It is challenging to recover local optic axis orientation from samples probed with fiber-based polarization-sensitive optical coherence tomography (PS-OCT). In addition to the effect of preceding tissue layers, the transmission through fiber and system elements, and imperfect system alignment, need to be compensated. Here, we present a method to retrieve the required correction factors from measurements with depth-multiplexed PS-OCT, which accurately measures the full Jones matrix. The correction considers both retardation and diattenuation and is applied in the wavenumber domain, preserving the axial resolution of the system. The robustness of the method is validated by measuring a birefringence phantom with a misaligned system. Imaging ex-vivo lamb trachea and human bronchus demonstrates the utility of reconstructing the local optic axis orientation to assess smooth muscle, which is expected to be useful in the assessment of airway smooth muscle thickness in asthma, amongst other fiber-based applications.

Introduction: Small airway abnormalities are implicated as a primary cause of functional impairment in obstructive airway disease. Contraction of the airway smooth muscle (ASM) layer in the absence of an exogenous stimulus (i.e. intrinsic tone) may enhance force production through ‘force adaptation’. This study determined the relationship between intrinsic ASM tone and subsequent response to contractile activation. Methods: Subjects (n=18) undergoing lobectomies were recruited and baseline lung function assessed before surgery. Peripheral airways were dissected from resected tissue and cut into bronchial rings for further in vitro studies. Length-force curves were constructed to KCl to establish optimum contractile length, at which dose-response curves to acetylcholine (ACh) were performed. Intrinsic force was determined after complete relaxation to theophylline. Forces were converted to stress after normalising for muscle thickness and ring width. Data are mean±SEM. Results: Subjects had a pre-bronchodilator FEV1(%Pred) of 93±3.91 and FEV1/FVC of 0.73±0.02. Bronchial rings exhibited a mean intrinsic stress of 29±5.14mN/mm2 which comprised ~28% of the total (intrinsic + active) stress. Intrinsic stress was positively correlated with maximal response to ACh (r=0.55, p<0.05) but not sensitivity. There was no association between lung function and intrinsic ASM stress or maximal stress induced by ACh. Conclusion: Results demonstrate that increased intrinsic tone in the peripheral ASM layer increases the subsequent response of the airway to contractile activation. This suggests that elevated intrinsic tone may increase induced bronchoconstriction to inhaled stimuli and promote airway hyperresponsiveness.

Introduction: We have previously observed an inverse relationship between FEV1 and the volume fraction of extracellular matrix (VVECM) within the layer of airway smooth muscle (ASM) in smokers with airflow obstruction. Many patients with asthma have a degree of fixed airflow obstruction. We hypothesized that fixed and variable obstruction may differ with regard to VVECM within the ASM layer. Aim: To compare the VVECM within the ASM layer in asthmatic subjects with (n=7, FEV1<80% predicted) or without (n=8, FEV1>80% predicted) fixed airflow obstruction. Methods: The FEV1, measured pre-operatively in patients undergoing lobectomy (n=12), or obtained from medical records from post-mortem cases (n=3), was recorded. Airways were paraffin embedded and thin (0.5µm) transverse sections were cut and stained using the Masson’s trichrome technique. Point counts were made within the ASM layer to estimate the VVECM and the correlation between FEV1 and VVECM was estimated using Spearman’s correlation coefficient. Results: Mean ± SD, *=p<0.001. VVECM negatively correlated with FEV1 (r=0.62, p=0.02) but not in non-smoking asthma cases analyzed separately (r=0.81, p=0.09). Conclusion: The VVECM within the ASM layer negatively correlated with FEV1 in asthmatic subjects, with a similar trend seen in non-smoking asthma subjects. These data suggest that, as seen in smokers, fixed airflow obstruction in asthma is related to increased ECM within the ASM layer.

