Reduced endogenous secretory RAGE in blood and bronchoalveolar lavage fluid is associated with poor prognosis in idiopathic pulmonary fibrosis.

BACKGROUND: The endogenous secretory receptor for advanced glycation end products (esRAGE) is a soluble isoform produced by alternative splicing of the RAGE gene. The isoform has anti-inflammatory properties due to its inhibition of the RAGE/ligand interaction and is reduced in the lung tissue of patients with idiopathic pulmonary fibrosis (IPF). This study aimed to investigate the association of esRAGE serum and bronchoalveolar lavage fluid (BALF) levels with progression of IPF. METHODS: This study included 79 IPF patients and 90 healthy controls. IPF and control serum esRAGE levels were compared, and the correlation between serum and BALF esRAGE levels was analyzed in 57 IPF patient samples. We also investigated the relationship of esRAGE serum and BALF levels with prognoses and lung function parameters in patients with IPF. RESULTS: Serum esRAGE levels in IPF patients were significantly lower than those in healthy controls (162.0 ± 102.4 ng/ml and 200.7 ± 107.3 ng/ml, p = 0.009), although the baseline characteristics of age and smoking history were not matched. Serum levels of esRAGE were correlated with BALF esRAGE levels (rs = 0.317). The BALF esRAGE levels were also correlated with diffusion capacity for carbon monoxide (rs = 0.406). A Kaplan-Meier curve analysis and univariate/multivariate Cox hazard proportion analysis revealed that lower levels of esRAGE in blood and BALF were significantly associated with poorer prognoses in patients with IPF. CONCLUSIONS: Decreased esRAGE levels in BALF and blood were associated with poor prognoses in patients with IPF. These results suggest that esRAGE could be related to the pathophysiology of IPF and serum esRAGE could be a potential prognostic marker of IPF.

AGER gene polymorphisms and soluble receptor for advanced glycation end product in patients with idiopathic pulmonary fibrosis.

BACKGROUND AND OBJECTIVE: The receptor for advanced glycation end product (RAGE) is a multiligand cell-surface receptor abundantly expressed in the lung. RAGE/ligand interaction has been postulated to participate in the pathogenesis of inflammatory diseases, while soluble RAGE (sRAGE) might act as a decoy receptor. A functional polymorphism rs2070600 in the gene coding RAGE (AGER) might modulate its receptor function. The aim of this study was to investigate the association of AGER polymorphisms and circulatory sRAGE with the development and progression of idiopathic pulmonary fibrosis (IPF). METHODS: This study comprised 87 Japanese patients with IPF and 303 healthy controls. Seven tag polymorphisms in AGER were genotyped and their distributions were compared. We also measured serum sRAGE levels, and evaluated the correlations of sRAGE levels with AGER polymorphisms and the prognosis of the patients with IPF. RESULTS: The frequency of AGER rs2070600 genotype with minor allele was significantly higher in patients with IPF (OR = 1.84, 95% CI = 1.08-3.10). Additionally, the carriage of the rs2070600 minor allele and the presence of IPF were independently associated with reduced serum levels of sRAGE. Moreover, reduced sRAGE (≤471.8 pg/mL) was related to acute exacerbation of IPF and was an independent predictor of 5-year survival in patients with the disease (hazard ratio (HR) = 7.956, 95% CI = 1.575-53.34). CONCLUSION: These results suggest a possible association between a functional polymorphism in AGER and IPF disease susceptibility, and indicate a potential prognostic value of circulatory sRAGE.

Lung tissue proteomics identifies elevated transglutaminase 2 levels in stable chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease characterized by irreversible airflow limitation. Cigarette smoking represents the main risk factor, but the specific mechanisms of COPD are not completely understood. Our aim was to identify COPD-specific proteomic changes involved in disease onset and severity. A comparative proteomic analysis of 51 lung tissues from nonsmokers, smokers, smokers with mild to moderate (stage I-II) COPD, severe to very severe COPD (stage III-IV), and patients with α-1-antitrypsin deficiency (AATD) and idiopathic pulmonary fibrosis (IPF) was performed by cysteine-specific two-dimensional difference gel electrophoresis (2D-DIGE) coupled with mass spectrometry. Selected COPD-specific changes were validated by immunoblotting and further by ELISA in 120 induced sputum and plasma samples from nonsmokers, smokers, and patients with COPD (stage I-III). Altogether 82 altered proteins were identified comprising COPD-, AATD-, and IPF-specific, overlapping, and unspecific changes. Cathepsin D (CTSD), dihydropyrimidinase-related protein 2 (DPYSL2), transglutaminase 2 (TGM2), and tripeptidyl-peptidase 1 (TPP1) were validated as COPD-specific. TGM2 was not associated with smoking and correlated with COPD severity in lung tissue. TGM2 levels in sputum and plasma were elevated in patients with COPD (stage II-III) and correlated with lung function. In conclusion, new proteins related to COPD onset and severity could be identified with TGM2 being a novel potential diagnostic and therapeutic target for COPD. Further studies in carefully characterized cohorts are required to validate the identified changes.

