Serum Calprotectin Is a Potential Marker in Patients with Asthma.

BACKGROUND: Calprotectin is the major cytosolic protein in neutrophil granulocytes. Although asthma is known to cause eosinophilic inflammation, some patients with asthma have non-eosinophilic inflammation, which is characterized by local neutrophilic inflammation. The aim of this study was to assess calprotectin expression levels in a mouse model of asthma, and to observe the relationship of serum calprotectin level and clinical variables in patients with asthma. METHODS: Mice were sensitized and challenged with 10 µg and 20 µg of Aspergillus fumigatus, respectively; mice treated with saline were used as a control. The levels of calprotectin were determined using enzyme-linked immunosorbent assay, immunoblotting, and immunohistochemical analysis. The serum levels of calprotectin were also assessed in patients with asthma. The relationship between calprotectin and clinicopathological characteristics was determined. RESULTS: Calprotectin, S100A8, and S100A9 expression was elevated in the mouse lungs, calprotectin levels were higher in the serum of patients with asthma (n = 33) compared with those of healthy individuals (n = 28). Calprotectin levels correlated with forced expiratory volume in one second/forced vital capacity (r = -0.215, P = 0.043), smoke amount (r = 0.413, P = 0.017), body mass index (r = -0.445, P = 0.000), and blood neutrophil percentage (r = 0.300, P = 0.004) in patients with asthma. CONCLUSION: Our data suggest that calprotectin could potentially be used as a biomarker for asthma.

Involvement of Alveolar Epithelial Cell Necroptosis in Idiopathic Pulmonary Fibrosis Pathogenesis.

Alveolar epithelial cell (AEC) injury leading to cell death is involved in the process of fibrosis development during idiopathic pulmonary fibrosis (IPF). Among regulated/programmed cell death, the excessive apoptosis of AECs has been widely implicated in IPF pathogenesis. Necroptosis is a type of regulated/programmed necrosis. A multiprotein complex composed of receptor-interacting protein kinase (RIPK)-1 and -3 plays a key regulatory role in initiating necroptosis. Although necroptosis participates in disease pathogeneses through the release of damage-associated molecular patterns, its association with IPF progression remains elusive. In this study, we attempted to illuminate the involvement of RIPK3-regulated necroptosis in IPF pathogenesis. IPF lung tissues were used to detect necroptosis, and the role of RIPK3 was determined using cell culturing models of AECs. Lung fibrosis models of bleomycin (BLM) treatment were also used. RIPK3 expression levels were increased in IPF lungs, and both apoptosis and necroptosis were detected mainly in AECs. Necrostatin-1 and RIPK3 knockout experiments in AECs revealed the participation of necroptosis in BLM and hydrogen peroxide-induced cell death. BLM treatment induced RIPK3 expression in AECs and increased high-mobility group box 1 and IL-1ß levels in mouse lungs. The efficient attenuation of BLM-induced lung inflammation and fibrosis was determined in RIPK3 knockout mice and by necrostatin-1 with a concomitant reduction in high-mobility group box 1 and IL-1ß. RIPK3-regulated necroptosis in AECs is involved in the mechanism of lung fibrosis development through the release of damage-associated molecular patterns as part of the pathogenic sequence of IPF.

Annexin A1 in plasma from patients with bronchial asthma: its association with lung function.

BACKGROUND: Annexin-A1 (ANXA1) is a glucocorticoid-induced protein with multiple actions in the regulation of inflammatory cell activation. The anti-inflammatory protein ANXA1 and its N-formyl peptide receptor 2 (FPR2) have protective effects on organ fibrosis. However, the exact role of ANXA1 in asthma remains to be determined. The aim of this study was to identify the role of ANXA1 in bronchial asthma. METHODS: In mice sensitized and challenged with ovalbumin (OVA-OVA mice) and mice sensitized with saline and challenged with air (control mice), we investigated the potential links between ANXA1 levels and bronchial asthma using ELISA, immunoblotting, and immunohistochemical staining. Moreover, we also determined ANXA1 levels in blood from 50 asthmatic patients (stable and exacerbated states). RESULTS: ANXA1 protein levels in lung tissue and bronchoalveolar lavage fluid were significantly higher in OVA-OVA mice compared with control mice. FPR2 protein levels in lung tissue were significantly higher in OVA-OVA mice compared with control mice. Plasma ANXA1 levels were increased in asthmatic patients compared with healthy controls. Plasma ANXA1 levels were significantly lower in exacerbated patients compared with stable patients with bronchial asthma (p < 0.05). The plasma ANXA1 levels in controlled asthmatic patients were correlated with forced expiratory volume in 1 s (FEV1) (r = - 0.191, p = 0.033) and FEV1/forced vital capacity (FVC) (r = -0.202, p = 0.024). CONCLUSION: These results suggest that ANXA1 may be a potential marker and therapeutic target for asthma.

