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Contribution of alpha- and beta-defensins to lung function decline and infection in smokers: an association study.

ABSTRACT: Alpha-defensins, which are major constituents of neutrophil azurophilic granules, and beta-defensins, which are expressed in airway epithelial cells, could contribute to the pathogenesis of chronic obstructive pulmonary disease by amplifying cigarette smoke-induced and infection-induced inflammatory reactions leading to lung injury. In Japanese and Chinese populations, two different beta-defensin-1 polymorphisms have been associated with chronic obstructive pulmonary disease phenotypes. We conducted population-based association studies to test whether alpha-defensin and beta-defensin polymorphisms influenced smokers' susceptibility to lung function decline and susceptibility to lower respiratory infection in two groups of white participants in the Lung Health Study (275 = fast decline in lung function and 304 = no decline in lung function).Subjects were genotyped for the alpha-defensin-1/alpha-defensin-3 copy number polymorphism and four beta-defensin-1 polymorphisms (G-20A, C-44G, G-52A and Val38Ile).There were no associations between individual polymorphisms or imputed haplotypes and rate of decline in lung function or susceptibility to infection.These findings suggest that, in a white population, the defensin polymorphisms tested may not be of importance in determining who develops abnormally rapid lung function decline or is susceptible to developing lower respiratory infections.

SUBMITTER: Wallace AM

PROVIDER: S-EPMC1523340 | biostudies-literature | 2006 May

REPOSITORIES: biostudies-literature

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Contribution of alpha- and beta-defensins to lung function decline and infection in smokers: an association study.

Wallace Alison M AM He Jian-Qing JQ Burkett Kelly M KM Ruan Jian J Connett John E JE Anthonisen Nicholas R NR Paré Peter D PD Sandford Andrew J AJ

Respiratory research 20060515

<h4>Background</h4>Alpha-defensins, which are major constituents of neutrophil azurophilic granules, and beta-defensins, which are expressed in airway epithelial cells, could contribute to the pathogenesis of chronic obstructive pulmonary disease by amplifying cigarette smoke-induced and infection-induced inflammatory reactions leading to lung injury. In Japanese and Chinese populations, two different beta-defensin-1 polymorphisms have been associated with chronic obstructive pulmonary disease p ...[more]

PMID: 16700921

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Project description:Alpha-defensins are released from granules of leukocytes and are implicated in inflammatory and fibrotic lung diseases. In the present study, the effects of alpha-defensins on the proliferation and collagen synthesis of lung fibroblasts were examined. We found that alpha-defensin-1 and alpha-defensin-2 induced dose-dependent increases in the incorporation of 5-bromo-2'-deoxy-uridine into newly synthesized DNA in two lines of human lung fibroblasts (HFL-1 and LL-86), suggesting that alpha-defensin-1 and alpha-defensin-2 stimulate the proliferation of lung fibroblasts. alpha-defensin-1 and alpha-defensin-2 also increased collagen-I mRNA (COL1A1) levels and protein contents of collagen-I and active/dephosphorylated beta-catenin without changes in total beta-catenin protein content in lung fibroblasts (HFL-1 and LL-86). Inhibition of the beta-catenin signaling pathway using quercetin prevented increases in cell proliferation and the protein content of collagen-I and active/dephosphorylated beta-catenin in lung fibroblasts, and in COL1A1 mRNA levels and collagen release into culture medium induced by alpha-defensin-1 and alpha-defensin-2. Knocking-down beta-catenin using small interfering RNA technology also prevented alpha-defensin-induced increases in cell proliferation and the protein content of collagen-I and active/dephosphorylated beta-catenin in lung fibroblasts, and in COL1A1 mRNA levels. Moreover, increases in the phosphorylation of glycogen synthase kinase 3beta, accumulation/activation of beta-catenin, and collagen synthesis induced by alpha-defensin-1 and alpha-defensin-2 were prevented by p38 mitogen-activated protein kinase inhibitor SB203580 and phosphoinositide 3-kinase inhibitor LY294002. These results indicate that alpha-defensin-1 and alpha-defensin-2 stimulate proliferation and collagen synthesis of lung fibroblasts. The beta-catenin signaling pathway mediates alpha-defensin-induced increases in cell proliferation and collagen synthesis of lung fibroblasts. alpha-defensin-induced activation of beta-catenin in lung fibroblasts might be caused by phosphorylation/inactivation of glycogen synthase kinase 3beta as a result of the activation of the p38 mitogen-activated protein kinase and phosphoinositide 3-kinase/Akt pathways.

