Eosinophil peroxidase activates cells by HER2 receptor engagement and ß1-integrin clustering with downstream MAPK cell signaling.

Eosinophils account for 1-3% of peripheral blood leukocytes and accumulate at sites of allergic inflammation, where they play a pathogenic role. Studies have shown that treatment with mepolizumab (an anti-IL-5 monoclonal antibody) is beneficial to patients with severe eosinophilic asthma, however, the mechanism of precisely how eosinophils mediate these pathogenic effects is uncertain. Eosinophils contain several cationic granule proteins, including Eosinophil Peroxidase (EPO). The main significance of this work is the discovery of EPO as a novel ligand for the HER2 receptor. Following HER2 activation, EPO induces activation of FAK and subsequent activation of ß1-integrin, via inside-out signaling. This complex results in downstream activation of ERK1/2 and a sustained up regulation of both MUC4 and the HER2 receptor. These data identify a receptor for one of the eosinophil granule proteins and demonstrate a potential explanation of the proliferative effects of eosinophils.

SMAD Signaling in the Airways of Healthy Rhesus Macaques versus Rhesus Macaques with Asthma Highlights a Relationship Between Inflammation and Bone Morphogenetic Proteins.

Bone morphogenetic protein (BMP) signaling is important for correct lung morphogenesis, and there is evidence of BMP signaling reactivation in lung diseases. However, little is known about BMP signaling patterns in healthy airway homeostasis and inflammatory airway disease and during epithelial repair. In this study, a rhesus macaque (Macaca mulatta) model of allergic airway disease was used to investigate BMP signaling throughout the airways in health, disease, and regeneration. Stereologic quantification of immunofluorescent images was used to determine the expression of BMP receptor (BMPR) Ia and phosphorylated SMAD (pSMAD) 1/5/8 in the airway epithelium. A pSMAD 1/5/8 expression gradient was found along the airways of healthy juvenile rhesus macaques (n = 3, P < 0.005). Membrane-localized BMPRIa expression was also present in the epithelium of the healthy animals. After exposure to house dust mite allergen and ozone, significant down-regulation of nuclear pSMAD 1/5/8 occurs in the epithelium. When the animals were provided with a recovery period in filtered air, proliferating cell nuclear antigen, pSMAD 1/5/8, and membrane-localized BMPRIa expression were significantly increased in the epithelium of conducting airways (P < 0.005). Furthermore, in the asthmatic airways, altered BMPRIa localization was evident. Because of the elevated eosinophil presence in these airways, we investigated the effect of eosinophil-derived proteins on BMPRIa trafficking in epithelial cells. Eosinophil-derived proteins (eosinophil-derived neurotoxin, eosinophil peroxidase, and major basic protein) induced transient nuclear translocation of membrane-bound BMPRIa. This work mapping SMAD signaling in the airways of nonhuman primates highlights a potential mechanistic relationship between inflammatory mediators and BMP signaling and provides evidence that basal expression of the BMP signaling pathway may be important for maintaining healthy airways.

A method to assess adherence in inhaler use through analysis of acoustic recordings of inhaler events.

RATIONALE: Poor adherence to inhaler use can be due to poor temporal and/or technique adherence. Up until now there has been no way of reliably tracking both these factors in everyday inhaler use. OBJECTIVES: This paper introduces a device developed to create time stamped acoustic recordings of an individual's inhaler use, in which empirical evidence of temporal and technique adherence in inhaler use can be monitored over time. The correlation between clinical outcomes and adherence, as determined by this device, was compared for temporal adherence alone and combined temporal and technique adherence. FINDINGS: The technology was validated by showing that the doses taken matched the number of audio recordings (r2 = 0.94, p<0.01). To demonstrate that audio analysis of inhaler use gives objective information, in vitro studies were performed. These showed that acoustic profiles of inhalations correlated with the peak inspiratory flow rate (r2 = 0.97, p<0.01), and that the acoustic energy of exhalations into the inhaler was related to the amount of drug removed. Despite training, 16% of participants exhaled into the mouthpiece after priming, in >20% of their inhaler events. Repeated training reduced this to 7% of participants (p = 0.03). When time of use was considered, there was no evidence of a relationship between adherence and changes in AQLQ (r2 = 0.2) or PEFR (r2 = 0.2). Combining time and technique the rate of adherence was related to changes in AQLQ (r2 = 0.53, p = 0.01) and PEFR (r2 = 0.29, p = 0.01). CONCLUSIONS: This study presents a novel method to objectively assess how errors in both time and technique of inhaler use impact on clinical outcomes. TRIAL REGISTRATION: EudraCT 2011-004149-42.

The role of nasal CPAP in obstructive sleep apnoea syndrome due to mandibular hypoplasia.

Melnick Needles syndrome (MNS), Treacher Collins syndrome (TCS) and Pierre Robin syndrome (PRS) are congenital abnormalities with characteristic facial appearances that include micrognathia. A 20-year-old girl with MNS, a 16-year-old boy with TCS and a 12-year-old girl with PRS attended the sleep apnoea clinic at our institution at different times. Diagnostic sleep studies were initially performed on all three patients to confirm the diagnosis of obstructive sleep apnoea syndrome (OSAS). They subsequently commenced nasal CPAP (nCPAP) treatment and their progress was followed. A limited sleep study on the patient with MNS demonstrated moderate/severe OSAS with an AHI of 33 events/h. Commencement of nCPAP resulted in symptomatic improvement. Overnight oximetry in the patient with TCS showed repeated desaturation to SpO2<90%. Subsequent treatment by nCPAP almost completely abolished the desaturation events. Overnight polysomnography in the patient with PRS demonstrated severe OSAS with an AHI of 49 events/h. After 3 years of nCPAP therapy, this patient requested discontinuation of treatment. Subsequent polysomnography without nCPAP revealed an AHI of <5 events/h. The use of nCPAP in the patients with MNS and TCS resulted in effective control of their sleep abnormalities. Mandibular growth and enlargement of the posterior airway space led to resolution of OSAS in the patient with PRS. There is a definite role for nCPAP therapy in patients with congenital micrognathia and OSAS. The use of nCPAP may obviate the need for more invasive corrective surgery for OSAS and is not necessarily a life-long requirement.