A Mathematical Model for the Macrophage Response to Respiratory Viral Infection in Normal and Asthmatic Conditions.

Respiratory viral infections are common in the general population and one of the most important causes of asthma aggravation and exacerbation. Despite many studies, it is not well understood how viral infections cause more severe symptoms and exacerbations in asthmatics. We develop a mathematical model of two types of macrophages that play complementary roles in fighting viral infection: classically [Formula: see text]-[Formula: see text] and alternatively activated macrophages [Formula: see text]-[Formula: see text]. [Formula: see text]-[Formula: see text] destroy infected cells and tissues to remove viruses, while [Formula: see text]-[Formula: see text] repair damaged tissues. We show that a higher viral load or longer duration of infection provokes a stronger immune response from the macrophage system. By adjusting the parameters, we model the differences in response to respiratory viral infection in normal and asthmatic subjects and show how this skews the system toward a response that generates more severe symptoms in asthmatic patients.

Role of lung ornithine aminotransferase in idiopathic pulmonary fibrosis: regulation of mitochondrial ROS generation and TGF-ß1 activity.

Idiopathic pulmonary fibrosis (IPF) is characterized by aberrant lung remodeling and the excessive accumulation of extracellular matrix (ECM) proteins. In a previous study, we found that the levels of ornithine aminotransferase (OAT), a principal enzyme in the proline metabolism pathway, were increased in the lungs of patients with IPF. However, the precise role played by OAT in the pathogenesis of IPF is not yet clear. The mechanism by which OAT affects fibrogenesis was assessed in vitro using OAT-overexpressing and OAT-knockdown lung fibroblasts. The therapeutic effects of OAT inhibition were assessed in the lungs of bleomycin-treated mice. OAT expression was increased in fibrotic areas, principally in interstitial fibroblasts, of lungs affected by IPF. OAT levels in the bronchoalveolar lavage fluid of IPF patients were inversely correlated with lung function. The survival rate was significantly lower in the group with an OAT level >75.659 ng/mL than in the group with an OAT level ≤75.659 ng/mL (HR, 29.53; p = 0.0008). OAT overexpression and knockdown increased and decreased ECM component production by lung fibroblasts, respectively. OAT knockdown also inhibited transforming growth factor-ß1 (TGF)-ß1 activity and TGF-ß1 pathway signaling. OAT overexpression increased the generation of mitochondrial reactive oxygen species (ROS) by activating proline dehydrogenase. The OAT inhibitor L-canaline significantly attenuated bleomycin-induced lung injury and fibrosis. In conclusion, increased OAT levels in lungs affected by IPF contribute to the progression of fibrosis by promoting excessive mitochondrial ROS production, which in turn activates TGF-ß1 signaling. OAT may be a useful target for treating patients with fibrotic lung diseases, including IPF.

Overexpression of fatty acid synthase attenuates bleomycin induced lung fibrosis by restoring mitochondrial dysfunction in mice.