Differences in plasma and sputum biomarkers between COPD and COPD-asthma overlap.

The pathophysiological features of chronic obstructive pulmonary disease (COPD)-asthma overlap are poorly understood and there has been no study of plasma or sputum biomarkers in overlap patients. In order to clarify the similarity and differences between overlap and COPD or asthma, we have investigated four potential biomarkers of COPD: surfactant protein A (SP-A), soluble receptor for advanced glycation end-products (sRAGE), myeloperoxidase (MPO) and neutrophil gelatinase-associated lipocalin (NGAL). SP-A and sRAGE are pneumocyte-derived markers. MPO and NGAL are neutrophil-derived molecules, but NGAL can also be expressed by respiratory epithelial cells. Plasma levels of SP-A and sRAGE and induced sputum levels of MPO and NGAL were measured by enzyme immunoassay/ELISA in 134 subjects: nonsmokers (n=26), smokers (n=23), asthma (n=32), COPD (n=39) and COPD-asthma overlap patients (n=14). In patients with COPD-asthma overlap, sputum MPO and plasma SP-A were significantly elevated whereas plasma sRAGE levels were reduced compared with asthma patients. Only sputum NGAL was significantly elevated in COPD-asthma overlap compared with COPD (p=0.00016) and could be used to differentiate patients with overlap from those with COPD. Increased induced sputum levels of NGAL might be a characteristic feature of overlap, suggesting enhanced neutrophilic airway inflammation and/or airway epithelial injury in COPD-asthma overlap.

Soluble receptor for advanced glycation end-products and progression of airway disease.

BACKGROUND: The receptor for advanced glycation end-products (RAGE) is highly expressed in the lung, where it is believed to have a homeostatic role. Reduced plasma levels of soluble RAGE (sRAGE) have been reported in patients with chronic obstructive pulmonary disease (COPD). The aim of the present study was to evaluate the association of plasma sRAGE levels with a longitudinal decline of lung function. We have also measured plasma levels of high mobility group box 1 (HMGB1), a RAGE ligand which has been associated with chronic inflammatory diseases including COPD. METHODS: Baseline plasma concentrations of sRAGE and HMGB1 were measured in non-smokers (n = 32), smokers without COPD (n = 212), and smokers with COPD (n = 51), and the associations of the plasma sRAGE and HMGB1 levels with longitudinal declines of lung function during a 4-year follow-up period were analysed. RESULTS: The plasma levels of sRAGE were significantly lower in smokers without COPD and in smokers with COPD, as compared to those of non-smokers. Plasma sRAGE levels positively correlated with FVC and FEV1 and inversely correlated with BMI and pack-years. Lower sRAGE levels were associated with greater declines of FEV1/FVC over 4 years in all participants. Moreover, multivariate regression analysis indicated that the baseline plasma sRAGE concentration was an independent predictor of FEV1/FVC decline in all groups. A subgroup analysis showed that decreased sRAGE levels are significantly associated with a more rapid decline of FEV1/FVC in smokers with COPD. There was no significant correlation between plasma HMGB1 levels and longitudinal decline of lung function. CONCLUSIONS: Lower plasma concentrations of sRAGE were associated with greater progression of airflow limitations over time, especially in smokers with COPD, suggesting that RAGE might have a protective role in the lung.

Co-morbidities are the key nominators of the health related quality of life in mild and moderate COPD.

