Download the Free Unbound MEDLINE PubMed App to your smartphone or tablet.
Available for iPhone, iPad, iPod touch, and Android.
- The orl rat is more responsive to methacholine challenge than wild type. [JOURNAL ARTICLE]
- Pulm Pharmacol Ther 2014 Sep 10.
This study presents an animal model of native airway hyperresponsiveness (AHR). AHR is a fundamental aspect of asthma and reflects an abnormal response characterized by airway narrowing following exposure to a wide variety of non-immunological stimuli. Undescended testis (UDT) is one of the most common male congenital anomalies. The orl rat is a Long Evans substrain with inherited UDT. Since boys born with congenital UDT are more likely to manifest asthma symptoms, the main aim in this study was to investigate the alternative hypothesis that orl rats have greater AHR to a methacholine aerosol challenge than wild type rats.Long Evans wild type (n=9) and orl (n=13) rats were anesthetized, tracheostomized, and mechanically ventilated at 4 weeks of age. Escalating concentrations of inhaled methacholine were delivered. The methacholine potency and efficacy in the strains were measured. Respiratory resistance was the primary endpoint. After the final methacholine aerosol challenge, the short-acting β2-adrenoceptor agonist albuterol was administered as an aerosol and lung/diaphragm tissues were assayed for interleukin (IL)-4, IL-6, and tumor necrosis factor (TNF)-α. Histological and histomorphometrical analyses were performed.The methacholine concentration-response curve in the orl group indicated increased sensitivity, hyperreactivity, and exaggerated maximal response in comparison with the wild type group, indicating that orl rats had abnormally greater AHR responses to methacholine. Histological findings in orl rats showed the presence of eosinophils, unlike wild type rats. β2-adrenoceptor agonist intervention resulted in up-regulation of IL-4 diaphragmatic levels and down-regulation of IL-4 and IL-6 in the lungs of orl rats.orl rats had greater AHR than wild type rats during methacholine challenge, with higher IL-4 levels in diaphragmatic tissue homogenates. Positive immunostaining for IL-4 was detected in lung and diaphragmatic tissue in both strains. This model offers advantages over other pre-clinical murine models for studying potential mechanistic links between cryptorchidism and asthma. This animal model may be useful for further testing of compounds/therapeutics options for treating AHR.
- Mechanisms of glucocorticoid action and insensitivity in airways disease. [JOURNAL ARTICLE]
- Pulm Pharmacol Ther 2014 Sep 9.
Glucocorticoids are the mainstay for the treatment of chronic inflammatory diseases including asthma and chronic obstructive pulmonary disease (COPD). However, it has been recognized that glucocorticoids do not work well in certain patient populations suggesting reduced sensitivity. The ultimate biologic responses to glucocorticoids are determined by not only the concentration of glucocorticoids but also the differences between individuals in glucocorticoid sensitivity, which is influenced by multiple factors. Studies are emerging to understand these mechanisms in detail, which would help in increasing glucocorticoid sensitivity in patients with chronic airways disease. This review aims to highlight both classical and emerging concepts of the anti-inflammatory mechanisms of glucocorticoids and also review some novel strategies to overcome steroid insensitivity in airways disease.
- Herpes zoster is associated with herpes simplex and other infections in under 60 year-olds. [JOURNAL ARTICLE]
- J Infect 2014 Sep 8.
We assessed the association between herpes zoster (HZ) and herpes simplex (HS) occurrence whilst controlling for risk factors of HZ.Using a Belgian general practitioner network, a retrospective cohort study with 3736 HZ patients and 14076 age-gender-practice matched controls was performed, covering over 1.5 million patient-years. Multiple logistic regression was used with HZ as outcome and several diagnoses (malignancy, depression, diabetes mellitus, auto-immune diseases, asthma, multiple sclerosis, HIV, fractures), medications (systemic corticosteroids, biologicals, vaccination), HS and other infections as variables.HS was significantly associated with HZ for all analysed time intervals (up to five years) post HZ (OR of 3.51 [2.09 5.88] 95%CI one year post HZ) and to a lesser extent for time ranges pre HZ. Registration of other infections was significantly associated with HZ in all time intervals pre and post HZ (OR up to 1.37). Malignancy up to five years pre HZ, depression up to one year pre or post HZ, fractures up to two year pre HZ, asthma, auto-immune diseases, and immunosuppressive medication one year pre or post HZ were also associated with HZ.HZ and HS occurrences are significantly associated and potentially share a common susceptibility beyond the known risk factors.