Project description:BackgroundFormer smokers now outnumber current smokers in many developed countries, and current smokers are smoking fewer cigarettes per day. Some data suggest that lung function decline normalises with smoking cessation; however, mechanistic studies suggest that lung function decline could continue. We hypothesised that former smokers and low-intensity current smokers have accelerated lung function decline compared with never-smokers, including among those without prevalent lung disease.MethodsWe used data on six US population-based cohorts included in the NHLBI Pooled Cohort Study. We restricted the sample to participants with valid spirometry at two or more exams. Two cohorts recruited younger adults (≥17 years), two recruited middle-aged and older adults (≥45 years), and two recruited only elderly adults (≥65 years) with examinations done between 1983 and 2014. FEV1 decline in sustained former smokers and current smokers was compared to that of never-smokers by use of mixed models adjusted for sociodemographic and anthropometric factors. Differential FEV1 decline was also evaluated according to duration of smoking cessation and cumulative (number of pack-years) and current (number of cigarettes per day) cigarette consumption.Findings25 352 participants (ages 17-93 years) completed 70 228 valid spirometry exams. Over a median follow-up of 7 years (IQR 3-20), FEV1 decline at the median age (57 years) was 31·01 mL per year (95% CI 30·66-31·37) in sustained never-smokers, 34·97 mL per year (34·36-35·57) in former smokers, and 39·92 mL per year (38·92-40·92) in current smokers. With adjustment, former smokers showed an accelerated FEV1 decline of 1·82 mL per year (95% CI 1·24-2·40) compared to never-smokers, which was approximately 20% of the effect estimate for current smokers (9·21 mL per year; 95% CI 8·35-10·08). Compared to never-smokers, accelerated FEV1 decline was observed in former smokers for decades after smoking cessation and in current smokers with low cumulative cigarette consumption (<10 pack-years). With respect to current cigarette consumption, the effect estimate for FEV1 decline in current smokers consuming less than five cigarettes per day (7·65 mL per year; 95% CI 6·21-9·09) was 68% of that in current smokers consuming 30 or more cigarettes per day (11·24 mL per year; 9·86-12·62), and around five times greater than in former smokers (1·57 mL per year; 1·00-2·14). Among participants without prevalent lung disease, associations were attenuated but were consistent with the main results.InterpretationFormer smokers and low-intensity current smokers have accelerated lung function decline compared with never-smokers. These results suggest that all levels of smoking exposure are likely to be associated with lasting and progressive lung damage.FundingNational Institutes of Health, National Heart Lung and Blood Institute, and US Environmental Protection Agency.

Project description:β-Defensins protect the respiratory tract against the myriad of microbial pathogens entering the airways with each breath. However, this potentially hostile environment is known to serve as a portal of entry for herpesviruses. The lack of suitable respiratory model systems has precluded understanding of how herpesvirus virions overcome the abundant mucosal β-defensins during host invasion. We demonstrate how a central alphaherpesvirus, equine herpesvirus type 1 (EHV1), actually exploits β-defensins to invade its host and initiate viral spread. The equine β-defensins (eBDs) eBD1, -2, and -3 were produced and secreted along the upper respiratory tract. Despite the marked antimicrobial action of eBD2 and -3 against many bacterial and viral pathogens, EHV1 virions were resistant to eBDs through the action of the viral glycoprotein M envelope protein. Pretreatment of EHV1 virions with eBD2 and -3 increased the subsequent infection of rabbit kidney (RK13) cells, which was dependent on viral N-linked glycans. eBD2 and -3 also caused the aggregation of EHV1 virions on the cell surface of RK13 cells. Pretreatment of primary equine respiratory epithelial cells (EREC) with eBD1, -2, and -3 resulted in increased EHV1 virion binding to and infection of these cells. EHV1-infected EREC, in turn, showed an increased production of eBD2 and -3 compared to that seen in mock- and influenza virus-infected EREC. In addition, these eBDs attracted leukocytes, which are essential for EHV1 dissemination and which serve as latent infection reservoirs. These novel mechanisms provide new insights into herpesvirus respiratory tract infection and pathogenesis.IMPORTANCE How herpesviruses circumvent mucosal defenses to promote infection of new hosts through the respiratory tract remains unknown due to a lack of host-specific model systems. We used the alphaherpesvirus equine herpesvirus type 1 (EHV1) and equine respiratory tissues to decipher this key event in general alphaherpesvirus pathogenesis. In contrast to several respiratory viruses and bacteria, EHV1 resisted potent antimicrobial equine β-defensins (eBDs) eBD2 and eBD3 by the action of glycoprotein M. Instead, eBD2 and -3 facilitated EHV1 particle aggregation and infection of rabbit kidney (RK13) cells. In addition, virion binding to and subsequent infection of respiratory epithelial cells were increased upon preincubation of these cells with eBD1, -2, and -3. Infected cells synthesized eBD2 and -3, promoting further host cell invasion by EHV1. Finally, eBD1, -2, and -3 recruited leukocytes, which are well-known EHV1 dissemination and latency vessels. The exploitation of host innate defenses by herpesviruses during the early phase of host colonization indicates that highly specialized strategies have developed during host-pathogen coevolution.

Dataset Information

Contribution of alpha- and beta-defensins to lung function decline and infection in smokers: an association study.

Publications

Contribution of alpha- and beta-defensins to lung function decline and infection in smokers: an association study.

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