases, such as MMP-9 and neutrophil elastase in COPD patients with bacterial colonisation [96]. The colonization-induced triggering of PRR by microbial PAMPS amplifies the chronic neutrophilic airway inflammation in COPD. These adaptive immune responses contribute locally to the development of B-cell lymphoid follicles and mucosal IgA production, and systemically to the production of IgG antibodies in serum [108].
Why are macrophages increased in smokers?
The increased numbers of macrophages in smokers and COPD patients may be due to increased recruitment of monocytes from the circulation in response to monocyte selective chemokines . Macrophages also have the capacity to release the chemokines interferon-c inducible protein (IP-10), interferon-inducible T-cell chemoattractant (I-TAC), and monokine-induced by interferon-c (Mig), which are chemotactic for CD8z Tc1 cells via interaction with the CXCR3 receptor expressed on these cells [28]. The increased numbers of macrophages in COPD may be due to increased recruitment of monocytes but may also due to increased proliferation and prolonged survival in the lungs.
Where are CD4+ cells found in smokers?
Numbers of CD4+ cells are raised in the airways and lungs of smokers with COPD. Two types of CD4+ cells accumulate in the lungs of stable COPD patients, Th1 and Th17 cells [82–84]. Th1 cells secrete more interferon γ, while Th17 cells regulate tissue inflammation by producing IL-17A and IL-17F [85]. Th17 cytokines induce epithelial cells to produce antimicrobial peptides, chemokines, and granulocyte growth factors G-CSF and GM-CSF to promote neutrophil accumulation at the site of injury. Patients with COPD have increased numbers of IL-23 and IL-17 in bronchial epithelium.