Objective: To document the changing levels of tobacco smoking, respiratory symptoms, doctor-diagnosed asthma, and lung function in Busselton adults aged 46-65 years over the past 50 years. Design, setting, participants: Repeated cross-sectional population surveys (1966 to 2010-2015) of adults registered to vote in the Busselton shire, Western Australia, including a modified version of the British Medical Research Council questionnaire on respiratory symptoms. Main outcome measures: History of doctor-diagnosed asthma and chronic obstructive pulmonary disease (COPD), tobacco smoking history, respiratory medications used, spirometry parameters (forced expiratory volume in one second [FEV1], forced vital capacity [FVC]). Results: The prevalence of tobacco smoking among men declined from 53% in 1966 to 12% in 2010-2015, and from 26% to 9% among women. The prevalence of ever-smoking (ie, smokers and ex-smokers) decreased from 80% to 57% for men but increased from 33% to 50% for women. The prevalence of doctor-diagnosed asthma increased, as did the use of long-acting bronchodilator aerosol medications by people with asthma and COPD. There have been no consistent changes in the prevalence of specific respiratory symptoms, but measures of lung function have significantly improved. Conclusions: Smoking rates declined as a result of changes in pricing, prohibitions on smoking and the feedback of survey results to Busselton participants. Significant improvements in lung function were measured, and it can be anticipated that the prevalence of other smoking-related diseases will also decline.

Background: Asthma is a complex disease with sex-specific differences in prevalence, clinical and biological features. Asthma is more prevalent in males during childhood, while it becomes more frequent in females in adolescence and adulthood. The mechanisms behind these sex-specific differences are not well understood and may involve hormonal changes together with differential genetic predisposition. Objective: Our goal was to identify genetic variants interacting with sex that influence time-to-asthma onset (TAO). Methods: We conducted a large-scale meta-analysis of nine genome-wide interaction studies (GEWIS) of TAO (totaling 7,104 men and 6,970 females of European ancestry) using survival analysis methods applied to pediatric and adult asthmatic and non-asthmatic subjects. Results: We detected three independent loci showing SNP×Sex interaction at the 10-5 level. The most significant association with TAO was female-specific in an intergenic region at 5q32 (Pfemale = 9.1x10-8versus Pmale=0.56). The other two associations were male-specific: within SORCS2 intron 2 at 4q16 (Pmale=1.3x10-7versus Pfemale=0.15) and within DGKB intron 1 at 7p21 (Pmale= 3.9x10-7versus Pfemale=0.23). Functional annotations indicated co-localization of these genetic variants with epigenetic marks and DNA regulatory elements in fibroblasts, lung or blood. Conclusion: By testing gene-by-sex interactions, we identified novel loci influencing asthma risk in a sex-specific manner. Candidate genes in these loci are involved in inflammatory process and immune cell regulation. Further replication of these findings are ongoing.

BACKGROUND:Previous studies have reached conflicting conclusions about the role of atopy as a risk factor for COPD. In part, this is attributable to variation in the definitions of airflow limitation and the treatment of people with asthma.OBJECTIVE:To establish whether there is any independent association between atopy and post-bronchodilator airflow limitation in the general population aged 40 years and over.METHODS:A cross-sectional survey was conducted in a general population sample of 2415 people aged 40 years and over in Australia. A history of ever being diagnosed with asthma was elicited by questionnaire. Atopy was defined as any skin prick test weal to common aeroallergens ≥4 mm. Airflow limitation was defined as post-bronchodilator spirometric (FEV1 /FVC) ratio <lower limit of normal. Analyses were adjusted for potential confounding due to age, sex, smoking, race and socio-economic status.RESULTS:The prevalence of atopy, ever diagnosed asthma and post-bronchodilator airflow obstruction was 44.8%, 19.3% and 7.5%, respectively. In the population as a whole, atopy was associated with lower FEV₁ (adjusted difference -0.068L, 95% confidence interval (CI) -0.104 to -0.032), FVC (adj. difference -0.043L, 95% CI -0.086 to -0.0009) and post-bronchodilator FEV₁/FVC ratio (adj. difference -0.011, 95% CI -0.017 to -0.0055). The effect of atopy on lung function was no longer apparent when participants who reported ever diagnosed asthma were excluded (FEV₁ -0.011L, [95% CI -0.05 to 0.028L], FVC -0.012L [95% CI -0.060 to 0.036] and FEV₁/FVC ratio -0.0012 [95% CI -0.0072 to 0.0047L]).CONCLUSION AND CLINICAL RELEVANCE:The apparent association between atopy and post-bronchodilator airflow limitation in the general population appears to be explained by the association between atopy and having ever diagnosed asthma and the effect of asthma on lung function.