- Inhaled corticosteroid beliefs, complementary and alternative medicine, and uncontrolled asthma in urban minority adults. [JOURNAL ARTICLE]
- J Allergy Clin Immunol 2014 Sep 10.
Many factors contribute to uncontrolled asthma; negative inhaled corticosteroid (ICS) beliefs and complementary and alternative medicine (CAM) endorsement are 2 that are more prevalent in black compared with white adults.This mixed-methods study (1) developed and psychometrically tested a brief self-administered tool with low literacy demands to identify negative ICS beliefs and CAM endorsement and (2) evaluated the clinical utility of the tool as a communication prompt in primary care.Comprehensive literature reviews and content experts identified candidate items for our instrument that were distributed to 304 subjects for psychometric testing. In the second phase content analysis of 33 audio-recorded primary care visits provided a preliminary evaluation of the instrument's clinical utility.Psychometric testing of the instrument identified 17 items representing ICS beliefs (α = .59) and CAM endorsement (α = .68). Test-retest analysis demonstrated a high level of reliability (intraclass correlation coefficient = 0.77 for CAM items and 0.79 for ICS items). We found high rates of CAM endorsement (93%), negative ICS beliefs (68%), and uncontrolled asthma (69%). CAM endorsement was significantly associated with uncontrolled asthma (P = .04). Qualitative data analysis provided preliminary evidence for the instrument's clinical utility in that knowledge of ICS beliefs and CAM endorsement prompted providers to initiate discussions with patients.Negative ICS beliefs and CAM endorsement were common and associated with uncontrolled asthma. A brief self-administered instrument that identifies beliefs and behaviors that likely undermine ICS adherence might be a leveraging tool to change the content of communications during clinic visits.
- Prostaglandin D2: A dominant mediator of aspirin-exacerbated respiratory disease. [JOURNAL ARTICLE]
- J Allergy Clin Immunol 2014 Sep 10.
Aspirin desensitization followed by high-dose aspirin therapy is routinely performed for patients with aspirin-exacerbated respiratory disease (AERD). Little is known about the contributions of mediators other than cysteinyl leukotrienes to aspirin reactions and to the therapeutic benefit of high-dose aspirin therapy.We investigated differences in urinary eicosanoid metabolite levels and blood eosinophil counts in patients with AERD who tolerate and those who fail aspirin desensitization and also in patients with AERD who were successfully treated with high-dose aspirin therapy.Twenty-nine patients with AERD were stratified into those who tolerated aspirin desensitization (group I) and those who did not (group II). Urine was analyzed for eicosanoid metabolites at baseline, during aspirin reactions, and during high-dose aspirin therapy. Blood was analyzed for cell differentials at baseline and during aspirin therapy.Basal prostaglandin D2 metabolite (PGD-M; 13.6 ± 2.7 vs 7.0 ± 0.8 pmol/mg creatinine [Cr], P < .05) and thromboxane metabolite (TX-M; 1.4 ± 0.3 vs 0.9 ± 0.1 pmol/mg Cr, P < .01) levels were higher in group II than in group I. During aspirin reactions, PGD-M levels remained unchanged, whereas TX-M levels (0.7 ± 0.1 pmol/mg Cr, P = .07) tended to decrease in group I. In contrast, PGD-M levels increased dramatically in group II (61.3 ± 19.9 pmol/mg Cr, P < .05), whereas TX-M levels did not change. The decrease in FEV1 inversely correlated with basal urinary levels of both leukotriene E4 and PGD-M. Blood eosinophil and basophil levels increased and urinary PGD-M levels (2.2 ± 0.8 pmol/mg Cr, P < .001) decreased on 2 months of high-dose aspirin therapy in group I.Failure to tolerate aspirin desensitization in a subset of patients with AERD is associated with prostaglandin D2 overproduction. The increase in blood eosinophil and basophil counts during high-dose aspirin therapy might reflect the functional consequences of decreased prostaglandin D2 release and the therapeutic benefit of aspirin.
