Reversible Airway Obstruction Research Articles

Airway smooth muscle in asthma: Phenotype plasticity and function

Clinical asthma is characterized by reversible airway obstruction which is commonly due to an exaggerated airway narrowing referred to as airway hyperresponsiveness (AHR). Although debate exists on the complex etiology of AHR, it is clear that airway smooth muscle (ASM) mediated airway narrowing is a major contributor to airway dysfunction. More importantly, it is now appreciated that smooth muscle is far from being a simple cell with only contractile ability properties. Rather, it is more versatile with the capacity to exhibit numerous cellular functions as it adapts to the microenvironment to which it is exposed. The emerging ability of individual smooth muscle cells to undergo changes in their phenotype (phenotype plasticity) and function (functional plasticity) in response to physiological and pathological cues is an important and active area of research. This article provides a brief review of the current knowledge and emerging concepts in the field of ASM phenotype and function both under healthy and asthmatic conditions.

The effects of interleukin-8 on airway smooth muscle contraction in cystic fibrosis.

BackgroundMany cystic fibrosis (CF) patients display airway hyperresponsiveness and have symptoms of asthma such as cough, wheezing and reversible airway obstruction. Chronic airway bacterial colonization, associated with neutrophilic inflammation and high levels of interleukin-8 (IL-8) is also a common occurrence in these patients. The aim of this work was to determine the responsiveness of airway smooth muscle to IL-8 in CF patients compared to non-CF individuals.MethodsExperiments were conducted on cultured ASM cells harvested from subjects with and without CF (control subjects). Cells from the 2nd to 5th passage were studied. Expression of the IL-8 receptors CXCR1 and CXCR2 was assessed by flow cytometry. The cell response to IL-8 was determined by measuring intracellular calcium concentration ([Ca2+]i), cell contraction, migration and proliferation.ResultsThe IL-8 receptors CXCR1 and CXCR2 were expressed in both non-CF and CF ASM cells to a comparable extent. IL-8 (100 nM) induced a peak Ca2+ release that was higher in control than in CF cells: 228 ± 7 versus 198 ± 10 nM (p < 0.05). IL-8 induced contraction was greater in CF cells compared to control. Furthermore, IL-8 exposure resulted in greater phosphorylation of myosin light chain (MLC20) in CF than in control cells. In addition, MLC20 expression was also increased in CF cells. Exposure to IL-8 induced migration and proliferation of both groups of ASM cells but was not different between CF and non-CF cells.ConclusionASM cells of CF patients are more contractile to IL-8 than non-CF ASM cells. This enhanced contractility may be due to an increase in the amount of contractile protein MLC20. Higher expression of MLC20 by CF cells could contribute to airway hyperresponsiveness to IL-8 in CF patients.

Adherence to Follow-up Recommendations in Asthma

van Gent R, de Meer G, Rovers MM, Kimpen JL, van der Ent CK, van Essen LE. Arch Dis Child. 2008;93(3):236–238 PURPOSE OF THE STUDY. To assess the willingness of parents of children with possible asthma to visit their general practitioner (GP). STUDY POPULATION. A cross-sectional group of 130 Dutch children aged 7 to 10 years with possible asthma were studied. METHODS. Participating parents completed the International Study of Asthma and Allergies in Childhood questionnaire. A child was considered to have “diagnosed asthma” if a doctor had diagnosed him or her with asthma in the preceding 12 months. A child was considered to have “possible asthma” if the child had (1) no physician-diagnosed asthma in the preceding 12 months, (2) asthma symptoms in the preceding 12 months, and (3) either reversible airway obstruction or bronchial hyperreactivity. Parents of children with possible asthma were sent a letter recommending further medical evaluation by their GP. The GP received a letter with the results of the questionnaire and lung-function tests. A research nurse contacted parents to conduct a telephone interview regarding adherence to recommendations. RESULTS. A total of 2745 children were invited to participate in the study, and 1758 children participated. Eighty-one (5%) children were diagnosed with asthma and 130 (8%) had a possible diagnosis of asthma, which represented the study population. A follow-up interview was completed for 114 children (88%). Sixty-two percent of the children visited a doctor, and 38% of the parents refused to visit the GP. The main reason for parents not visiting a GP was absence or mildness of symptoms. Most of the parents stated that they would visit a GP if symptoms worsened. CONCLUSIONS. Two thirds of the children with undiagnosed asthma visited their GP. Willingness to follow-up the recommendations was greater for children with more severe airway reversibility and if the mother was less well educated. REVIEWER COMMENTS. Asthma screening in children relies on parental recognition of asthma symptoms. The authors pointed out that parents often underrecognize symptoms of asthma in their child. However, when confronted with information of a possible asthma diagnosis, the majority of parents sought advice from their GP. Asthma screening programs can be a useful tool for helping children with undiagnosed asthma to seek professional care.

