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BACKGROUND Idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD) share common risk factors. They could therefore be expressed in a single patient. However, the prevalence, clinical characteristics and prognosis of individuals with comorbid IPF and COPD are not known. METHOD From 2003 to 2007, the Korean Interstitial Lung Disease Study Group created a register for idiopathic interstitial pneumonia using 2002 ATS/ERS (American Thoracic Society/European Respiratory Society) criteria. Of the 1546 IPF patients assessed, 143 had decreased lung function consistent with COPD (IPF-COPD). COPD was diagnosed based on age (≥40 years) and pulmonary function (forced expiratory volume in 1 sec [FEV1]/forced vital capacity [FVC] ratio RESULTS The median age of the IPF-COPD group was 71.0 years (interquartile range 66.0-76.0); most patients were male (88.1%). FVC (%) was significantly higher in the IPF-COPD group; however, FEV1 (%) was significantly lower in the IPF-COPD group (P CONCLUSION The prevalence of IPF-COPD was estimated to be ∼9.2% among all IPF patients; prognosis of patients with IPF-COPD was not worse than those with IPF alone. .

SummaryBackground Asthma is characterized by chronic airway inflammation triggered by various allergens in the environment. Defects in the bronchial epithelial interface with the external environment are the hallmark of asthma. Apolipoprotein A-1 (ApoA1) or ApoA1 mimetics have demonstrated anti-inflammatory activity and preventive effects in mouse models. Objective We investigated airway levels of ApoA1 in asthmatics and the possible role of ApoA1 in protection of the bronchial epithelium and in resolution of inflammation in cellular and animal models of asthma. Methods ApoA1 levels were measured in bronchoalveolar lavage fluid (BALF) from asthmatics and healthy controls. With treatment of ApoA1, mouse model of house dust mite (HDM)-driven asthma and cultured primary bronchial epithelial cells obtained from asthmatics were examined. Tight junction (TJ) expression in the bronchial epithelial cells was assessed by using confocal microscopy and immunoblot. Results Asthmatics showed significantly lower ApoA1 levels in bronchoalveolar lavage fluid than did healthy controls. Local ApoA1 treatment significantly decreased lung IL-25, IL-33, and thymic stromal lymphopoietin levels in HDM-challenged mice and inhibited allergen-induced production of these cytokines in cultured primary bronchial epithelial cells. ApoA1 promoted recovery of disrupted TJ proteins zonula occludens-1 and occludin in cultured primary bronchial epithelium obtained from asthmatics. ApoA1-induced increases in the TJ proteins were dependent on increased production of lipoxin A4 (LX A4). Conclusions and Clinical Relevance ApoA1 enhances resolution of allergen-induced airway inflammation through promoting recovery of damaged TJs in the bronchial epithelium. ApoA1 could be a therapeutic strategy in chronic airway inflammatory diseases that are associated with a defective epithelial barrier, including asthma.

Summary Background Peroxisome proliferator-activated receptor gamma coactivator 1 beta (PPARGC1B) is a co-activator for intracellular receptors such as the estrogen receptor, PPAR, and glucocorticoid receptor, which are involved in asthma development. Objectives Genetic association of single-nucleotide polymorphisms (SNPs) in the PPARGC1B gene with the risk of asthma and airway hyperreactivity (AHR) was investigated, as well as the functional effects of these SNPs on PPARGC1B gene and protein expression. Methods Direct sequencing of DNA from 24 Korean was performed to identify PPARGC1B SNPs. Genotyping was done in 264 controls and 949 asthmatics using single-base extension methods. PPARGC1B mRNA levels were measured using real-time PCR methodology. Luciferase and electrophoretic mobility shift assays (EMSA) were performed to functionally analyse PPARGC1B SNPs on promoter. Results Eighteen SNPs and one insertion/deletion polymorphism were identified, and seven SNPs were genotyped. No significant difference existed in the distribution of SNPs and haplotypes between the asthmatics and controls. However, the allele frequency of −427C>T and +102525G>A;R265Q showed a significant association with log-transformed PC20 methacholine values in the asthmatics (P=0.005–0.0004). Real-time PCR demonstrated higher PPARGC1B mRNA levels in asthmatics having −427CC allele than in those having −427TT or CT alleles (P=0.048). The ratio of the mRNA expression for each PPARGC1B exon4-mRNA compared with the wild type was similar in peripheral blood mononuclear cells carrying the +102525G>A allele. Luciferase reporter assays revealed that −427C allele caused higher promoter activity than −427T allele. EMSA demonstrated that −427C allele exhibited stronger binding activity to a nuclear protein in 293T cells than did the −427T allele. Conclusions and Clinical Relevance Polymorphisms of −427C>T on the promoter and those of +102525G>A on exon 5 of the PPARGC1B gene may affect the development of AHR through the modulation of PPARGC1B gene products. The PPARGC1B genotypes may serve as genetic markers for AHR. Cite this as: S.-H. Lee, A.-S. Jang, S. Woo Park, J. -S. Park, Y. K. Kim, S.-T. Uh, Y. H. Kim, I. Y. Chung, B.-L. Park, H. D. Shin and C.-S. Park, Clinical & Experimental Allergy, 2011 (41) 1533–1544.