Proper lipid metabolism is crucial to maintain alveolar epithelial cell (AEC) function, and excessive AEC death plays a role in the pathogenesis of idiopathic pulmonary fibrosis (IPF). The mRNA expression of fatty acid synthase (FASN), a key enzyme in the production of palmitate and other fatty acids, is downregulated in the lungs of IPF patients. However, the precise role of FASN in IPF and its mechanism of action remain unclear. In this study, we showed that FASN expression is significantly reduced in the lungs of IPF patients and bleomycin (BLM)-treated mice. Overexpression of FASN significantly inhibited BLM-induced AEC death, which was significantly potentiated by FASN knockdown. Moreover, FASN overexpression reduced BLM-induced loss of mitochondrial membrane potential and the production of mitochondrial reactive oxygen species (ROS). Oleic acid, a fatty acid component increased by FASN overexpression, inhibited BLM-induced cell death in primary murine AECs and rescue BLM induced mouse lung injury/fibrosis. FASN transgenic mice exposed to BLM exhibited attenuated lung inflammation and collagen deposition compared to controls. Our findings suggest that defects in FASN production may be associated with the pathogenesis of IPF, especially mitochondrial dysfunction, and augmentation of FASN in the lung may have therapeutic potential in preventing lung fibrosis.

Association of the Tight Junction Protein Claudin-4 with Lung Function and Exacerbations in Chronic Obstructive Pulmonary Disease.

PURPOSE: Chronic obstructive pulmonary disease (COPD) imposes a major healthcare burden. A tight junction protein, claudin-4 (CLDN4), may play a protective role in acute lung injury, but its role in COPD is unclear. To investigate the relationship between CLDN4 and COPD, we evaluated the association of CLDN4 with the clinical parameters of COPD, including exacerbations. PATIENTS AND METHODS: We analyzed a cohort of 30 patients with COPD and 25 healthy controls and evaluated their clinical parameters, including lung function. The plasma CLDN4 level in stable and exacerbated COPD was measured. RESULTS: The COPD patients were all males and predominantly smokers; their initial lung function was poorer than the healthy controls. The mean CLDN4 plasma level was 0.0219 ± 0.0205 ng/mg in the control group, 0.0086 ± 0.0158 ng/mg in the stable COPD group (COPD-ST) and 0.0917 ± 0.0871 ng/mg in the exacerbated COPD (COPD-EXA) group. The plasma CLDN4 level was significantly lower in the COPD-ST than the control group, but was significantly elevated in the COPD-EXA group. The plasma CLDN4 level was inversely correlated with forced vital capacity and forced expiratory volume in 1 second in the COPD-EXA group (r=0.506, P=0.001 and r=0.527, P<0.001, respectively). CONCLUSION: The plasma CLDN4 level is closely correlated with COPD exacerbations and decreased lung function. This suggests that CLDN4 has potential as a severity marker for COPD.

The impact of smoking on clinical and therapeutic effects in asthmatics.

Smoking is associated with poor symptom control and impaired therapeutic responses in asthma. A total of 843 patients with asthma were recruited. The patients received treatment for 1 yr according to the severity of their asthma. We compared the forced expiratory volume in 1 sec (FEV1), the ratio of FEV1 to forced vital capaity (FVC), atopy, total IgE, emphysema on high-resolution computed tomography (HRCT), the number of near-fatal asthma attacks, and physiological fixed airway obstruction between the smoking and nonsmoking groups. The study population consisted of 159 (18.8%) current smokers, 157 (18.7%) ex-smokers, and 525 (62.5%) nonsmokers. Although the prevalence of atopy was not different between the smoking and nonsmoking groups, the total IgE was higher among the smokers than the nonsmokers. Compared with the nonsmoking group, the smokers had a lower FEV1 % predicted and forced expiratory flow between 25 and 75% of FVC. A greater prevalence of emphysema and a significantly higher number of asthmatic patients with fixed airway obstruction were detected in the smoking versus nonsmoking group. The 37.5% of asthmatic patients who were former or current smokers showed decreased pulmonary function and increased IgE, emphysema on HRCT, and fixed airway obstruction, indicating that smoking can modulate the clinical and therapeutic responses in asthma.

Genetic effect of CCR3 and IL5RA gene polymorphisms on eosinophilia in asthmatic patients.

