A novel anti-IL4Rα nanoparticle efficiently controls lung inflammation during asthma

Drug resistance and the harmful side effects accompanying the prolonged corticosteroid treatment of chronic pulmonary diseases prompted the development of more specific anti-inflammatory approaches. Several strategies aiming to block IL4Rα, the receptor for a key pro-inflammatory pathway, were investigated. However, their efficiency was limited, mostly due to the systemic or subcutaneous route of administrations. In this paper, we examined the ability of an intranasal treatment with biocompatible nanoparticles targeting IL4Rα to control lung inflammation in ovalbumin (OVA)-sensitized mice. OVA-sensitized mice were treated with anti-IL4Rα-conjugated nanoparticles. The levels of pro-inflammatory cytokines in the lungs and broncho-alveolar lavage fluid (BALF) were determined using a cytokine array assay. The effects of nanoparticle treatment on the activation of lung inflammatory cells and their ability to proliferate and produce cytokines were determined using fluorescence-activated cell sorting (FACS) analysis. Lung inflammation was also monitored using immunohistochemical staining. