David R. Curran

Advances in Mucous Cell Metaplasia: A Plug for Mucus as a Therapeutic Focus in Chronic Airway Disease

Mucous cell metaplasia is induced in response to harmful insults and provides front-line protection to clear the airway of toxic substances and cellular debris. In chronic airway diseases mucous metaplasia persists and results in airway obstruction and contributes significantly to morbidity and mortality. Mucus hypersecretion involves increased expression of mucin genes, and increased mucin production and release. The past decade has seen significant advances in our understanding of the molecular mechanisms by which these events occur. Inflammation stimulates epidermal growth factor receptor activation and IL-13 to induce both Clara and ciliated cells to transition into goblet cells through the coordinated actions of FoxA2, TTF-1, SPDEF, and GABA(A)R. Ultimately, these steps lead to up-regulation of MUC5AC expression, and increased mucin in goblet cell granules that fuse to the plasma membrane through actions of MARCKS, SNAREs, and Munc proteins. Blockade of mucus in exacerbations of asthma and chronic obstructive pulmonary disease may affect morbidity. Development of new therapies to target mucus production and secretion are now possible given the advances in our understanding of molecular mechanisms of mucous metaplasia. We now have a greater incentive to focus on inhibition of mucus as a therapy for chronic airway diseases.

Short Palate, Lung, and Nasal Epithelial Clone–1 Is a Tightly Regulated Airway Sensor in Innate and Adaptive Immunity

Short palate, lung, and nasal epithelial clone-1 (SPLUNC1) is a protein abundantly expressed by the respiratory epithelium of the proximal lower respiratory tract, a site of great environmental exposure. Previous studies showed that SPLUNC1 exerts antimicrobial effects, regulates airway surface liquid and mucociliary clearance, and suppresses allergic airway inflammation. We studied SPLUNC1 to gain insights into its role in host defense. In the lower respiratory tract, concentrations of SPLUNC1 are high under basal conditions. In models of pneumonia caused by common respiratory pathogens, and in Th1-induced and Th2-induced airway inflammation, SPLUNC1 secretion is markedly reduced. Pathogen-associated molecular patterns and IFN-γ act directly on airway epithelial cells to inhibit SPLUNC1 mRNA expression. Thus, SPLUNC1 is quickly suppressed during infection, in response to an insult on the epithelial surface. These experiments highlight the finely tuned fluctuations of SPLUNC1 in response to exposures in the respiratory tract, and suggest that the loss of SPLUNC1 is a crucial feature of host defense across air-breathing animal species.

Rare causes of persistent wheeze that mimic poorly controlled asthma

Upper airway obstruction can present with stridor or expiratory or inspiratory wheeze and is commonly misdiagnosed as asthma. As asthma is common, such cases can remain hidden among patients with lower airway obstruction who attend primary care or respiratory clinics. We describe four causes of upper airway obstruction (paradoxical vocal cord movement, subglottic stenosis, retrosternal goitre and double aortic arch) which were misdiagnosed as ‘poorly controlled asthma’.

Positional therapy may be a cheap and effective alternative to continuous positive airway pressure in positional obstructive sleep apnoea

The role of sleep position in Obstructive Sleep Apnoea (OSA) is well recognised. The Amsterdam Positional OSA Classification (APOC) has been recently published1 and, with the development of improved positional therapy (PT) devices2, the use of PT is likely to increase. We performed a retrospective review of PT in a tertiary referral centre. Patients referred for PT from September 2011 to January 2015 were reviewed. Compliance with therapy was assessed. Apnoea hypopnoea index pre-treatment and on PT were compared, as were Epworth Sleepiness Score (ESS) and supine time. Statistical analysis was performed using the paired t-test in SPSS. Of 93 patients referred for PT, 58.89% were compliant with therapy. 77.4% of these had a follow-up limited multi-channel sleep study. The mean AHI was reduced from 14.21/hr (12.09 – 16.34) to 4.54/hr (3.61 – 5.48), p<0.0001. There was a statistically significant improvement in ESS and supine sleep time. Data regarding outcomes of PT is limited. Newly developed devices may improve compliance. Prospective studies looking at long-term outcomes are warranted. Our data indicate that positional therapy can play a significant role in the management of positional OSA. 1. Frank MH, Ravesloot MJL, van Maanen, Verhagen E, de Lange J, de Vries N. Positional OSA part 1: towards a clinical classification system for position-dependent obstructive sleep apnoea. Sleep Breath 2014 Jun 19. [Epub ahead of print]. 2. Oksenberg, A. and Gadoth, N. (2014), Are we missing a simple treatment for most adult sleep apnea patients? The avoidance of the supine sleep position. Journal of Sleep Research, 23: 204–210.