BACKGROUND: Eosinophilic infiltration and peripheral blood eosinophilia in asthma require the cooperation of eosinophil-specific cytokines and chemokines and their receptors. OBJECTIVE: We investigated the association of polymorphisms in CCR3 and IL5RA with asthma susceptibility or peripheral blood eosinophilia and the effects of the polymorphisms on receptor expression. METHODS: Polymorphisms in CCR3 and IL5RA were identified and genotyped in 576 asthmatic patients and 180 healthy control subjects. CCR3 and IL-5 receptor alpha (IL-5R alpha) protein expression on eosinophils was measured by means of flow cytometry. RESULTS: Although polymorphisms in CCR3 were not associated with asthma susceptibility, the CCR3 haplotype ht2 showed a negative gene dose effect on the eosinophil count (P = .003-.009). IL5RA c.-5091G>A was weakly associated with eosinophil count. The effects of ht2 were greater when paired with IL5RA c.-5091A (P = .001-.002). CCR3 protein expression was higher on eosinophils of asthmatic patients without ht2 than in those with ht2. Asthmatic patients with the IL5RA c.-5091A allele showed higher IL-5R alpha expression than those who were homozygous for the G allele. CONCLUSION: The genetic association between CCR3 polymorphisms and the number of circulating eosinophils was revealed as a novel finding. These associations were more pronounced when the CCR3 polymorphisms were paired with polymorphisms in IL5RA. The protein expression levels of CCR3 and IL-5R alpha on peripheral blood eosinophils are associated with the polymorphisms on their own genes. CLINICAL IMPLICATIONS: The identification of single nucleotide polymorphisms and haplotypes of CCR3 and IL5RA might be useful in developing markers for intermediate phenotypes of eosinophil number and in designing strategies to control diseases related to hypereosinophilia.

Impact of the Endothelial Tight Junction Protein Claudin-5 on Clinical Profiles of Patients With COPD.

PURPOSE: The tight junction protein claudin-5 (CLDN5) is critical to the control of endothelial cellular polarity and pericellular permeability. The role of CLDN5 in chronic obstructive pulmonary disease (COPD) remains unclear. The aim of this study was to investigate the association between CLDN5 levels and clinical variables in patients with COPD. METHODS: In total, 30 patients with COPD and 30 healthy controls were enrolled in the study. The plasma CLDN5 level was checked in patients with stable or exacerbated COPD and in healthy controls. RESULTS: The mean plasma CLDN5 level of patients with COPD was 0.63 ± 0.05 ng/mL and that of healthy controls was 6.9 ± 0.78 ng/mL (P = 0.001). The mean plasma CLDN5 level was 0.71 ± 0.05 ng/mL in exacerbated COPD patients and 0.63 ± 0.04 ng/mL in patients with stable COPD (P < 0.05). The plasma CLDN5 level among COPD subjects was correlated with the smoking amount (r = -0.530, P = 0.001). The plasma CLDN5 level in stable COPD patients was correlated with forced expiratory volume in one second (FEV1, %pred.) (r = -0.481, P = 0.037). CONCLUSIONS: The plasma CLDN5 level was not correlated with age. CLDN5 may be involved in the pathogenesis of COPD. Further studies having a larger sample size will be needed to clarify CLDN5 in COPD.

Comparison of plasma eotaxin family level in aspirin-induced and aspirin-tolerant asthma patients.

STUDY OBJECTIVE: Eosinophilic infiltration of airway tissue is a central feature of aspirin-induced asthma (AIA). Eotaxins belong to the family of CC chemokines, which coordinate the recruitment of inflammatory cells bearing chemokine (C-C motif) receptor-3 to sites of allergic inflammation. In the present study, the levels of eotaxin-1, eotaxin-2, and eotaxin-3 following an oral aspirin provocation test (APT) were measured, and the relationship between the eotaxin level and clinical parameters in patients with asthma was evaluated. PATIENTS AND DESIGN: An APT was performed in patients with asthma. Twenty AIA patients and 23 aspirin-tolerant asthma (ATA) patients were identified. Plasma levels of eotaxin-1, eotaxin-2, and eotaxin-3 levels were measured by enzyme-linked immunosorbent assay in the 43 patients with asthma and in 39 control subjects. RESULTS: The proportion of blood eosinophils was significantly higher in asthmatic patients than in control subjects. Nasal polyps were more common in AIA patients than in ATA patients (p < 0.05). In addition, the eotaxin-1 level was higher in AIA and ATA patients than in control subjects (p < 0.01 for each). The eotaxin-2 level was higher in ATA patients than in either the AIA patients (p < 0.05) or control subjects (p < 0.01). Similarly, the eotaxin-3 level was higher in ATA patients than in control subjects. A trend toward higher plasma levels of eotaxin-1 and eotaxin-3 at baseline and at 4 h after APT administration in the ATA group was noted but was not significant. Eotaxin-2 was also higher in ATA patients than in AIA patients at baseline and at 4 h after the APT. CONCLUSION: This study shows that eotaxin-2 is differentially secreted in patients with asthma according to aspirin intolerance, and that secretion is not time-dependent in response to the APT in AIA and ATA patients. It therefore appears that eotaxin-2 may be up-regulated and may act differentially in patients with ATA.