BACKGROUND: Co-morbidities are common in chronic obstructive pulmonary disease (COPD). We assessed the contribution of common co-morbidities on health related quality of life (HRQoL) among COPD patients. METHODS: Using both generic (15D) and respiratory-specific (AQ20) instruments, HRQoL was assessed in a hospital based COPD population (N = 739, 64% males, mean age 64 years, SD 7 years) in this observational study with inferential analysis. The prevalence of their co-morbidities was compared with those of 5000 population controls. The patients represented all severity stages of COPD and the patterns of common concomitant disorders differed between patients. RESULTS: Co-morbidities such as psychiatric conditions, alcohol abuse, cardiovascular diseases, and diabetes were more common among COPD patients than in age and gender matched controls. Psychiatric conditions and alcohol abuse were the strongest determinants of HRQoL in COPD and could be detected by both 15D (Odds Ratio 4.7 and 2.3 respectively) and AQ20 (OR 2.0 and 3.0) instruments. Compared to respiratory specific AQ20, generic 15D was more sensitive to the effects of comorbidities while AQ20 was slightly more sensitive for the low FEV1. FEV1 was a strong determinant of HRQoL only at more severe stages of disease (FEV1 < 40% of predicted). Poor HRQoL also predicted death during the next five years. CONCLUSIONS: The results suggest that co-morbidities may impair HRQoL at an early stage of the disease, while bronchial obstruction becomes a significant determinant of HRQoL only in severe COPD.

[Update on current care guideline: chronic obstructive pulmonary disease (COPD)]. / Keuhkoahtaumatauti.

Clinical serverity of COPD is based not only on the grade of obstruction in spirometry, but also on symptoms and risk of exacerbations. Symptoms can be defined by questionnaires, such as CAT-test (COPD assessment -test) or mMRC (modified Medical Research Council -test). Smoking cessation and physical activity are important treatment options. Pharmacological treatment is selected by symptoms, risk of exacerbations and co-occurrence of asthma and COPD. Non-invasive ventilation (NIV) is recommended in the treatment of severe hypercapnic exacerbations. Palliative treatment of end stage COPD is included in the guidelines.

Successful Use of Easyhaler® Dry Powder Inhaler in Patients with Chronic Obstructive Pulmonary Disease; Analysis of Peak Inspiratory Flow from Three Clinical Trials.

INTRODUCTION: There is increasing pressure to use environmentally friendly dry powder inhalers (DPI) instead of pressurized metered-dose inhalers (pMDI). However, correct inhalation technique is needed for effective inhaler therapy, and there is persistent concern whether patients with chronic obstructive pulmonary disease (COPD) can generate sufficient inspiratory effort to use DPIs successfully. The aims of this study were to find clinical predictors for peak inspiratory flow rate (PIF) and to assess whether patients with COPD had difficulties in generating sufficient PIF with a high resistance DPI. METHODS: Pooled data of 246 patients with COPD from previous clinical trials was analyzed to find possible predictors of PIF via the DPI Easyhaler (PIFEH) and to assess the proportion of patients able to achieve an inhalation flow rate of 30 l/min, which is needed to use the Easyhaler successfully. RESULTS: The mean PIF was 56.9 l/min and 99% (243/246) of the study patients achieved a PIF ≥ 30 l/min. A low PIF was associated with female gender and lower forced expiratory volume in 1 s (FEV1), but the association was weak and a statistical model including both only accounted for 18% of the variation seen in PIFEH. CONCLUSIONS: Based on our results, impaired expiratory lung function or patient characteristics do not predict patients' ability to use DPIs in COPD; 99% of the patients generated sufficient PIFEH for successful dose delivery. Considering the targets for sustainability in health care, this should be addressed as DPIs are a potential option for most patients when choosing the right inhaler for the patient. TRIAL REGISTRATION: Two of three included trials were registered under numbers NCT04147572 and NCT01424137. Third trial preceded registration platforms and therefore, was not registered.

Chronic smoke exposure induces rheumatoid factor and anti-heat shock protein 70 autoantibodies in susceptible mice and humans with lung disease.

