Background Cigarette smoke-induced chronic obstructive pulmonary disease (COPD) is a life-threatening inflammatory disorder of the lung. The development of effective therapies for COPD has been hampered by the lack of an animal model that mimics the human disease in a short time-frame. Objectives To create an early onset mouse model of cigarette smoke-induced COPD that develops the hallmark features of the human condition in a short time-frame. To use this model to better understand pathogenesis and the roles of macrophages and mast cells (MCs) in COPD. Methods Tightly controlled amounts of cigarette smoke were delivered to the airways of mice, and the development of the pathological features of COPD was assessed. The roles of macrophages and MC tryptase in pathogenesis were evaluated using depletion and in vitro studies and MC protease-6 deficient mice. Results After just 8 weeks of smoke exposure, wild-type mice developed chronic inflammation, mucus hypersecretion, airway remodeling, emphysema, and reduced lung function. These characteristic features of COPD were glucocorticoid-resistant and did not spontaneously resolve. Systemic effects on skeletal muscle and the heart, and increased susceptibility to respiratory infections also were observed. Macrophages and tryptase-expressing MCs were required for the development of COPD. Recombinant MC tryptase induced pro-inflammatory responses from cultured macrophages. Conclusion A short-term mouse model of cigarette smoke-induced COPD was developed in which the characteristic features of the disease were induced more rapidly than existing models. The model can be used to better understand COPD pathogenesis, and we show a requirement for macrophages and tryptase-expressing MCs.

Recent advances in the field mark a point where animal models recapitulate the pathologies of COPD patients in a short time frame. They also reveal novel insights into the pathogenesis and potential treatment of this debilitating disease.

Exposure to particulate matter (PM), a major component of air pollution, contributes to increased morbidity and mortality worldwide. PM induces innate immune responses and contributes to allergic sensitization, although the mechanisms governing this process remain unclear. Lung mucosal uric acid has also been linked to allergic sensitization. The links among PM exposure, uric acid, and allergic sensitization remain unexplored. We therefore investigated the mechanisms behind PM-induced allergic sensitization in the context of lung mucosal uric acid. PM10 and house dust mite exposure selectively induced lung mucosal uric acid production and secretion in vivo, which did not occur with other challenges (lipopolysaccharide, virus, bacteria, or inflammatory/fibrotic stimuli). PM10-induced uric acid mediates allergic sensitization and augments antigen-specific T-cell proliferation, which is inhibited by uricase. We then demonstrate that human airway epithelial cells secrete uric acid basally and after stimulation through a previously unidentified mucosal secretion system. Our work discovers a previously unknown mechanism of air pollution-induced, uric acid-mediated, allergic sensitization that may be important in the pathogenesis of asthma.

Background: Abnormal wound repair is implicated in asthma pathogenesis. The nose is the point of first contact with the environment, yet wound repair ability of the nasal epithelium has received little attention. We sought to determine the impact of atopy and asthma on wound healing of nasal epithelium. Methods: Primary nasal epithelial cells harvested from adult volunteers classified into mutually exclusive groups [healthy (H), atopic non-asthmatic (ANA), non-atopic asthmatic (NAA) and atopic asthmatic (AA)] were grown into well-differentiated epithelium at the air-liquid interface. The ability of the epithelium to heal a mechanical wound was determined under various conditions. Results: Wound healing rate (%/hour) was slowest in ANA (2.9±1.8, vs 4.3±1.9 in H, p=0.02). Healing rates of AA (3.8±1.0) and NAA (4.1±1.1) were not different from H. Exogenous IL-13 slowed healing (2.2±1.1 vs 4.0±1.3, p<0.002) across all subject groups (p<0.001). However, blocking endogenous IL-13 had no effect on wound healing (p=0.68). Blocking endogenous EGF markedly slowed wound healing (0.6±0.4 vs 4.1±1.9, p=0.006), whereas adding exogenous EGF had no effect (p=0.58). Wound healing was significantly faster (4.4±1.0 vs 3.4±0.9, p=0.013) in subjects (6 AA, 9 NAA) who took regular inhaled corticosteroids prior to cell harvesting. Infecting epithelial cultures with RSV 6 days prior to wounding slowed healing in all groups (p<0.001). Prior inhaled steroids also improved wound healing following RSV infection (P<0.001). Conclusion: Nasal epithelium from atopic adults heal wounds more slowly. Inhaled corticosteroids taken in vivo prior to harvest influence their responses in vitro, improving wound healing.

Frailty as a clinical syndrome is becoming more widely recognized and current evidence shows the importance of early detection of pre-frail states with a potential for reversibility of poor outcomes. The purpose of this review is to present the latest literature on frailty since the last review in this journal in 2007, with a particular focus on interventions aimed at reversing the processes of frailty.