Whereas cigarette smoking remains the main risk factor for emphysema, recent studies in β-epithelial Na(+) channel-transgenic (βENaC-Tg) mice demonstrated that airway surface dehydration, a key pathophysiological mechanism in cystic fibrosis (CF), caused emphysema in the absence of cigarette smoke exposure. However, the underlying mechanisms remain unknown. The aim of this study was to elucidate mechanisms of emphysema formation triggered by airway surface dehydration. We therefore used expression profiling, genetic and pharmacological inhibition, Foerster resonance energy transfer (FRET)-based activity assays, and genetic association studies to identify and validate emphysema candidate genes in βENaC-Tg mice and patients with CF. We identified matrix metalloproteinase 12 (Mmp12) as a highly up-regulated gene in lungs from βENaC-Tg mice, and demonstrate that elevated Mmp12 expression was associated with progressive emphysema formation, which was reduced by genetic deletion and pharmacological inhibition of MMP12 in vivo. By using FRET reporters, we show that MMP12 activity was elevated on the surface of airway macrophages in bronchoalveolar lavage from βENaC-Tg mice and patients with CF. Furthermore, we demonstrate that a functional polymorphism in MMP12 (rs2276109) was associated with severity of lung disease in CF. Our results suggest that MMP12 released by macrophages activated on dehydrated airway surfaces may play an important role in emphysema formation in the absence of cigarette smoke exposure, and may serve as a therapeutic target in CF and potentially other chronic lung diseases associated with airway mucus dehydration and obstruction.

MMP12 is a metalloproteinase implicated in inflammation. To monitor its activity, we synthesized a membrane-targeted reporter (LaRee1) based on Foerster resonance energy transfer (FRET). Unlike existing sensors, LaRee1 detects MMP12 activity by loss of FRET plus internalization of the lipidated fragment. In bronchoalveolar lavages from a mouse model of pulmonary inflammation, LaRee1 detected MMP12 activity at the surface of activated macrophages. LaRee1 may become a powerful tool for monitoring lung disease.

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Background: Cystic fibrosis (CF) related diabetes (CFRD) is a common complication of CF. CFRD is associated with declining lung function even before its onset. Regular screening for CFRD using oral glucose tolerance test (OGTT) is recommended. Additionally, continuous glucose monitoring (CGM) has surfaced as a possible surveillance method, but evidence for its use and concordance with OGTT has not been established. Methods: Children were prospectively recruited at CF center Lund to undergo both intermittent scan CGM (isCGM) and OGTT. Lung function was evaluated by spirometry and multiple breath washout. Demographic and clinical data were collected from the Swedish national CF registry. Results: 32 patients participated in the study, yielding 28 pairs of isCGMs and OGTTs. The OGTTs showed that two patients met the criteria of CFRD, seven had impaired glucose tolerance (IGT) and indeterminate glycemia (INDET) was found in eleven cases. The isCGM percent of measurements > 8mmol/L and the number of peaks per day > 11 mmol/L have correlations with intermediate OGTT glucose time points, but not the 2hour glucose value. Patients with abnormal glucose tolerance (AGT) had lower lung function than those with normal glucose tolerance demonstrated by both FEV1% predicted and lung clearance index (LCI). Conclusion: Correlations can be found between isCGM and OGTT in regards to the latter's intermediate time points. LCI demonstrates as well as FEV1% of predicted, worse lung function in children and adolescents with abnormal glucose tolerance in CF.

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Background. Large-scale population-based seroprevalence studies of SARS-CoV-2 are essential to characterize the cumulative incidence of SARS-CoV-2 infection and to extrapolate the prevalence of presumptive immunity at the population level. Objective. The objective of our survey was to estimate the cumulative population immunity for COVID-19 and to identify individual characteristics associated with positive serostatus. Materials and Methods. This was a clustered cross-sectional study conducted from July 12 to August 20, 2021, in households in the city of Bangui, the capital of the Central African Republic. Information regarding demographic characteristics (age, gender, and place of residence), and comorbidities (chronic diseases) was collected. A venous blood sample was obtained from each participant to determine the level of total anti-SARS-CoV-2 antibodies using a WANTAI SARS-CoV-2 Ab ELISA kit. Results. All up, 799 participants were surveyed. The average age was 27 years, and 45.8% of the respondents were male (sex ratio: 0.8). The overall proportion of respondents with positive serostatus was 74.1%. Participants over 20 years of age were twice as likely to have positive serostatus, with an OR of 2.2 (95% CI: [1.6, 3.1]). Interpretation. The results of this survey revealed a high cumulative level of immunity in Bangui, thus indicating a significant degree of spread of SARS-CoV-2 in the population. The public health implications of this immunity to SARS-CoV-2 such as the post-vaccination total antibody kinetics remain to be determined.

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