Respiratory surfaces are exposed to billions of particulates and pathogens daily. A protective mucus barrier traps and eliminates them via mucociliary clearance (MCC)1,2. However, excessive mucus contributes to transient respiratory infections and to the pathogenesis of numerous respiratory diseases1. MUC5AC and MUC5B are evolutionarily conserved genes that encode structurally related mucin glycoproteins, the principal macromolecules in airway mucus1,3. Genetic variants are linked to diverse lung diseases4-6, but specific roles for MUC5AC and MUC5B in MCC, and the lasting effects of their inhibition, are unknown. Here we show that Muc5b (but not Muc5ac) is required for MCC, for controlling infections in the airways and middle ear, and for maintaining immune homeostasis in the lungs. Muc5b deficiency caused materials to accumulate in upper and lower airways. This defect led to chronic infection by multiple bacterial species, including Staphylococcus aureus, and to inflammation that failed to resolve normally7. Apoptotic macrophages accumulated, phagocytosis was impaired, and IL-23 production was reduced inMuc5b−/− mice. By contrast, in Muc5b transgenic (Tg) mice, macrophage functions improved. Existing dogma defines mucous phenotypes in asthma and chronic obstructive pulmonary disease (COPD) as driven by increased MUC5AC, with MUC5B levels either unaffected or increased in expectorated sputum1,8. However, in many patients, MUC5B production at airway surfaces decreases by as much as 90%9-11. By distinguishing a specific role for Muc5b in MCC, and by determining its impact on bacterial infections and inflammation in mice, our results provide a refined framework for designing targeted therapies to control mucin secretion and restore MCC.

Objective The debilitating and persistent effects of intensive care unit (ICU)-acquired delirium and weakness warrant testing of prevention strategies. The purpose of this study was to evaluate the effectiveness and safety of implementing the Awakening and Breathing Coordination, Delirium monitoring/management, and Early exercise/mobility (ABCDE) bundle into everyday practice. Design Eighteen-month, prospective, cohort, before-after study conducted between November 2010 and May 2012. Setting Five adult ICUs, one step-down unit, and one oncology/hematology special care unit located in a 624-bed tertiary medical center. Patients Two hundred ninety-six patients (146 pre- and 150 post-bundle implementation), age ≥ 19 years, managed by the institutions’ medical or surgical critical care service. Interventions ABCDE bundle. Measurements For mechanically ventilated patients (n = 187), we examined the association between bundle implementation and ventilator-free days. For all patients, we used regression models to quantify the relationship between ABCDE bundle implementation and the prevalence/duration of delirium and coma, early mobilization, mortality, time to discharge, and change in residence. Safety outcomes and bundle adherence were monitored. Main Results Patients in the post-implementation period spent three more days breathing without mechanical assistance than did those in the pre-implementation period (median [IQR], 24 [7 to 26] vs. 21 [0 to 25]; p = 0.04). After adjusting for age, sex, severity of illness, comorbidity, and mechanical ventilation status, patients managed with the ABCDE bundle experienced a near halving of the odds of delirium (odds ratio [OR], 0.55; 95% confidence interval [CI], 0.33–0.93; p = 0.03) and increased odds of mobilizing out of bed at least once during an ICU stay (OR, 2.11; 95% CI, 1.29–3.45; p = 0.003). No significant differences were noted in self-extubation or reintubation rates. Conclusions Critically ill patients managed with the ABCDE bundle spent three more days breathing without assistance, experienced less delirium, and were more likely to be mobilized during their ICU stay than patients treated with usual care.

Animal models to study these mechanisms are limited. This study investigated the effects of single vs. repetitive dust-induced airway inflammation in mice by intranasal exposure method. Mice were exposed to swine facility dust extract (DE) or saline once and once daily for 1 and 2 wk. Dust exposure resulted in increased bronchoalveolar lavage fluid neutrophils and macrophages after single and repetitive exposures. Lavage fluid TNF␣, IL-6, keratinocyte chemoattractant, and macrophage inflammatory protein-2 were significantly increased after single and repetitive dust exposures, but were dampened in 2-wk dust-exposed mice compared with single exposure. Dust exposure induced PKC␣ and -ε activation in isolated tracheal epithelial cells but were dampened with repetitive exposures. Ex vivo stimulation of alveolar macrophages from 2-wk animals demonstrated reduced cytokine responsiveness and phagocytic ability. Significant lung pathology occurred with development of mixed mononuclear cellular aggregates (T and B lymphocytes, phagocytes) after repetitive dust exposure, a novel observation. Airway hyperresponsiveness to methacholine occurred after single dust exposure but resolved after 2 wk. Collectively, intranasal exposure to DE results in significant lung inflammatory and pathological responses marked by a modulated innate immune response to single and repetitive dust exposures that is associated with PKC activity.

SummaryWe hypothesized that a high-speed all-digital video imaging system, with computerized analysis, would precisely capture and measure ciliary beat frequency (CBF) and would shorten the time from data capture to data analysis. We compared a conventional analog video system with a new high-speed digital system we developed for CBF analysis. Using ciliated primary bovine bronchial epithelial cells we made simultaneous analog and digital CBF measurements of the same region of interest (ROI) while temperature was varied. This yielded nearly identical data over a wide range of frequencies (7-15 Hz) using either system. Unlike the digital system however, the analog system did not accurately detect CBF above 15 Hz (temperatures higher than 30 ° C). We also compared ROI analysis with a new analysis algorithm we have named wholefield analysis (WFA). WFA measurement of CBF agreed with ROI and reduced operator time required to analyse data by more than 90% compared with the analog system. We conclude that all-digital computerized CBF analysis correlates closely with standard video methods, markedly speeds up data analysis and provides new ways, including WFA, to analyse entire fields of motile cilia simultaneously. We have termed this system 'Sisson-Ammons Video Analysis' (SAVA).