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Introduction: Alpha-1 antitrypsin (AAT) deficiency (AATD) is associated with early onset emphysema. The aim of this study was to investigate whether AAT binding to plasma constituents could regulate their activation, and in AATD, exploit this binding event to better understand the condition and uncover novel biomarkers of therapeutic efficacy., Methods: To isolate AAT linker proteins, plasma samples were separated by size exclusion chromatography, followed by co-immunoprecipitation. AAT binding proteins were identified by mass spectrometry. Complement turnover and activation was determined by ELISA measurement of C3, C3a and C3d levels in plasma of healthy controls (n=15), AATD (n=51), non-AATD patients with obstructive airway disease (n=10) and AATD patients post AAT augmentation therapy (n=5)., Results: Direct binding of complement C3 to AAT was identified in vivo and in vitro. Compared with healthy controls, a breakdown product of C3, C3d, was increased in AATD (0.04 µg/mL vs 1.96 µg/mL, p=0.0002), with a significant correlation between radiographic pulmonary emphysema and plasma levels of C3d (R 2 =0.37, p=0.001). In vivo, AAT augmentation therapy significantly reduced plasma levels of C3d in comparison to patients not receiving AAT therapy (0.15 µg/mL vs 2.18 µg/mL, respectively, p=0.001)., Discussion: Results highlight the immune-modulatory impact of AAT on the complement system, involving an important potential role for complement activation in disease pathogenesis in AATD. The association between plasma C3d levels and pulmonary disease severity, that decrease in response to AAT augmentation therapy, supports the exploration of C3d as a candidate biomarker of therapeutic efficacy in AATD., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Cigarette smoking is the strongest risk factor for COPD. Smoking burden is frequently measured in pack-years, but the relative contribution of cigarettes smoked per day versus duration towards the development of structural lung disease, airflow obstruction and functional outcomes is not known., Methods: We analysed cross-sectional data from a large multicentre cohort (COPDGene) of current and former smokers. Primary outcome was airflow obstruction (FEV 1 /FVC); secondary outcomes included five additional measures of disease: FEV 1 , CT emphysema, CT gas trapping, functional capacity (6 min walk distance, 6MWD) and respiratory morbidity (St George's Respiratory Questionnaire, SGRQ). Generalised linear models were estimated to compare the relative contribution of each smoking variable with the outcomes, after adjustment for age, race, sex, body mass index, CT scanner, centre, age of smoking onset and current smoking status. We also estimated adjusted means of each outcome by categories of pack-years and combined groups of categorised smoking duration and cigarettes/day, and estimated linear trends of adjusted means for each outcome by categorised cigarettes/day, smoking duration and pack-years., Results: 10 187 subjects were included. For FEV 1 /FVC, standardised beta coefficient for smoking duration was greater than for cigarettes/day and pack-years (P<0.001). After categorisation, there was a linear increase in adjusted means FEV 1 /FVC with increase in pack-years (regression coefficient β=-0.023±SE0.003; P=0.003) and duration over all ranges of smoking cigarettes/day (β=-0.041±0.004; P<0.001) but a relatively flat slope for cigarettes/day across all ranges of smoking duration (β=-0.009±0.0.009; P=0.34). Strength of association of duration was similarly greater than pack-years for emphysema, gas trapping, FEV 1 , 6MWD and SGRQ., Conclusion: Smoking duration alone provides stronger risk estimates of COPD than the composite index of pack-years., Trial Registration Number: Post-results; NCT00608764., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Coal mining provided the power for the industrial development of the West, at great cost to the health of the workforce and, from industrial pollution, of the population. Medical appreciation of the diseases of miners was slow to develop and has been marked by controversy relating to the roles of coal and quartz and the causation of emphysema. Research by the MRC and the British coal industry resolved these issues as the industry itself declined. However, from the research has come an understanding of the influence of inhalation of different inhaled pollutants on human health that has been applied to predicting and preventing possible hazards of developing nanotechnologies., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Background: During the last decade it has been clarified that the inhalation of indium compounds can evoke alveolar proteinosis, cholesterol granuloma, pulmonary fibrosis and emphysema. In this study, we aimed to elucidate the characteristics and time course of pulmonary disorders among indium workers using comprehensive pulmonary examinations at an indium-processing factory., Methods: Data for 84 male workers who underwent the examinations for nine consecutive years from 2002 to 2010 were analysed regarding their symptoms, serum indium concentration (sIn), serum markers of interstitial pneumonia, pulmonary function test parameters and high-resolution CT (HRCT) findings of the lungs., Results: In association with improvements in the work environment and work practice, the sIn levels decreased with significant reductions in the KL-6 and surfactant protein D (SP-D) levels. Regarding the HRCT findings, the interstitial lesions regressed partially, whereas emphysematous lesions increased progressively in the workers with high sIn values. FEV1/FVC decreased with the years and the rate of decrease was significantly greater in those with high sIn. The biological half-life of sIn was estimated to be 8.09 years., Conclusions: The present findings suggest that the sIn, SP-D, KL-6 levels and radiological interstitial changes can be reduced in indium workers by alleviating exposure to indium, whereas emphysematous lesions can progress among those with a history of heavy exposure., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Individuals with severe alpha-1-antitrypsin (alpha1AT) deficiency (phenotype Pi ZZ) are abnormally liable to develop emphysema, but it is uncertain whether those with partial alpha1AT deficiency (phenotypes Pi MS and MZ) are similarly susceptible. This study was undertaken to determine the frequency of the various Pi phenotypes in a working population in Northern Ireland and to compare the performance of simple pulmonary function tests and prevalence of respiratory symptoms and chest illness between different phenotypes. The population sample consisted of 1995 working men and women aged between 35 and 70 years. The MRC Questionnaire (1966) was used to assess respiratory symptoms, a forced expiratory spirogram was recorded, and a blood sample was analysed for alpha1AT phenotype by acid starch gel electrophoresis and antigen-antibody crossed electrophoresis in every case. The percentage frequencies of the alpha1AT phenotypes were: Pi MM 86-5; MS 7-97; MZ 3-86; IM 0-6; FM 0-4; SZ 0-25; M 0-15; SS 0-1; Z 0-05; MP 0-05; FS 0-05. Respiratory symptoms and a history of previous chest illness occurred with similar frequency among the Pi M, MS, and MZ phenotypes, and a comparison of the regression coefficients for FEV1, FVC, and MMF on age for each phenotype group showed no significant differences between them overall, or when subdivided according to smoking habits or dust exposure. These findings provide no evidence that individuals of phenotype Pi MS or MZ are more than usually liable to develop chronic airways obstruction.