The impact of cigarette smoke (CS), a risk factor for rheumatoid arthritis (RA), on sauto-antibody production was studied in humans and mice with and without chronic lung disease (LD). Rheumatoid factor (RF), anti-cyclic citrullinated peptides (CCPs), and anti-HSP70 autoantibodies were measured in several mouse strains and in cohorts of smokers and nonsmokers with and without autoimmune disease. Chronic smoking-induced RFs in AKR/J mice, which are most susceptible to LD. RFs were identified in human smokers, preferentially in those with LD. Anti-HSP70 auto-antibodies were identified in CS-exposed AKR/J mice but not in ambient air exposed AKR/J controls. Whereas inflammation could induce anti-HSP70 IgM, smoke exposure promoted the switch to anti-HSP70 IgG autoantibodies. Elevated anti-CCP autoantibodies were not detected in CS-exposed mice or smokers. AKR/J splenocytes stimulated in vitro by immune complexes (ICs) of HSP70/anti-HSP70 antibodies produced RFs. The CD91 scavenger pathway was required as anti-CD91 blocked the HSP70-IC-induced RF response. Blocking Toll-like receptors did not influence the HSP70-IC-induced RFs. These studies identify both anti-HSP70 and RFs as serological markers of smoke-related LD in humans and mice. Identification of these autoantibodies could suggest a common environmental insult, namely CS, in a number of different disease settings.

[Chronic obstructive pulmonary disease (COPD) phenotypes]. / Keuhkoahtaumataudin kliiniset alatyypit.

COPD--a progressive inflammatory disorder in the airways and lung parenchyma - is also associated with manifestations beyond the lungs. Although the diagnosis of COPD is based on spirometry, severity of airflow obstruction poorly predicts clinically important outcomes. Recently a COPD phenotype was defined as "a single or combination of disease attributes that describe differences between individuals with COPD as they relate to clinically meaningful outcomes". Four predominant clinical phenotypes were introduced. Awareness of them can lead to more accurate diagnostics and treatments specifically targeted for a specific subpopulation.

Mortality of asthma, COPD, and asthma-COPD overlap during an 18-year follow up.

BACKGROUND: We studied asthma, COPD, and asthma-COPD overlap (ACO) to predict mortality in a cohort of Finnish adults with an 18-year follow up. METHODS: A national health examination survey representing Finnish adults aged ≥30 years was performed in 2000-2001. The study cohort included 5922 participants (73.8% of the sample) with all relevant data, including a comprehensive clinical examination and spirometry. These participants were followed continuously from baseline until end of 2018 for total, cardiovascular, cancer, and respiratory mortality through a record linkage. Asthma, COPD, and ACO were defined based on the survey data, including spirometry and register data. There were three separate groups of obstructive subjects (one definition excluding the others). RESULTS: Asthma and COPD were significantly associated with higher total mortality in Cox's model adjusted for sex, age, smoking, education level, BMI, leisure time physical activity, cardiovascular disease, diabetes, and hypertension. Hazard ratios (HR) (95% confidence interval [CI]) for asthma, COPD, and ACO were 1.29 (1.05-1.58), 1.50 (1.20-1.88), and 1.26 (0.97-1.65), respectively. Additionally, asthma (HR 1.47, 95% CI 1.09-1.97) and COPD (HR 1.53, 95% CI 1.08-2.16) were associated with cardiovascular mortality. Although ACO did not predict mortality in the whole cohort, there was a significant association with mortality risk among those with hs-CRP 1-2.99 mg/l. CONCLUSIONS: Asthma or COPD predicts higher total mortality and premature death from cardiovascular diseases.

Sputum proteomics identifies elevated PIGR levels in smokers and mild-to-moderate COPD.

Chronic obstructive pulmonary disease (COPD) is one of the leading causes of morbidity and mortality around the world. However, the exact mechanisms leading to COPD and its progression are still poorly understood. In this study, induced sputum was analyzed by cysteine-specific two-dimensional difference gel electrophoresis (2D-DIGE) coupled with mass spectrometry to identify proteins involved in COPD pathogenesis. The comparison of nonsmokers, smokers, and smokers with moderate COPD revealed 15 changed proteins with the majority, including polymeric immunoglobulin receptor (PIGR), being elevated in smokers and subjects with COPD. PIGR, which is involved in specific immune defense and inflammation, was further studied in sputum, lung tissue, and plasma by Western blot, immunohistochemistry/image analysis, and/or ELISA. Sputum PIGR was characterized as glycosylated secretory component (SC). Lung PIGR was significantly elevated in the bronchial and alveolar epithelium of smokers and further increased in the alveolar area in mild to moderate COPD. Plasma PIGR was elevated in smokers and smokers with COPD compared to nonsmokers with significant correlation to obstruction. In conclusion, new proteins in smoking-related chronic inflammation and COPD could be identified, with SC/PIGR being one of the most prominent not only in the lung but also in circulating blood.