Management of Chronic Asthma in Adults

Asthma is a chronic inflammatory disease of the airways. It is characterized by recurrent episodes of dyspnoea, wheeze and cough caused by reversible airways obstruction. Three factors are responsible for the airways narrowing: bronchial muscle contraction, mucosal swelling/inflammation and increased mucous production ( Fig. 1 ). About 10–15% of the UK population have asthma and the number appears to be growing although there is some difficulty understanding why. It affects 1 in 20 adults and 1 in 10 children. Approximately 5.1 million people are currently being treated for asthma in the UK.

Diagnosis of Asthma

Asthma is a condition of paroxysmal, reversible airways obstruction. It is due to a chronic underlying inflammatory process and has characteristic features of reversible airway narrowing and airway hyper-responsiveness to a wide range of stimuli.

PULMONARY DYSFUNCTIONS AS MEASURED BY IMPULSE OSCILLOMETRY (IOS) AMONG PATIENTS WITH MORQUIO'S SYNDROME (MUCOPOLYSACCHARIDOSIS TYPE IVA)

PURPOSE: Morquio's Syndrome (MS) is an inherited metabolic disorder caused by a deficiency of a specific lysosomal enzyme. Patients develop respiratory failure secondary to reduced chest wall compliance, reversible and irreversible airway obstruction, chronic obstructive lung disease and obstructive sleep apnea. Formal respiratory function tests are difficult to perform and to interpret owing to the small size of these patients and to poor patient cooperation. The advent of infant pulmonary function testing (IOS) may identify MS children with significant pulmonary limitations. The aim of this study is to evaluate this hypothesis.

Asthma: where is it going?

Asthma is characterized by reversible airway obstruction, airway hyperresponsiveness, and airway inflammation. Although our understanding of its pathophysiological mechanisms continues to evolve, the relative contributions of airway hyperresponsiveness and inflammation are still debated. The first mechanism identified as important for asthma was bronchial hyperresponsiveness. In a second step, asthma was recognized also as an inflammatory disease, with chronic inflammation inducing structural changes or remodeling. However, persistence of airway dysfunction despite inflammatory control is observed in chronic severe asthma of both adults and children. More recently, a potential role for epithelial-mesenchymal communication or transition is emerging, with epithelial injury often resulting in a self-sustaining phenotype of wound repair modulation by activation/reactivation of the epithelial-mesenchymal trophic unit, suggesting that chronic asthma can be more than an inflammatory disease. It is noteworthy that the gene-environmental interactions critical for the development of a full asthma phenotype involve processes similar to those occurring in branching morphogenesis. In addition, a central role for airway smooth muscle in the pathogenesis of the disease has been explored, highlighting its secretory function as well as different intrinsic properties compared to normal subjects. These new concepts can potentially shed light on the mechanisms underlying some asthma phenotypes and improve our understanding of the disease in terms of the therapeutic strategies to be applied. How we understand asthma and its mechanisms along time will be the focus of this overview.

Hypertonic saline cough provocation test with salbutamol pre‐treatment: evidence for sensorineural dysfunction in asthma