The etiology of aspirin-exacerbated respiratory disease (AERD) has been attributed to the combination of environmental and genetic risk factors. Although widely investigated in various diseases associated with immune dysfunction, the human zinc ribbon domain containing 1 (ZNRD1) gene is thought to play a role in the pathogenesis of AERD by altering the mechanisms involved in disease development.We selected 6 single-nucleotide polymorphisms (SNPs) for genotyping from the International HapMap database in order to analyze the association between polymorphisms in ZNRD1 and AERD in a Korean asthma cohort. Genotyping was carried out using the TaqMan assay, and differences in genotype frequency distributions were analyzed using logistic regression models.Nominal associations were found between ZNRD1 rs1150740 and risk ofAERD via codominant and dominant genetic inheritance (P=.03; odds ratio, 1.14 [1.14-10.16]). The same polymorphism was found to be significantly associated with a decrease in forced expiratory volume in the first second of expiration, an important diagnostic marker of AERD, even after multiple testing corrections (P=.006, P(corr)=.03 in codominant and dominant models).These preliminary findings suggest a possible relationship between ZNRD1 and aspirin-induced respiratory dysfunctions in a Korean population and provide essential information on the etiology of AERD.

Aspirin-exacerbated respiratory disease (AERD) is prevalent in about 10% of asthma patients and is characterized by a severe decline in forced expiratory volume in 1-s (FEV(1) ), an important phenotype for total lung capacity, upon ingestion of aspirin. The general transcription factor IIH subunit 4 (GTF2H4) is positioned at 6p21.33, a part of the major histocompatibility complex (MHC) class II region that contains a number of genes that play an important role in the immune system. In addition, genetic variants in another general transcription factor IIH gene have revealed significant association with lung disease. To investigate whether GTF2H4 genetic variants could be a causative factor for AERD development and FEV(1) decline by aspirin provocation, five common single-nucleotide polymorphisms (SNPs) were genotyped in 93 patients with AERD and 96 aspirin-tolerant asthma (ATA) controls. As a result, when adjusted for age, gender, smoking status and atopy as covariates, the rs1264307 variant and two haplotypes showed nominal signals in the association with AERD (P = 0.02-0.04), but the significances disappeared after corrections for multiple testing (corrected P0.05). In further multiple regression analysis, no genetic variants of GTF2H4 showed significant associations with FEV(1) decline by aspirin provocation in asthmatics (P0.05). Despite the need for replications in larger cohorts, our preliminary findings suggest that GTF2H4 variants may not be associated with susceptibility to AERD and obstructive symptoms in asthmatics.

Lymphocyte-oriented kinase deficiency encoded by the serine/threonine kinase 10 (STK10) gene correlates with the intracellular adhesion molecule 1 (ICAM-1)/lymphocyte function associated antigen 1 (LFA-1) complex in aspirin hypersensitivity. This study investigated the association between single nucleotide polymorphisms (SNPs) of STK10 and aspirin-intolerant asthma (AIA).A total of 54 SNPs were genotyped in 163 AIA patients and 429 aspirin-tolerant asthma (ATA) controls.Logistic regression revealed that a synonymous variant (rs2306961GA) had the most significant association with AIA (P = .008 under the codominant model; P = .004 under the dominant model), suggesting that tissue-specific codon usage between Lys_TTT and Lys_CTT could play a role in regulating expression of STK10 in airway epithelium. Haplotype analysis revealed that 4 haplotypes, including STK10_BL4-ht1, which is unique to rs2306961GA, were significantly associated with aspirin hypersensitivity in asthmatics (P.05).Although replications in independent cohorts and further functional evaluations are needed, our preliminary findings suggest that STK10 polymorphisms might be susceptible genetic markers of AIA and that gene expression could be mediated by tissue-specific codon usage.