Factors influencing the responsiveness to inhaled glucocorticoids of patients with moderate-to-severe asthma.

STUDY OBJECTIVES: Inhaled glucocorticoids (GCs) are the most effective control therapy for asthma. Although the clinical effects of inhaled GCs vary, there are few data on the differences in the responsiveness of individuals to inhaled GCs. The purpose of this study was to identify those factors that are associated with responsiveness to high-dose inhaled GCs in patients with moderate-to-severe asthma. DESIGN: This study was a prospective analysis. SETTING: Outpatient clinics of tertiary hospitals. PATIENTS: Eighty-six adult outpatients with moderate-to-severe asthma. METHODS: Eighty-six patients with asthma who had initial FEV1 values of < 80% predicted after they had received inhaled GCs (fluticasone propionate, 1,000 microg/d) for 4 weeks. The primary end points were FEV1, FEV1/FVC ratio, forced expiratory flow (midexpiratory phase), and the score at presentation in the asthma-related quality-of-life questionnaire (AQLQ). RESULTS: The inhalation of GCs for 4 weeks had significant improvements in the FEV1% predicted and in the AQLQ score compared with the baseline values. Asthmatic patients with responses of > 12% (n = 46, 53.4%) in the change in FEV1 (deltaFEV1 = [FEV1 at 4 weeks--baseline FEV1]/baseline FEV1 x 100) also had significantly higher proportions of blood eosinophils and lower FEV1 values (in liters) prior to treatment. The change in FEV1 values correlated with the number of sputum eosinophils prior to GC inhalation (r = 0.242; p < 0.05) and correlated inversely with the FEV1 percent predicted values prior to GC inhalation (r = -0.462; p < 0.001). CONCLUSION: The FEV1 percent predicted and the blood and sputum eosinophil levels prior to GC inhalation are associated with the responsiveness to inhaled GCs in patients with moderate-to-severe asthma.

Interleukin-13 and interleukin-5 in induced sputum of eosinophilic bronchitis: comparison with asthma.

STUDY OBJECTIVES: Experimental studies on asthma have indicated that interleukin (IL)-13 induces airway hyperreactivity (AHR). However, it remains unproven that IL-13 is responsible for AHR in asthmatic patients. Eosinophilic bronchitis (EB) shows normal airway responsiveness despite eosinophilic airway inflammation of severity similar to that of asthma. This study evaluated the role of IL-13 in asthma by comparing the sputum IL-5 and IL-13 levels in both groups. METHODS: Comparisons between asthma and EB would clarify the role of IL-13 in AHR. IL-5 and IL-13 were assayed in the sputum and culture supernatants of peripheral blood mononuclear cells (PBMCs) from 22 asthmatic patients, 12 EB patients, and 11 healthy control subjects. RESULTS: IL-13 levels were higher in the asthmatic patients than in the EB patients or healthy control subjects (p = 0.001). IL-5 levels were similar in the asthmatic patients and EB patients, who had significantly higher levels than those of healthy control subjects. Sputum IL-13, but not IL-5, is inversely correlated with the provocative concentration of a substance causing a 20% fall in FEV1 for methacholine in asthmatic patients (r = -0.502; p = 0.017). IL-13 production by PBMCs was significantly higher in asthmatic patients than in EB patients (p = 0.015), but the levels between EB patients and healthy control subjects was comparable. CONCLUSION: The results of the present study indicate that IL-13 is related to AHR in asthmatic patients.

Association analysis of monocyte chemotactic protein-3 (MCP3) polymorphisms with asthmatic phenotypes.