Cough is one of the most common symptoms of asthma. However, studies using capsaicin, citric acid, or tartaric acid to document cough threshold have repeatedly failed to show statistically significant differences between asthmatic and healthy subjects. The studies using hypertonic aerosols as the cough stimulant have suggested an enhanced sensitivity in asthmatic subjects but the induced bronchoconstriction has made the interpretation of the results difficult. To determine the cough sensitivity to hypertonicity in healthy subjects, patients with chronic cough, and patients with asthma in a setting where the induction of bronchoconstriction is prevented. Nineteen healthy subjects, 21 non-asthmatic patients with chronic cough, and 26 asthmatic patients with chronic cough underwent an incremental hypertonic saline challenge including a pre-treatment with 0.4 mg of salbutamol. Spirometry was performed before the challenge, after salbutamol, and after the challenge. The patients with cough also underwent skin testing, histamine challenge, exhaled nitric oxide measurement, ambulatory peak flow monitoring, kept cough diary, and filled in the Leicester Cough Questionnaire. Eighteen patients repeated the saline challenge. The challenge did not induce bronchoconstriction in any group. The osmolality to provoke 15 cumulative coughs was significantly smaller in the asthmatic patients than in the healthy subjects (P<0.001) and in the cough patients without asthma (P=0.04). According to multivariate analysis among all the 47 patients with cough, female sex (P<0.001) and large spontaneous peak flow variation in the ambulatory recording (P=0.001) were associated with high sensitivity to saline. The saline challenge response was well repeatable (intraclass correlation coefficient 0.90). The findings of the present study are not affected by induced bronchoconstriction. Asthma or, more specifically, spontaneous, reversible airway obstruction is associated with an enhanced sensitivity to the cough-provoking effect of hypertonic saline. This suggests a pathological function of the sensorineural apparatus in this disorder.

The Treatment Targets of Asthma: From Laboratory to Clinic

Asthma is a chronic disease characterised by airways hyperresponsiveness, airways inflammation, airways remodelling and reversible airways obstruction. Airway structural cells, recruited inflammatory cells and many mediators such as cytokines, chemokines and adhesion molecules are involved in the pathogenesis of asthma. Although asthma is treatable in most, but not all patients by currently available drugs, no treatment is preventive or curative and the disease has reached epidemic proportions worldwide and its incidence is continuing to increase. Many thousands have chronic, severe asthma and suffer daily symptoms making it imperative that we continue to improve our understanding of the mechanisms of asthma particularly related to airway inflammation and remodelling, the hallmarks of asthma, and to identify new therapeutic targets. In this review we will discuss current drugs and potential targets in the treatment of asthma.

Management of life-threatening asthma in adults

Asthma is a disease of predominantly reversible airway obstruction characterized by a triad of bronchial smooth muscle contraction, airway inflammation, and increased secretions; it is a major health problem for all age groups. For the majority, control of asthma symptoms is readily achieved; however, in a small minority, asthma may cause death. Although the mortality rate for asthma in those aged less than 65 yrs is now falling, there remain around 1400 asthma deaths in the UK each year (http:// www.laia.ac.uk/kf_asthma_03.htm). Most of these occur in the pre-hospital setting and, in retrospect, the majority is considered potentially preventable. Factors associated with asthma death include disease severity, inadequate treatment, inadequate monitoring, the under use of written asthma management plans and adverse psychosocial and behavioural factors (www.sign.ac.uk/guidelines/fulltext/63/ index.html). Levels of severity of acute asthma exacerbations have been defined. The features of acute severe, life–threatening, and near fatal asthma are listed in Table 1. Of note, patients with life-threatening asthma may not appear distressed and might only display one of the features listed. Life-threatening asthma tends to occur as two sub-types. Most commonly, there is a history of progressive worsening of symptoms over several days; the majority of patients in this group report nocturnal dyspnoea in the previous three nights. As a result of greater bronchial inflammation and mucous secretion, this group (occurring more frequently in females) tends to respond more slowly to treatment. In contrast, a smaller sub-group, more frequently male, presents with a rapidly progressive condition with highly reactive airways. These patients have intense bronchospasm that often responds more rapidly to bronchodilator therapy. In February 2003, The British Thoracic Society together with the Scottish Intercollegiate Guidelines Network published guidelines on the management of asthma (http://www.britthoracic.org.uk/asthma-guideline-download.html). They were updated in November 2007. In common with other recommendations, these give guidance only up to the commencement of intensive care. Evidence for therapies in intensive care from randomized controlled trials remains sparse. Ongoing management of lifethreatening episodes (Fig. 1) is often difficult with rapid and dynamic changes in physiology. Complications of treatment are frequent.

Bronchodilator response in residual volume in irreversible airway obstruction.