In bronchiectasis, poor physical capacity correlates with poor quality of life.

Purpose: Patients with bronchiectasis (BE) who suffer frequent exacerbations are likely to experience negative effects on quality of life (QoL) and require more healthcare utilization. We aimed to discover, in a cohort of Finnish BE patients, those risk factors that influence QoL. Methods: Non-cystic fibrosis BE patients of a Helsinki University Hospital cohort were examined with high-resolution computed tomography (HRCT) of the chest. They completed a disease-specific quality of life-bronchiectasis (QoL-B) questionnaire in Finnish translation. We considered scores in the lowest quarter (25%) of that QoL-B scale to indicate poor QoL. The bronchiectasis severity index (BSI), FACED score, and modified Medical Research Council (mMRC) dyspnoea scale were used. Results: Overall, of 95 adult BE patients, mean age was 69 (SD ± 13) and 79% were women. From the cohort, 82% presented with chronic sputum production and exacerbations, at a median rate of 1.7 (SD ± 1.6). The number of exacerbations (OR 1.7), frequent exacerbations (≥3 per year) (OR 4.9), high BSI score (OR 1.3), and extensive disease (≥3 lobes) (OR 3.7) were all predictive of poor QoL. Frequent exacerbations were associated with bronchial bacterial colonisation, low forced expiratory volume in 1 s (FEV1), and radiological disease severity. Based on the BSI, 34.1% of our cohort had severe disease, with 11.6% classified as severe according to their FACED score. The mMRC dyspnoea score (r = -0.57) and BSI (r = -0.60) correlated, in the QoL-B questionnaire, negatively with physical domain. Conclusion: The strongest determinants of poor QoL in the cohort of Finnish BE patients were frequent exacerbations, radiological disease severity, and high BSI score. Neither comorbidities nor BE aetiology appeared to affect QoL. Reduced physical capacity correlated with dyspnoea and severe disease. Study registration: University of Helsinki, Faculty of Medicine, 148/16.08.2017.

Comparison between the disease-specific Airways Questionnaire 20 and the generic 15D instruments in COPD.

BACKGROUND: Given that the assessment of health-related quality of life (HRQoL) is an essential outcome measure to optimize chronic obstructive pulmonary disease (COPD) patient management, there is a need for a short and fast, reliable and valid instrument for routine use in clinical practice. The objective of this study was to analyse the relationship between the disease-specific Airways questionnaire (AQ20) and the generic 15D health-related quality of life (HRQoL) instrument simultaneously in a large cohort of patients with COPD. We also compare the HRQoL of COPD patients with that of the general population. METHODS: The AQ20 and 15D were administered to 739 COPD patients representing an unselected hospital-based COPD population. The completion rates and validity of, and correlations among the questions and dimension scores were examined. A factor analysis with varimax rotation was performed in order to find subsets of highly correlating items of the questionnaires. RESULTS: The summary scores of AQ20 and 15D were highly correlated (r = - 0.71, p < 0.01). In AQ20 over 50% of patients reported frequent cough, breathlessness during domestic work, and chest problem limiting their full enjoyment of life. 15D results showed a noteworthy decrease of HRQoL in breathing, mobility, sleeping, usual activities, discomfort and symptoms, vitality, and sexual activity (scores ≤ 0.75). Compared to the age- and gender-standardized Finnish general population, the COPD patients were statistically significantly worse off on 13 of 15 dimensions. CONCLUSIONS: The AQ20 and 15D summary scores are comparable in terms of measuring HRQoL in COPD patients. The data support the validity of 15D to measure the quality of life in COPD. COPD compromises the HRQoL broadly, as reflected by the generic instrument. Both questionnaires are simple and short, and could easily be used in clinical practice with high completion rates.

Ageing and smoking contribute to plasma surfactant proteins and protease imbalance with correlations to airway obstruction.