Peroxisome proliferator-activated receptor gamma coactivator 1 beta (PPARGC1B) is a co-activator for intracellular receptors such as the estrogen receptor, PPAR, and glucocorticoid receptor, which are involved in asthma development.Genetic association of single-nucleotide polymorphisms (SNPs) in the PPARGC1B gene with the risk of asthma and airway hyperreactivity (AHR) was investigated, as well as the functional effects of these SNPs on PPARGC1B gene and protein expression.Direct sequencing of DNA from 24 Korean was performed to identify PPARGC1B SNPs. Genotyping was done in 264 controls and 949 asthmatics using single-base extension methods. PPARGC1B mRNA levels were measured using real-time PCR methodology. Luciferase and electrophoretic mobility shift assays (EMSA) were performed to functionally analyse PPARGC1B SNPs on promoter.Eighteen SNPs and one insertion/deletion polymorphism were identified, and seven SNPs were genotyped. No significant difference existed in the distribution of SNPs and haplotypes between the asthmatics and controls. However, the allele frequency of -427CT and +102525GA;R265Q showed a significant association with log-transformed PC(20) methacholine values in the asthmatics (P=0.005-0.0004). Real-time PCR demonstrated higher PPARGC1B mRNA levels in asthmatics having -427CC allele than in those having -427TT or CT alleles (P=0.048). The ratio of the mRNA expression for each PPARGC1B exon4-mRNA compared with the wild type was similar in peripheral blood mononuclear cells carrying the +102525GA allele. Luciferase reporter assays revealed that -427C allele caused higher promoter activity than -427T allele. EMSA demonstrated that -427C allele exhibited stronger binding activity to a nuclear protein in 293T cells than did the -427T allele.Polymorphisms of -427CT on the promoter and those of +102525GA on exon 5 of the PPARGC1B gene may affect the development of AHR through the modulation of PPARGC1B gene products. The PPARGC1B genotypes may serve as genetic markers for AHR.

The expression of inducible nitric oxide synthase (iNOS) by macrophages is stimulated by coexposure to IFN-gamma and a number of stimuli, including TNF-alpha. Recent work has shown that TNF-alpha activates members of the mitogen-activated protein kinase family that subsequently trans-activate transcription factors implicated in the regulation of iNOS expression. The objective of this study was to systematically evaluate the role of: 1) p42mapk/erk2, 2) p46 c-Jun NH2-terminal kinase/stress-activated protein kinase (p46 JNK/SAPK), and 3) p38mapk in the induction of iNOS expression during costimulation of mouse macrophages with IFN-gamma and TNF-alpha. All three kinases were activated during costimulation with IFN-gamma and TNF-alpha. However, specific antagonism of the p42mapk/erk2 and p38mapk with PD98059 and SKF86002, respectively, had no effect on the induction of iNOS expression. In contrast, blockade of all three kinases with N-acetylcysteine completely blocked the induction of iNOS expression. In addition, specific antagonism of the JNK/SAPK upstream kinases MEKK (mitogen-activated protein kinase/extracellular signal-regulated kinase kinase kinase) and MKK4 (mitogen-activated protein kinase kinase 4) with dominant inhibitory mutants blocked transcriptional activation of the iNOS promoter in response to costimulation with IFN-gamma and TNF-alpha. Collectively, these findings support the involvement of p46 JNK/SAPK and its upstream kinases in regulating the induction of iNOS following ligation of the TNF-alpha receptor CD120a (p55) in the presence of IFN-gamma.

Insulin-like growth factor-I (IGF-I) has been implicated in the pathogenesis of idiopathic pulmonary fibrosis (IPF) through its ability to stimulate fibroblast proliferation and collagen synthesis. However, although alveolar macrophages (AM) have been shown to express this growth factor, it is likely to also have other cellular sources. We sought to determine the distribution of cells expressing IGF-I in lung tissues obtained from 10 patients with IPF and 10 control subjects. We evaluated the levels of IGF-I and of a macrophage/monocyte-specific marker, CD68, by immunocytochemistry and quantified by morphometry. In control subjects, IGF-I was localized principally to AM. In contrast, in IPF patients IGF-I was localized to AM, interstitial macrophages, alveolar epithelial cells, and ciliated columnar epithelial cells. The normalized volume density (Vv) of IGF-I-positive (IGF-I+) interstitial macrophages (Vv of IGF-I+ interstitial macrophages/Vv of lung x 100) was increased in patients with IPF as compared with control subjects, and the ratio of Vv of IGF-I+ to CD68(+) interstitial macrophages correlated with: (1) the degree of clinical impairment in patients with IPF as measured by their clinical-radiologic-physiologic (CRP) score; and (2) the degree of collagen deposition in the interstitium. These findings support a role for interstitial macrophages as a source of IGF-I in IPF.