Although airway obstruction, as defined by improvement of forced expiratory volume in one second (FEV1) and/or forced vital capacity (FVC), is irreversible in patients with COPD, they clearly seem to benefit from treatment with inhaled bronchodilators. To assess the response pattern of residual volume (RV) compared to FEV1 after bronchodilation in patients with reversible and irreversible airway obstruction. Changes in static lung volumes were compared with improvement in dynamic lung volumes in 396 consecutive patients undergoing reversibility testing with repeat bodyplethysmography. Reversibility was defined as improvement of FEV1 >200 ml and >12% after inhalation of fenoterol hydrobromide. Irreversibility was found in 297 out of 396 patients with airway obstruction. Except for total lung capacity (TLC), all parameters (residual volume [RV], vital capacity [VC], forced inspiratory vital capacity [IVC], forced vital capacity [FVC], forced expiratory volume in one second [FEV1] and the FEV1/VC ratio) showed statistically significant changes after bronchodilation in 396 patients. The multiple linear regression model adjusted for age, sex and BMI showed a non-linear relationship between DeltaFEV1 or DeltaVC compared to DeltaRV after bronchodilation. If the increase in DeltaFEV1 is lower than 0.1 L, DeltaRV remains constant. However, if the increase in DeltaFEV1 is more than 0.1 L, DeltaRV decreases too. The same is found at an increase in VC of 0.3 L. In summary, in patients with irreversible airway obstruction DeltaRV cannot be predicted by DeltaFEV1 or DeltaVC after bronchodilation. Therefore, spirometric assessment should be complemented by bodyplethysmography.

Multiple Roles of Phospholipase A2during Lung Infection and Inflammation

Inflammation of the lung marked by excessive recruitment of neutrophils from circulation to the airway is a common feature among several pathological lung disorders, particularly those involving infection (13, 17, 64, 69, 73, 76). Although neutrophils serve a protective role by targeting and eliminating bacterial invaders, excessive neutrophil recruitment and accumulation can cause overactivity of the nonspecific neutrophil destructive capabilities, resulting in severe host lung tissue damage (127). Inflammation associated with bacterial pneumonia results from direct infection of the upper airway by either gram-positive pathogens, such as Streptococcus pneumoniae, or gram-negative species, such as Pseudomonas aeruginosa (73). P. aeruginosa is also the major pathogen colonizing the airway and resulting in neutrophilic lung destruction occurring in the heritable disease cystic fibrosis (CF) (69). Acute respiratory distress syndrome (ARDS) is marked by an influx of inflammatory cells, largely consisting of neutrophils, resulting in increased permeability of the capillary/alveolar barrier and severely impairing oxygenation (76). Although ARDS is not necessarily associated with infection by a specific pathogen, it is often a consequence of sepsis and frequently associated with nosocomial infections (76). Asthma causes reversible airway obstruction involving an aberrantly regulated inflammatory response (64). Eosinophils are the effector immune cells during the asthmatic process and allergens more so than infectious organisms serve as the trigger for an asthmatic attack (64). Severe asthmatic attacks can be exacerbated by respiratory infections, and the pathological process in these severe attacks involves a significant neutrophil presence (13). Chronic obstructive pulmonary disease (COPD) results in airway obstruction that is not fully reversible and is generally brought on by environmental exposure to pollutants, such as cigarette smoke and asbestos (111). Inflammation and airway remodeling are key features in the progression of COPD (13). Since inflammation is a key common component characterizing the pathology of many clinically distinct lung diseases, understanding the mechanisms governing the inflammatory process in the lung may reveal versatile treatment options that could have a beneficial impact on multiple lung disorders. It has become increasingly appreciated over the past couple of decades that the enzyme phospholipase A2 (PLA2) is an important factor in lung diseases that involve inflammation (106). The defining enzymatic function of PLA2 is the cleavage of membrane phospholipids into smaller bioactive molecules that can then participate in a plethora of cellular processes (Fig. ​(Fig.1).1). Determining the particular role of PLA2 in the setting of lung inflammation has proven quite challenging, because this enzyme represents a family of over 20 distinct proteins with various structural and biochemical characteristics (106). For the purposes of this review, the PLA2 enzymes are segregated into six major classes based on biochemical properties: secretory PLA2s (sPLA2s), cytoplasmic PLA2s (cPLA2s), calcium-independent PLA2s (iPLA2s), lysosomal PLA2s, platelet-activating factor acetylhydrolases (PAF-AHs), and PLA2s of bacterial origin (Table ​(Table1).1). PLA2 isoforms representing each of these major groups have been reported to contribute to either the promotion or the resolution of inflammation occurring in the lung during various disease processes (106). A unifying principle for the role of PLA2s in lung disease remains elusive owing to the numbers of PLA2 isoforms that are expressed in the lung combined with the multiple and distinct functions attributable to each isoform. These circumstances represent a significant challenge for the design of anti-inflammatory therapeutics based on modulating the PLA2 enzymatic activity. The purposes of this review are to highlight findings of the roles various PLA2s take part in during lung infection and inflammation and to illustrate the importance of PLA2 in lung disease. FIG. 1. Small arrows depict cleavage sites for the enzymes PLA2, PLA1, and LPLA on the membrane phospholipid, PC. Large arrows depict a sequential reaction beginning with PC, which is converted to lysophosphocholine (LPC) and AA by PLA2. Lysophosphocholine is ... TABLE 1. Phospholipase A2s involved in lung diseasea