The monocyte chemotactic protein-3 (MCP3), on chromosome 17q11.2-q12, is a secreted chemokine, which attracts macrophages during inflammation and metastasis. In an effort to discover additional polymorphism(s) in genes whose variant(s) have been implicated in asthma, we scrutinized the genetic polymorphisms in MCP3 to evaluate it as a potential candidate gene for asthma host genetic study. By direct DNA sequencing in twenty-four individuals, we identified four sequence variants within the 3 kb full genome including 1,000bp promoter region of MCP3; one in promoter region (-420T>C), three in intron (+136C>G, +563C>T, +984G>A) respectively. The frequencies of those four SNPs were 0.020 (-420T>C), 0.038 (+136C>G), 0.080 (+563C>T), 0.035 (+984G>A), respectively, in Korean population (n = 598). Haplotypes, their frequencies and linkage disequilibrium coefficients (|D'|) between SNP pairs were estimated. The associations with the risk of asthma, skin-test reactivity and total serum IgE levels were analyzed. Using statistical analyses for association of MCP3 polymorphisms with asthma development and asthma-related phenotypes, no significant signals were detected. In conclusion, we identified four genetic polymorphisms in the important MCP3 gene, but no significant associations of MCP3 variants with asthma phenotypes were detected. MCP3 variation/haplotype information identified in this study will provide valuable information for future association studies of other allergic diseases.

Serum sickness reaction with skin involvement induced by bee venom injection therapy.

Bee venom injection therapy is an alternative treatment sometimes used for chronic inflammatory diseases, including rheumatoid arthritis and multiple sclerosis, to reduce pain. Several chemical components of bee venom have anti-inflammatory effects, and apitoxin, one of the mixed components, has been used for pain prevention therapy. However, there have been no large-scale investigations regarding the efficacy or side effects or apitoxin. In this study, a case of serum sickness reaction that developed after receiving bee venom injection therapy is reported.

Loeffler's Syndrome Induced by Ingestion of Urushiol Chicken.

Eosinophilic lung diseases are heterogeneous disorders characterized by varying degrees of pulmonary parenchyma or blood eosinophilia. Causes of eosinophilic lung diseases range from drug ingestion to parasitic or fungal infection as well as idiopathic. The exact pathogenesis of eosinophilic lung disease remains unknown. Urushiol chicken can frequently cause allergic reactions. Contact dermatitis (both local and systemic) represents the most-common side effect of urushiol chicken ingestion. However, there has been no previous report of lung involvement following urushiol chicken ingestion until now. A 66-year-old male was admitted to our hospital with exertional dyspnea. Serial chest X-ray revealed multiple migrating infiltrations in both lung fields, with eosinophilic infiltration revealed by lung biopsy. The patient had ingested urushiol chicken on two occasions within the 2 weeks immediately prior to disease onset. His symptoms and migrating lung lesions were resolved following administration of oral corticosteroids.

Changes in the expression of NO synthase isoforms after ozone: the effects of allergen exposure.

BACKGROUND: The functional role of nitric oxide (NO) and various nitric oxide synthase (NOS) isoforms in asthma remains unclear. OBJECTIVE: This study investigated the effects of ozone and ovalbumin (OVA) exposure on NOS isoforms. METHODS: The expression of inducible NOS (iNOS), neuronal NOS (nNOS), and endothelial NOS (eNOS) in lung tissue was measured. Enhanced pause (Penh) was measured as a marker of airway obstruction. Nitrate and nitrite in bronchoalveolar lavage (BAL) fluid were measured using a modified Griess reaction. RESULTS: The nitrate concentration in BAL fluid from the OVA-sensitized/ozone-exposed/OVA-challenged group was greater than that of the OVA-sensitized/saline-challenged group. Methacholine-induced Penh was increased in the OVA-sensitized/ozone-exposed/OVA-challenged group, with a shift in the dose-response curve to the left, compared with the OVA-sensitized/saline-challenged group. The levels of nNOS and eNOS were increased significantly in the OVA-sensitized/ozone-exposed/OVA-challenged group and the iNOS levels were reduced compared with the OVA-sensitized/saline-challenged group. CONCLUSION: In mice, ozone is associated with increases in lung eNOS and nNOS, and decreases in iNOS. None of these enzymes are further affected by allergens, suggesting that the NOS isoforms play different roles in airway inflammation after ozone exposure.

