Endoplasmic Reticulum - Mitochondrial Interactions in House Dust Mite Induced Inflammation

Rationale: Airway epithelial cells (AECs) are critical regulators of inflammatory, immune and injury responses to allergens that contribute to asthma pathogenesis. The response of AECs to allergens requires an integrated-complex, extracellular receptors and intracellular organelle interaction to achieve secretion of pro-inflammatory cytokines and chemokines. Endoplasmic reticulum (ER) and mitochondria interactions have previously been shown to induce mitochondrial fission. Mitochondrial fission may be a key parameter allergen induced airway inflammation in asthma. However, ER-mitochondria interactions, mitochondrial fission, and subsequent production and secretion of cytokines and chemokines in response to House Dust Mite (HDM) are not well understood. Objective: Here we will assess the ability of HDM to induce ER-mitochondrial interactions and subsequent mitochondrial fission in human bronchiolar epithelial (HBE) cells. We will also investigate the impact on cytokine production downstream of mitochondrial fission in HBE cells treated with HDM. Methods: ER-mitochondrial interactions were quantified using confocal and epifluorescence microscopy. Cytokine/chemokine profiles were determined by enzyme linked immunosorbant assay (ELISA) using HBE cells treated with HDM. Measurements and Main Results: Using epifluorescence and confocal microscopy we show that ER-mitochondrial contacts are increased in response to HDM treatment, as well as HDM-induced mitochondrial fission increased in HBE cells. Inhibition of DRP1, a protein essential for mitochondrial fission, decreases HDM induced ER-mitochondrial interaction. In addition, HDM-induced pro-inflammatory cytokines were decreased in HBE cells where mitochondrial fission is inhibited. Conclusion: HDM induces ER-Mitochondrial interactions that promote mitochondrial fission and subsequent production of pro-inflammatory cytokines

How should we use the coronary artery calcium score to predict cardiovascular risk?

The coronary artery calcium (CAC) score--an independent predictor of cardiovascular events (strength of recommendation [SOR]: C, systematic review of disease-oriented outcomes)--can be used, in addition to traditional risk factor assessment, to further stratify the risk of coronary heart disease (CHD) in asymptomatic patients (SOR: C, multiple large observational studies with disease-oriented outcomes). Although a high CAC score is associated with a greater risk of cardiovascular disease, no studies have evaluated cardiovascular outcomes of CAC-guided treatment, so its value remains theoretical

Upper Esophageal Sphincter Compression Device as an Adjunct to Proton Pump Inhibition for Laryngopharyngeal Reflux.

BackgroundThe Reflux Band, an external upper esophageal sphincter (UES) compression device, reduces esophago-pharyngeal reflux events. This study aimed to assess device efficacy as an adjunct to proton pump inhibitor (PPI) therapy in patients with laryngopharyngeal reflux (LPR).MethodsThis two-phase prospective clinical trial enrolled adults with at least 8 weeks of laryngeal symptoms (sore throat, throat clearing, dysphonia) not using PPI therapy at two tertiary care centers over 26 months. Participants used double dose PPI for 4 weeks in Phase 1 and the external UES compression device nightly along with PPI for 4 weeks in Phase 2. Questionnaire scores and salivary pepsin concentration were measured throughout the study. The primary endpoint of symptom response was defined as reflux symptom index (RSI) score ≤ 13 and/or > 50% reduction in RSI.ResultsThirty-one participants completed the study: 52% male, mean age 47.9 years (SD 14.0), and mean body mass index (BMI) 26.2 kg/m2 (5.1). Primary endpoint was met in 11 (35%) participants after Phase 1 (PPI alone) and 17 (55%) after Phase 2 (Device + PPI). Compared to baseline, mean RSI score (24.1 (10.9)) decreased at end of Phase 1 (PPI alone) (21.9 (9.7); p = 0.06) and significantly decreased at end of Phase 2 (Device + PPI) (15.5 (10.3); p < 0.01). Compared to non-responders, responders to Device + PPI had a significantly lower BMI (p = 0.02) and higher salivary pepsin concentration (p = 0.01).ConclusionThis clinical trial highlights the potential efficacy of the external UES compression device (Reflux Band) as an adjunct to PPI for patients with LPR (ClinicalTrials.Gov NCT03619811)

Protein disulfide isomerase–endoplasmic reticulum resident protein 57 regulates allergen-induced airways inflammation, fibrosis, and hyperresponsiveness