Prevention of airway inflammation with topical cream containing imiquimod and small interfering RNA for natriuretic peptide receptor

BackgroundAsthma is a complex disease, characterized by reversible airway obstruction, hyperresponsiveness and chronic inflammation. Principle pharmacologic treatments for asthma include bronchodilating beta2-agonists and anti-inflammatory glucocorticosteroids; but these agents do not target the main cause of the disease, the generation of pathogenic Th2 cells. We previously reported reduction in allergic inflammation in mice deficient in the ANP receptor NPRA. Here we determined whether siRNA for natriuretic peptide receptor A (siNPRA) protected against asthma when administered transdermally.MethodsImiquimod cream mixed with chitosan nanoparticles containing either siRNA green indicator (siGLO) or siNPRA was applied to the skin of mice. Delivery of siGLO was confirmed by fluorescence microscopy. The anti-inflammatory activity of transdermal siNPRA was tested in OVA-sensitized mice by measuring airway hyperresponsiveness, eosinophilia, lung histopathology and pro-inflammatory cytokines.ResultsSiGLO appearing in the lung proved the feasibility of transdermal delivery. In a mouse asthma model, BALB/c mice treated with imiquimod cream containing siNPRA chitosan nanoparticles showed significantly reduced airway hyperresponsiveness, eosinophilia, lung histopathology and pro-inflammatory cytokines IL-4 and IL-5 in lung homogenates compared to controls.ConclusionThese results demonstrate that topical cream containing imiquimod and siNPRA nanoparticles exerts an anti-inflammatory effect and may provide a new and simple therapy for asthma.

T Cells and NKT Cells in the Pathogenesis of Asthma

Asthma is an immunological disease with multiple inflammatory and clinical phenotypes, characterized by symptoms of wheezing, shortness of breath, and coughing due to airway hyperreactivity (AHR) and reversible airway obstruction. In allergic asthma, the most common form of asthma, airway inflammation is mediated by adaptive immune recognition of protein allergens by Th2 cells, resulting in airway eosinophilia. However, in other forms of asthma, inflammation is associated with immune responses to respiratory infections and airway neutrophilia. A central feature common to all forms of asthma is AHR, the heightened responsiveness of the airways to nonspecific stimuli. AHR has been shown recently in animal models of asthma to require the presence of CD1d-restricted, invariant T cell receptor-positive, natural killer T (iNKT) cells. Although allergen-specific Th2 cells and iNKT cells have many phenotypic similarities (e.g., expression of CD4 and production of Th2 cytokines), they have complementary activities, such as production of Th2 cytokines under different conditions, differential sensitivity to corticosteroids, and responsiveness to different classes of antigen (proteins versus glycolipids). We hypothesize that Th2 cells and iNKT cells interact synergistically to induce asthma but that different forms of asthma result from distinct roles of CD4(+) iNKT cells versus Th2 cells.

Abnormal spirometry in children with persistent allergic rhinitis due to mite sensitization: The benefit of nasal corticosteroids

Inflammatory processes affecting nasal and bronchial mucosa are similar in nature. The purpose of this study was to examine whether children with perennial allergic rhinitis, without underlying asthma, have impaired pulmonary function. We also investigated whether nasal corticosteroids and loratidine would improve the pulmonary function tests of those children with impaired lung function. Fifty subjects with moderate/severe persistent allergic rhinitis due to exclusively dust mite sensitization and no past medical history suggestive of asthma were assessed. The control group consisted of 26 matched healthy subjects. Subjects with airway obstruction, as detected by forced expiratory volume/1 s (FEV1) or forced expiratory flow from 25/% to 75% (FEF(25-75)) values <80% of those predicted, were treated with loratidine, once a day for 10 days, and daily nasal budesonide for 3 months. We found that 11 of 50 patients (22%) with perennial allergic rhinitis had impaired pulmonary function (FEF(25-75) values <80%), compared to 1/26 (3.8%) of the control group (p < or = 0.05). Reversibility was observed in 9/11 (81.8%), mean 24.7% +/- 10.3%. Within 3 months of treatment, 7/10 had FEF(25-75) > 80% of their predicted values as well as significant improvements in their FEV1 (p = 0.04), and FEV1/FVC (p = 0.04). We conclude that a substantial proportion of children with perennial allergic rhinitis have diminished FEF (25-75) values and reversible airway obstruction. Nasal corticosteroids improve the pulmonary function tests of these children with impaired lung function.