BACKGROUND: A significant number of young people start smoking at an age of 13-15, which means that serious smoking-evoked changes may have been occurred by their twenties. Surfactant proteins (SP) and matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) have been linked to cigarette smoke induced lung remodelling and chronic obstructive pulmonary disease (COPD). However, the level of these proteins has not been examined during ageing or in young individuals with short smoking histories. METHODS: Plasma levels of SP-A, SP-D, MMP-9, and TIMP-1 were measured by EIA/ELISA from young (18-23 years) non-smoking controls (YNS) (n = 36), smokers (YS) (n = 51), middle aged/elderly (37-77 years) non-smoking controls (ONS) (n = 40), smokers (OS) (n = 64) (FEV1/FVC >0.7 in all subjects) and patients with COPD (n = 44, 35-79 years). RESULTS: Plasma levels of SP-A increased with age and in the older group in relation to smoking and COPD. Plasma SP-D and MMP-9 levels did not change with age but were elevated in OS and COPD as compared to ONS. The TIMP-1 level declined with age but increased in chronic smokers when compared to ONS. The clearest correlations could be detected between plasma SP-A vs. age, pack years and FEV1/FVC. The receiver operating characteristic (ROC) curve analysis revealed SP-A to be the best marker for discriminating between patients with COPD and the controls (area under ROC curve of 0.842; 95% confidence interval, 0.785-0.899; p < 0.001). CONCLUSIONS: Age has a significant contribution to potential markers related to smoking and COPD; SP-A seems to be the best factor in differentiating COPD from the controls.

Ageing and long-term smoking affects KL-6 levels in the lung, induced sputum and plasma.

BACKGROUND: KL-6 is a high-molecular-weight glycoprotein classified as a human MUC1 mucin. It was hypothesized that KL-6 could be detectable in the circulating blood and especially in airway secretions in lung diseases associated with mucus production such as chronic obstructive pulmonary disease (COPD). Additional aims of this study were to investigate whether the levels of KL-6 in plasma and sputum are related to ageing and smoking history. METHODS: The concentrations of KL-6 in plasma and induced sputum supernatants from young and/or middle aged/elderly non-smokers, smokers and patients with COPD were assayed by ELISA (n = 201). The subjects were classified into five groups according to age, smoking status and presence of COPD. In addition, KL-6 expression in control and diseased lung i.e. samples from patients with COPD (n = 28), were analyzed by immunohistochemistry and digital image analysis. RESULTS: The plasma levels of KL-6 increased with age both in non-smokers and smokers. Among middle aged/elderly subjects, plasma KL-6 levels in all smokers regardless of COPD were significantly higher than in non-smokers, whereas sputum levels of KL-6 were significantly higher in COPD compared not only to non-smokers but also to smokers. KL-6 was more prominently expressed in the bronchiolar/alveolar epithelium in COPD than in the control lungs. Plasma and sputum KL-6 levels correlated inversely with obstruction and positively with smoking history and ageing. The linear multiple regression analysis confirmed that age and cigarette smoking had independent effects on plasma KL-6. CONCLUSIONS: KL-6 increases with ageing and chronic smoking history, but prospective studies will be needed to elucidate the significance of KL-6 in chronic airway diseases.

Hemoglobin α and ß are ubiquitous in the human lung, decline in idiopathic pulmonary fibrosis but not in COPD.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD) are disorders of the lung parenchyma. They share the common denominators of a progressive nature and poor prognosis. The goal was to use non-biased proteomics to discover new markers for these diseases. METHODS: Proteomics of fibrotic vs. control lung tissue suggested decreased levels of several spots in the lung specimens of IPF patients, which were identified as Hemoglobin (Hb) α and ß monomers and Hbα complexes. The Hbα and ß monomers and complexes were investigated in more detail in normal lung and lung specimens of patients with IPF and COPD by immunohistochemistry, morphometry and mass spectrometry (MS). RESULTS: Both Hb monomers, in normal lung, were expressed especially in the alveolar epithelium. Levels of Hbα and ß monomers and complexes were reduced/lost in IPF but not in the COPD lungs when compared to control lung. MS-analyses revealed Hbα modification at cysteine105 (Cysα105), preventing formation of the Hbα complexes in the IPF lungs. Hbα and Hbß were expressed as complexes and monomers in the lung tissues, but were secreted into the bronchoalveolar lavage fluid and/or induced sputum supernatants as complexes corresponding to the molecular weight of the Hb tetramer. CONCLUSIONS: The abundant expression of the oxygen carrier molecule Hb in the normal lung epithelium and its decline in IPF lung are new findings. The loss of Hb complex formation in IPF warrants further studies and may be considered as a disease-specific modification.

Peroxiredoxin 6 differentially regulates acute and chronic cigarette smoke–mediated lung inflammatory response and injury.