BackgroundEvidence for association between asthma and the unfolded protein response is emerging. Endoplasmic reticulum resident protein 57 (ERp57) is an endoplasmic reticulum-localized redox chaperone involved in folding and secretion of glycoproteins. We have previously demonstrated that ERp57 is upregulated in allergen-challenged human and murine lung epithelial cells. However, the role of ERp57 in asthma pathophysiology is unknown.ObjectivesHere we sought to examine the contribution of airway epithelium-specific ERp57 in the pathogenesis of allergic asthma.MethodsWe examined the expression of ERp57 in human asthmatic airway epithelium and used murine models of allergic asthma to evaluate the relevance of epithelium-specific ERp57.ResultsLung biopsy specimens from asthmatic and nonasthmatic patients revealed a predominant increase in ERp57 levels in epithelium of asthmatic patients. Deletion of ERp57 resulted in a significant decrease in inflammatory cell counts and airways resistance in a murine model of allergic asthma. Furthermore, we observed that disulfide bridges in eotaxin, epidermal growth factor, and periostin were also decreased in the lungs of house dust mite-challenged ERp57-deleted mice. Fibrotic markers, such as collagen and α smooth muscle actin, were also significantly decreased in the lungs of ERp57-deleted mice. Furthermore, adaptive immune responses were dispensable for house dust mite-induced endoplasmic reticulum stress and airways fibrosis.ConclusionsHere we show that ERp57 levels are increased in the airway epithelium of asthmatic patients and in mice with allergic airways disease. The ERp57 level increase is associated with redox modification of proinflammatory, apoptotic, and fibrotic mediators and contributes to airways hyperresponsiveness. The strategies to inhibit ERp57 specifically within the airways epithelium might provide an opportunity to alleviate the allergic asthma phenotype

Protein disulfide isomerase–endoplasmic reticulum resident protein 57 regulates allergen-induced airways inflammation, fibrosis, and hyperresponsiveness

BackgroundEvidence for association between asthma and the unfolded protein response is emerging. Endoplasmic reticulum resident protein 57 (ERp57) is an endoplasmic reticulum-localized redox chaperone involved in folding and secretion of glycoproteins. We have previously demonstrated that ERp57 is upregulated in allergen-challenged human and murine lung epithelial cells. However, the role of ERp57 in asthma pathophysiology is unknown.ObjectivesHere we sought to examine the contribution of airway epithelium-specific ERp57 in the pathogenesis of allergic asthma.MethodsWe examined the expression of ERp57 in human asthmatic airway epithelium and used murine models of allergic asthma to evaluate the relevance of epithelium-specific ERp57.ResultsLung biopsy specimens from asthmatic and nonasthmatic patients revealed a predominant increase in ERp57 levels in epithelium of asthmatic patients. Deletion of ERp57 resulted in a significant decrease in inflammatory cell counts and airways resistance in a murine model of allergic asthma. Furthermore, we observed that disulfide bridges in eotaxin, epidermal growth factor, and periostin were also decreased in the lungs of house dust mite-challenged ERp57-deleted mice. Fibrotic markers, such as collagen and α smooth muscle actin, were also significantly decreased in the lungs of ERp57-deleted mice. Furthermore, adaptive immune responses were dispensable for house dust mite-induced endoplasmic reticulum stress and airways fibrosis.ConclusionsHere we show that ERp57 levels are increased in the airway epithelium of asthmatic patients and in mice with allergic airways disease. The ERp57 level increase is associated with redox modification of proinflammatory, apoptotic, and fibrotic mediators and contributes to airways hyperresponsiveness. The strategies to inhibit ERp57 specifically within the airways epithelium might provide an opportunity to alleviate the allergic asthma phenotype

Advancing patient care through the Consortium of Eosinophilic Gastrointestinal Disease Researchers (CEGIR)

Recent advances in rare disease research are accelerated by the work of consortia that have been supported by the National Institutes of Health. Development of such consortia rely on multidisciplinary relationships and engagement with patient advocacy groups, as well as the National Institutes of Health and industry and academic partners. In this rostrum we present the development of such a process that focuses on eosinophilic gastrointestinal diseases. Principal investigators, patient advocacy groups, research assistants, and trainees work together to perform natural history studies that promote clinical trial readiness tools, conduct clinical trials, train a new generation of investigators, and perform innovative pilot studies