Relationship between exhaled nitric oxide and pulmonary function test in children with asthma

Purpose : Asthma is characterized by reversible airway obstruction and bronchial hyperresponsiveness result from airway inflammation. Fraction of nitric oxide in expired air (FeNO) has recently been investigated as a noninvasive measure of airway inflammation. FeNO has been reported to correlate with induced sputum eosinophilia and methacholine challenge test that it is represent severity of asthma. The purpose of this study was to analyze the relationship of FeNO with pulmonary function tests in patients with intermittent asthma. Methods : Eighty children included in this study were diagnosed as asthma from April through August, 2005 in Department of Pediatrics, College of Medicine, Kyunghee University. They aged from 4 to 15 years who were able to conduct spirometry and FeNO monitoring. They did not have upper respiratory tract infection and did not use an asthma controller which contain corticosteroids within 4 weeks. Pulmonary function test was done and FeNO was measured with online tidal breathing method using a chemiluminescence NO analyzer (CLD 88 sp, Eco Medics, Duernten, Switzerland). The correlations between pulmonary function test and FeNO were analyzed using Spearman correlation coefficient method. Results : The mean of FeNO of subject was 16.88 parts per billion (ppb). The mean of forced expiratory volume in 1 second (FEV1) was 0.890±0.455 L and forced vital capacity (FVC) was 1.071± 0.630 L. The mean of predicted FEV1% (FEV1%pred) was 98.39±34.27% and FEV1/FVC was 88.53± 19.49. FeNO was significantly correlate with FEV1 (r=0.345, P<0.01) and FVC (r=0.244, P<0.05). FeNO did not correlate with FEV1%pred or FEV1/FVC. Conclusion : The measurement of FeNO could be a useful marker in the management of childhood asthma and it is evolving to provide a complementary role alongside existing pulmonary function test. We propose that measuring technique and establishment of normal reference range are important area for future research. (Korean J Pediatr 2008;51:181-187)

IL-10, TGF-ß, IL-2, IL-12, and IFN-γ Cytokine Gene Polymorphisms in Asthma

Asthma is a complex respiratory disease, characterized by airway inflammation and reversible airway obstruction. Both genetic and environmental factors are important in the development and expression of the disease. In order to analyze the genetic profile of Th1 and Th2 cytokines in Iranian asthmatic patients, this study was performed. The allele and genotype frequencies of a number of polymorphic genes coding for IL-10, TGF-ß, IL-2, IL-12, and IFN-γ were investigated in 60 patients with asthma in comparison with 140 controls. The most frequent genotypes in our patients were IL-10 GA at position-1082 (p = 0.001), IL-10 CT at position −819 (p = 0.001), IL-10 CA at position −592 (p = 0.0001), IL-12 CA at position −1188 (p = 0.003), TGF-ß CG at codon 25 (p = 0.002), IL-2 GT at position -330 (p = 0.004). In contrast, the frequencies of the genotypes IL-10 AA at position −1082 (p = 0.0001) and GG at position −1082 (p = 0.01), IL-10 CC at position −819 (p = 0.001) and TT at position -819 (p = 0.01), TGF-ß TT at codon 10 (p = 0.001), TGF-ß GG at codon 25 (p = 0.005), IL-12 AA at position −1188 (p = 0.004), IL-2 TT at position −330 (p = 0.01) were significantly lower in the patient group. The most frequent haplotypes in the patients were IL-10 GCC (p = 0.008) and ATA (p = 0.0001) at position −1082, −819, −592, and TGF-ß CC (p = 0.036) at codon 10 and codon 25. In contrast, the frequencies of the IL-10 ACC (p = 0.001), TGF-ß TG (p = 0.024), and IL-2 TT (p = 0.001) and GT (p= 0.0001) in the patients were significantly lower than controls. Considering the high frequency of presence of IL-10 ATA haplotype and the IL-2 GT genotype, it seems that the production of IL-10 and IL-2 in the asthmatic patients could be lower than normal subjects.