Macrolide antibiotics have a range of immunomodulatory properties, which may influence clinical outcomes such as reduced exacerbations in patients with airways disease. Azithromycin (AZM) has been shown to reduce IL-1β release from blood monocytes, however little is known about the impact of AZM therapy on airway IL-1β. We tested the hypothesis that AZM would reduce sputum IL-1β and that this reduction would be associated with a reduction in sputum neutrophils. Induced Sputum collected from a randomized double-blind placebo controlled trial of oral AZM (500mg, 3 times weekly, 48 weeks) in adults with symptomatic asthma was dispersed using dithiothreitol and supernatant collected and assessed for IL-1β using ELISA in 195 paired samples. There was a significant reduction in sputum IL-1β following AZM therapy (median 398ng/mL at baseline to 168ng/mL following treatment, p=0.003). A significant reduction was observed in both eosinophilic (EA) and non-eosinophilic (NEA) participants, however, those with NEA had a three-fold larger reduction in IL-1β following AZM compared with EA, median change 234 ng/mL vs. 72 ng/mL, p=0.028. Baseline IL-1β was significantly positively associated with baseline neutrophil number in all participants (r = 0.499, p<0.001) and with baseline asthma control score in NEA only (r = 0.272 p=0.004) and negatively associated with FEV<1% predicted (r = -0.306 p=0.001) in NEA only. In those treated with AZM, the change in IL-1β was significantly positively associated with the change in neutrophil number (r=0.361, p<0.001). Sputum IL-1β was significantly reduced following AZM add-on therapy in poorly controlled asthma irrespective of baseline asthma phenotype.

Increased thickness of the airway smooth muscle (ASM) layer is a characteristic feature of airway remodelling in both asthma and chronic obstructive pulmonary disease (COPD) [1, 2]. The composition of the ASM layer has been well studied in asthma where the increased thickness of the ASM layer is due to hypertrophy and/or hyperplasia [3–5] of ASM cells. These changes are associated with a concomitant increase in absolute volumes of both ASM and extracellular matrix (ECM), without changes in their relative volume fractions [5]. Although ASM cell hypertrophy has been reported in the large airways of patients with COPD [6], these findings did not exclude the effect of an increase in the volume fraction of ECM on the estimated average volume of the ASM cells [7]. Remodelling of the layer of airway smooth muscle in COPD is characterised by an increase in the extracellular matrix http://ow.ly/YZqhz

Objectives: To estimate the proportion of ever‐smokers who are eligible for lung cancer screening in an Australian cohort, and to evaluate the effect of spirometry in defining chronic obstructive pulmonary disease (COPD) when assessing screening eligibility.

ABSTRACT COPD is defined as airflow limitation that is not reversed by treatment. In asthma, airflow limitation is not only reversible, but also inducible. This is called ‘airway hyperresponsiveness’ ( AHR ) and is associated with thickening of the airway wall, predominantly the layer of airway smooth muscle, due to more cells, bigger cells and more extracellular matrix ( ECM ) in proportion to the increase in smooth muscle. AHR is also observed in COPD if the changes in airflow are expressed as a percent of the baseline lung function. However, the absolute change in baseline lung function that can be induced in COPD is actually less than that seen in normal subjects, suggesting that the airways in COPD are resistant not only to opening, but also to closing. This observation agrees with physiological measures showing increased airway wall stiffness in COPD . Like asthma, airway wall thickness is increased in COPD , including the layer of smooth muscle. Unlike asthma, however, fixed airflow obstruction appears to be characterized by a disproportionate increase in the ECM within the smooth muscle layer. In this review, we summarize the studies of airway matrix deposition in COPD and put forward the proposal that the airway remodelling in COPD is different from that in asthma and call for a systematic analysis of airway matrix deposition in COPD .