- Is it safe to use inhaled corticosteroids in pregnancy? [Journal Article]
- Can Fam Physician 2014 Sep; 60(9):809-12.
A healthy woman with mild to moderate asthma came to my clinic today after learning that she was pregnant. She inquired about continuing her inhaled corticosteroid (ICS) medication and whether there would be any risks to her unborn child if she were to do so. What would you advise?Given the published evidence, ICSs should be continued throughout pregnancy at low to moderate doses sufficient to control asthma symptoms and prevent exacerbations. However, caution must be taken with doses greater than 1000 µg/d (chlorofluorocarbon beclomethasone equivalent), although whether such doses cause adverse effects is currently still questionable. Patient education on proper ICS administration and adherence, including during the first trimester, must be ongoing. Well controlled asthma will reduce the need for higher ICS doses and possible exposure to systemic corticosteroids, and might decrease the risk of adverse pregnancy or perinatal outcomes.
- MicroRNA-146a and microRNA-146b expression and anti-inflammatory function in human airway smooth muscle. [JOURNAL ARTICLE]
- Am J Physiol Lung Cell Mol Physiol 2014 Sep 12.
MicroRNA(miR)-146a and miR-146b are negative regulators of inflammatory gene expression in lung fibroblasts, epithelial cells, monocytes, and endothelial cells. The abundance of cyclooxygenase-2 (COX-2) and IL-1β is negatively regulated by the miR-146 family, suggesting miR-146a and/or miR-146b might modulate inflammatory mediator expression in airway smooth muscle thereby contributing to pathogenesis of asthma. To test this idea we compared miR-146a and miR-146b expression in human airway smooth muscle cells (hASMCs) from non-asthmatic and asthmatic subjects treated with cytomix (IL-1β, TNFα, and IFNγ) and examined the miRNAs' effects on COX-2 and IL-1β expression. We found that cytomix treatment elevated miR-146a and miR-146b abundance, induction with cytomix was greater than induction with individual cytokines, and asthmatic cells exhibited higher levels of miR-146a expression following cytomix treatment than non-asthmatic cells. Transfection of miR-146a or miR-146b mimics reduced COX-2 and IL-1β expression. A miR-146a inhibitor increased COX-2 and IL-1β expression, but a miR-146b inhibitor was ineffective. Repression of COX-2 and IL-1β expression by miR-146a correlated with reduced abundance of the RNA binding protein Human antigen R (HuR). These results demonstrate that miR-146a and miR-146b expression is inducible in hASMCs by proinflammatory cytokines, and that miR-146a expression is greater in asthmatic cells. Both miR-146a and miR-146b can negatively regulate COX-2 and IL-1β expression at pharmacological levels, but loss of function studies showed that only miR-146a is an endogenous negative regulator in hASMCs. The results suggest miR-146 mimics may be an attractive candidate for further preclinical studies as an anti-inflammatory treatment of asthma.
- Chronic exposure to perfluorinated compounds: impact on airway hyperresponsiveness and inflammation. [JOURNAL ARTICLE]
- Am J Physiol Lung Cell Mol Physiol 2014 Sep 12.
Emerging epidemiological evidence reveals a link between lung disease and exposure to indoor pollutants such as perfluorinated compounds (PFCs). PFC exposure during critical developmental stages may increase asthma susceptibility. Thus, in a murine model we tested the hypothesis that early life and continued exposure to two ubiquitous household PFCs, perfluorooctanoic acid (PFOA) and perflurooctanesulfonic acid (PFOS), can induce lung dysfunction that exacerbates allergen-induced airway hyperresponsiveness (AHR) and inflammation. Balb/c mice were exposed to PFOA or PFOS (4 mg/kg chow) from gestation day-2 to 12 weeks of age by feeding pregnant and nursing dams, and weaned pups. Some pups were also sensitized and challenged with ovalbumin (OVA). We assessed lung function, inflammatory cell and cytokine expression in the lung, and examined bronchial goblet cell number. PFOA, but not PFOS, without the OVA sensitization/challenge induced AHR concomitant with a 25-fold increase of lung macrophages. PFOA exposure did not affect OVA-induced lung inflammatory cell number. In contrast, PFOS exposure inhibited OVA-induced lung inflammation, decreasing total cell number in lung lavage by 68.7%. Interferon- γ mRNA in the lung was elevated in all PFC exposed groups. Despite these effects, neither PFOA nor PFOS affected OVA-induced AHR. Our data do not reveal PFOA or PFOS exposure as a risk factor for more severe allergic asthma-like symptoms, but PFOA alone can induce airway inflammation and alter airway function.