Asthma Genetics: Personalizing Medicine

Asthma is a chronic inflammatory lung disease that leads to significant morbidity, mortality, and economic burden. The clinical symptoms, which are a result of airway inflammation and reversible airway obstruction, have led to the mainstay of therapies for asthma: anti-inflammatory medications and bronchodilators. However, the efficacies of the various classes of medications are not equal among all patients and may be affected by asthma phenotypes, environmental exposures, and genetic differences. Similarly, the risk for developing asthma and the natural history of the disease show great inter-individual variability due to these same factors. Over the past few decades, much effort has been focused on the genetics of asthma, and investigators have identified more than one hundred potential asthma susceptibility genes, of which at least ten have been replicated in numerous independent studies. In parallel, researchers have also identified genetic factors that impact the pharmacotherapeutic responses to the major classes of asthma medications. While the results of previous studies have been promising, future investigations need to combine genetics, pharmacogenetics, accurate disease phenotyping, and environmental exposures to build the foundation for personalized and predictive medicine for the 21st century. The ultimate goal is to enable physicians to identify those at risk for asthma, intervene to prevent or attenuate the disease, and select the optimal medical regimen for each individual patient. If successful, the resulting paradigm shift in medical practice will lead to improved clinical outcomes and decreased health care expenditures.

Lentiviral-mediated GATA-3 RNAi Decreases Allergic Airway Inflammation and Hyperresponsiveness

GATA-3 is the key transcriptional factor for Th2 commitment in T cells and is strongly associated with asthma and allergic disease. We studied the silencing of the GATA-3 gene expression using RNA interference (RNAi) delivered by a lentiviral vector, to evaluate the therapeutic role of GATA-3 short hairpin RNAs (shRNAs) in a murine model of asthma. Mice were sensitized with OVA and instilled intratracheally (IT) with GATA-3 shRNAs lentiviral vector (Lenti-si-GATA-3) once, 48 hours before challenge. After three challenges with the OVA antigen, the mice were assessed for airway hyperresponsiveness (AHR) and inflammation. With infection of Lenti-si-GATA-3 in EL-4 cells, GATA-3 gene expression was abrogated and downstream Th2 cytokines, such as interleukin-4 (IL-4) and IL-5, were also significantly inhibited. IT delivery of Lenti-si-GATA-3 in OVA-immunized mice resulted in a strong inhibition of local GATA-3 gene expression. Treatment with Lenti-si-GATA-3 successfully alleviated OVA-induced airway eosinophilia and Th2 cytokine release. While evaluating AHR by means of enhanced pause (Penh) and pulmonary resistance (R(L)) using body plethysmography, it was found that the administration of Lenti-si-GATA-3 had significantly decreased AHR in OVA-immunized mice. These results suggest that inhibition of GATA-3 gene expression by shRNAs lentiviral vectors strongly attenuates antigen-induced airway inflammation and hyper-responsiveness in mice.

A carbohydrate fraction, AIP1 from Artemisia iwayomogi suppresses pulmonary eosinophilia and Th2-type cytokine production in an ovalbumin-induced allergic asthma. Down-regulation of TNF-α expression in the lung

Asthma is a chronic inflammatory disease of the airways characterized by reversible airway obstruction, airway hyperreactivity, and remodeling of the airways. The incidence of asthma is on the rise despite ongoing intensive asthma research. Artemisia iwayomogi, a member of the Compositae, is a perennial herb easily found around Korea and has been used as a traditional anti-inflammatory medicine in liver diseases. We investigated suppressive effects of AIP1, a water-soluble carbohydrate fraction from A. iwayomogi on ovalbumin-induced allergic asthma in BALB/c mice and studied the possible mechanisms of its anti-allergic action. AIP1 significantly reduced pulmonary eosinophilia and Th2 cytokine expression in the lungs as well as serum IgE levels. Flow cytometric analysis of lung-infiltrating cells showed that the surface levels of CD11c and MHC II in CD11c+MHC II+ cells, potent dendritic cells, decreased in animals treated with AIP1. Expression of TNF-α, one of several proinflammatory cytokines released into the airway during episodes of asthma, was down-regulated by AIP1 injection, suggesting that reduced expression of TNF-α could account for the suppression of pulmonary eosinophilia and Th2-type cytokine production by AIP1.