Introduction/Aim: Epidemiological studies have shown overweight or obese asthmatics have more severe disease than those of a healthy weight. This may result from an increased amount of adipose tissue within the airway wall that reduces the transmission of parenchymal elastic loads limiting muscle shortening. The aim of this study was to determine the relationship between Body Mass Index (BMI) and adipose tissue within the airway wall in control subjects (n=16) and cases of nonfatal (NFA, n=21) and fatal (FA, n=16) asthma. Methods: On transverse airway sections taken from formalin-fixed, paraffin-embedded post-mortem lungs, stained with haematoxylin and eosin, the area of adipose tissue within the outer airway wall was estimated by point counts and expressed as area per mm of basement membrane perimeter (Fat/Pbm). Results: In airways with Pbm >10mm, Fat/Pbm positively correlated with BMI in control (r=0.65, p=0.009), NFA (r=0.49, p=0.02) and FA (r=0.66, p=0.005), and with outer airway wall thickness in control (r=0.43, p=0.02) and NFA (r=0.55, p=0.005). BMI and the amount of Fat/Pbm was greater in airways 4-10mm Pbm from NFA than in other groups (p<0.05). Similar correlations between Fat/Pbm and BMI were seen in airways 4-10mm Pbm. There was no difference in gender or age between groups. Conclusion: These data show that the amount of adipose tissue within the airway wall increases with BMI in asthmatic and control subjects and contributes to outer airway wall thickness. While functional studies are required to determine the consequence of airway adipose tissue, we speculate that adipose tissue will increase airway narrowing capacity by reducing the afterload that opposes muscle shortening.

Background: The proportion of people eligible for lung cancer screening in Australia is unknown. Risk prediction models used for screening eligibility, such as the PLCOm2012, use self-reported Chronic Obstructive Pulmonary Disease (COPD) as a variable. Measured airflow obstruction has been advocated as part of eligibility assessment but this needs patient contact. The change in the proportion of people eligible if COPD is self-reported, defined by symptoms or airflow obstruction is unknown. Aim: To estimate the proportion of people eligible for lung cancer screening in Australia and to measure the effect of spirometry to identify COPD on the proportion eligible. Methods: Cross-sectional study of 2523 people aged 55-68 years who live in the Busselton Shire of Western Australia. Eligibility was based on United States Preventative Services Task Force (USPSTF) criteria or PLCOm2012 lung cancer risk >1.5%. Results: Using USPSTF criteria, 20.1%, (95%CI 17.9-22.3) of ever-smokers would be eligible for screening. Using PLCOm2012 criteria, fewer ever-smokers would be eligible (17.9%, 95%CI 15.8-20.0, p<0.01). This represents 8.9-10% of all people aged 55-68 years. There was a negligible and non-statistical difference in the proportion of eligible participants if airflow obstruction or symptoms was used to define COPD for PLCOm2012 risk (p=0.06). Conclusions: The proportion of ever-smokers eligible for lung cancer screening in this population is 17.9-20.1%. Up to 450,000 people in Australia may benefit from lung cancer screening. Using symptoms to identify COPD is an appropriate surrogate for spirometry when determining presence of COPD in this population.

Introduction/Aim: In patients with asthma, the airway smooth muscle (ASM) layer is thicker and is stable with age. Within the ASM layer, extracellular matrix (ECM) represents less than 20% of its total volume fraction (V V ). Departure from normal development of the ASM layer may alter V V ECM and result in airway hyperresponsiveness and asthma or contribute to fixed airflow obstruction later in life. The aim of this study was to compare the volume fractions of ECM, ASM and “Other” (space between ASM cells) within the ASM layer from infancy to adulthood in subjects with (n=84, age range 4-59yrs) and without (n=59, 0.2-57yrs) asthma. Methods: On transverse airways taken from formalin-fixed, post-mortem lungs, sections were cut from paraffin-embedded tissue blocks at 0.5microns and stained using the Masson9s trichrome technique. Volume fractions of ECM, ASM and Other within the ASM layer were measured (x1000) by point counting and then related to age in cases with and without asthma. Results: Cases of asthma had decreased V V ECM (17±5%, mean ± SD) compared with control subjects (19±4%, p=0.02) and no difference in V V ASM or V V Other. V V ECM and V V ASM positively correlated with age in control subjects (r 2 =0.13, p=0.005 and r 2 =0.11, p=0.01), but not in cases of asthma (r 2 =0.04, p=0.07 and r 2 =0.03, p=0.1). V V ASM and V V Other did not correlate with age. Discussion: These data suggest that the ASM layer normally undergoes structural change from infancy to adulthood and this involves changes in V V ECM. However in asthma, the ASM layer may not follow the same developmental trajectory as control subjects, possibly due to the confounding effect of early structural changes in the layer of ASM.