Peroxiredoxin 6 (Prdx6) exerts its protective role through peroxidase activity against H2O2 and phospholipid hydroperoxides. We hypothesized that targeted disruption of Prdx6 would lead to enhanced susceptibility to cigarette smoke (CS)-mediated lung inflammation and/or emphysema in mouse lung. Prdx6 null (Prdx6⁻/⁻mice exposed to acute CS showed no significant increase of inflammatory cell influx or any alterations in lung levels of proinflammatory cytokines compared to wild-type (WT) mice. Lung levels of antioxidant enzymes were significantly increased in acute CS-exposed Prdx6⁻/⁻ compared to WT mice. Overexpressing (Prdx6⁻/⁻) mice exposed to acute CS showed significant decrease in lung antioxidant enzymes associated with increased inflammatory response compared to CS-exposed WT mice or air-exposed Prdx6⁻/⁻ mice. However, chronic 6 months of CS exposure resulted in increased lung inflammatory response, mean linear intercept (Lm), and alteration in lung mechanical properties in Prdx6⁻/⁻ when compared to WT mice exposed to CS. These data show that targeted disruption of Prdx6 does not lead to increased lung inflammatory response but is associated with increased antioxidants, suggesting a critical role of lung Prdx6 and several compensatory mechanisms during acute CS-induced adaptive response, whereas this protection is lost in chronic CS exposure leading to emphysema.

Elevation of sputum matrix metalloproteinase-9 persists up to 6 months after smoking cessation: a research study.

BACKGROUND: Smoking cessation is the best possible way to prevent the progression of smoking related airway diseases. However, the effect and time scale of smoking cessation on airway inflammation/remodelling are largely unknown. This prospective study evaluated the effects of smoking cessation on induced sputum (IS) neutrophils, matrix metalloproteinases (MMP-7, -8, -9) and tissue inhibitor of metalloproteinase-1 (TIMP-1). METHODS: A total of 61 subjects participated in the study; 17 stopped smoking for 3 months and 9 for 6 months. The proportion of IS neutrophils and the levels of MMPs and TIMP-1 by ELISA were determined at baseline and at 3 and 6 months after cessation. RESULTS: In the smokers, baseline IS neutrophils, MMPs and TIMP-1 were significantly higher compared to non-smokers. Levels of MMP-7, -8 and TIMP-1 decreased nearly to those of non-smokers but the levels of MMP-9 increased significantly from the baseline of the same subjects at 3 months after cessation (p = 0.009) with no significant decline at 6 months after cessation. CONCLUSIONS: Sputum MMP-9 remained elevated after 6 months of smoking cessation, which may contribute to ongoing lung damage typical of COPD.

Sputum Vitamin D Binding Protein (VDBP) GC1S/1S Genotype Predicts Airway Obstruction: A Prospective Study in Smokers with COPD.

Introduction: The vitamin D binding protein (VDBP, also known as GC-globulin) and vitamin D deficiency have been associated with chronic obstructive pulmonary disease (COPD). rs7041 and rs4588 are two single nucleotide polymorphisms of the VDBP gene, including three common allelic variants (GC1S, GC1F and GC2). Previous studies primarily assessed the serum levels of vitamin D and VDBP in COPD. However, less is known regarding the impact of the local release of VDBP on COPD lung function. Thus, we examined the association of sputum and plasma VDBP with lung function at baseline and at four years, and examined potential genetic polymorphism interactions. Methods: The baseline levels of sputum VDBP, plasma VDBP and plasma 25-OH vitamin D, as well as the GC rs4588 and rs7041 genotypes, were assessed in a 4-year Finnish follow-up cohort (n = 233) of non-smokers, and smokers with and without COPD. The associations between the VDBP levels and the longitudinal decline of lung function were further analysed. Results: High frequencies of the haplotypes in rs7041/rs4588 were homozygous GC1S/1S (42.5%). Higher sputum VDBP levels in stage I and stage II COPD were observed only in carriers with GC1S/1S genotype when compared with non-smokers (p = 0.034 and p = 0.002, respectively). Genotype multivariate regression analysis indicated that the baseline sputum VDBP and FEV1/FVC ratio at baseline independently predicted FEV1% at follow-up. Discussion and Conclusion: The baseline sputum VDBP expression was elevated in smokers with COPD among individuals with the GC1S/1S genotype, and predicted follow-up airway obstruction. Our results suggest that the GC polymorphism should be considered when exploring the potential of VDBP as a biomarker for COPD.