Gene - Gene Interactions Among MCP Genes Polymorphisms in Asthma.

PURPOSE: Monocyte chemoattractant proteins (MCPs) are important cytokines that involved in cellular activation and releasing of inflammatoy mediators by basophils and eosinophils in allergic disease. Some MCP gene variants implicate in asthma and monoclonal antibody for MCP-3 blocks allergic inflammations in the patients with asthma. Detection of interactions between gene and environment or between genes for complex disease such as asthma is important. We searched for an evidence of genetic effect of single nucleotide polymorphisms (SNPs) of MCP genes as well as gene - gene interactions involved in asthma. METHODS: Four hundreds asthmatics and four hundreds normal controls were enrolled. Asthma was defined as a positive bronchodilator response or positive methacholine provocation test with compatible clinical symptoms. Seven MCP gene SNPs (2 SNPs in MCP-1, 1 in MCP-2, and 4 in MCP-3) were included. Association analyses between SNP and asthma, and the tests for gene - gene interaction were performed. RESULTS: Strong linkage disequilibria were found among 7 MCP gene polymorphisms. There was no SNP that showed a significant association with asthma among 7 SNPs of 3 MCP genes. No haplotype was associated with asthma, either. The combination of MCP1-2518G>A, MCP2+46A>C, and MCP3+563C>T was the best predictive model for asthma as compared to the control in tests for gene - gene interaction. The MCP1-2518G>A and MCP2+46A>C was the second best predictive combination and this had the highest synergistic interaction effect on the subject's status than any other combination of polymorphisms. Complete linkages were not associated with the gene - gene interactions models. CONCLUSIONS: MCP gene polymorphisms probably interact with each other; thus, these findings may help in developing a possible genetic marker to predict asthma.

Gene-Gene Interaction Between CCR3 and Eotaxin Genes: The Relationship With Blood Eosinophilia in Asthma.

PURPOSE: Eosinophils function as an effector cell in the development of asthma and allergic disease. Eotaxins are cytokines that promote pulmonary eosinophilia via the receptor CCR3. Single-nucleotide polymorphisms (SNPs) in CCR3 and eotaxin genes are associated with asthma. In this study, genetic interactions among SNPs of several eotaxin genes and CCR3 were assessed and their relationship with blood eosinophilia in asthma was examined. METHODS: A total of 533 asthmatics were enrolled in this study. Asthmatics with eosinophilia (>0.5×10(9)/L) were compared with those without eosinophilia (≤0.5×10(9)/L). Chi-square tests were used to compare SNP frequencies. Two different models were used to evaluate gene-gene interactions: logistic regression and generalized multifactor dimensionality reduction (GMDR). RESULTS: EOT2+304C>A (29L>I) was significantly associated with 3 of the 4 CCR3 SNPs among asthmatics with eosinophilia (P=0.037-0.009). EOT2+304C>A (29L>I) and the CCR3 SNPs were also significantly associated with blood eosinophilia in an interaction model constructed by logistic regression (P=0.0087). GMDR analysis showed that the combination of EOT2+304C>A (29L>I) and CCR3-174C>T was the best model (accuracy=0.536, P=0.005, CVC 9/10). CONCLUSIONS: The epistatic influence of CCR3 on eotaxin gene variants indicates that these variants may be candidate markers for eosinophilia in asthma.

Acute eosinophilic pneumonia related to a mesalazine suppository.

It has been well known that mesalazine can cause the interstitial lung disease, such as Bronchiolitis obliterans with organizing pneumonia (BOOP), Non-Specific Interstitial Pneumonia (NSIP), or eosinophilic pneumonia. 5-Aminosalicylic acid (5-ASA), mesalazine, and sulfasalazine are important drugs for treating inflammatory bowel disease. Topical products of these limited systemic absorption and have less frequent side effects, therefore suppository form of these drugs have been used more than systemic drug. Most cases of measalzine-induced lung toxicity develop from systemic use of the drug. A 30-year-old woman had an interstitial lung disease after using mesalazine suppository because of ulcerative colitis. The lung biopsy demonstrated eosinophilic pneumonia combined with BOOP. She was recovered after stopping of mesalazine suppository and treatment with systemic steroid.