- Interferon response and respiratory virus control are preserved in bronchial epithelial cells in asthma. [JOURNAL ARTICLE]
- J Allergy Clin Immunol 2014 Aug 23.
Some investigators find a deficiency in IFN production from airway epithelial cells infected with human rhinovirus in asthma, but whether this abnormality occurs with other respiratory viruses is uncertain.To assess the effect of influenza A virus (IAV) and respiratory syncytial virus (RSV) infection on IFN production and viral level in human bronchial epithelial cells (hBECs) from subjects with and without asthma.Primary-culture hBECs from subjects with mild to severe asthma (n = 11) and controls without asthma (hBECs; n = 7) were infected with live or ultraviolet-inactivated IAV (WS/33 strain), RSV (Long strain), or RSV (A/2001/2-20 strain) with multiplicity of infection 0.01 to 1. Levels of virus along with IFN-β and IFN-λ and IFN-stimulated gene expression (tracked by 2'-5'-oligoadenylate synthetase 1 and myxovirus (influenza virus) resistance 1 mRNA) were determined up to 72 hours postinoculation.After IAV infection, viral levels were increased 2-fold in hBECs from asthmatic subjects compared with nonasthmatic control subjects (P < .05) and this increase occurred in concert with increased IFN-λ1 levels and no significant difference in IFNB1, 2'-5'-oligoadenylate synthetase 1, or myxovirus (influenza virus) resistance 1mRNA levels. After RSV infections, viral levels were not significantly increased in hBECs from asthmatic versus nonasthmatic subjects and the only significant difference between groups was a decrease in IFN-λ levels (P < .05) that correlated with a decrease in viral titer. All these differences were found only at isolated time points and were not sustained throughout the 72-hour infection period.The results indicate that IAV and RSV control and IFN response to these viruses in airway epithelial cells is remarkably similar between subjects with and without asthma.
- Relation between eosinophilic esophagitis and oral immunotherapy for food allergy: a systematic review with meta-analysis. [JOURNAL ARTICLE]
- Ann Allergy Asthma Immunol 2014 Sep 9.
The onset of eosinophilic esophagitis (EoE) after oral immunotherapy (OIT) has been repeatedly described in patients with immunoglobulin E (IgE)-mediated food allergy in recent years, but the relation between the 2 conditions has not been fully assessed and quantified.To provide a systematic review of the evidence for an association between OIT and EoE.Electronic searches were performed with keywords relating to EoE and OIT in the MEDLINE, EMBASE, and SCOPUS databases. Summary estimates were calculated. A fixed-effects model was used depending on heterogeneity (I(2)). Risk of publication bias was assessed by funnel plot analysis and the Egger test.The search yielded 118 documents, 15 of which were included in the quantitative summary. Most reported information came from children undergoing peanut, milk, and egg OIT. Significant publication bias in favor of studies reporting the development of EoE after OIT was documented. The overall prevalence of EoE after OIT was 2.7% (95% confidence interval 1.7%-4.0%, I(2) = 0%). Differences between medium-to high-quality studies and those of low quality were documented (3.5% vs 2.5%, respectively). EoE often resolved after OIT discontinuation; histologic remission of EoE achieved after allergen immunotherapy also was documented in 2 patients whose topical fluticasone treatment failed.New onset of EoE after OIT occurs in up to 2.7% of patients with IgE-mediated food allergy undergoing this treatment strategy. The limited data on the utility of allergen immunotherapy as a therapy for EoE prevent a recommendation for this treatment option.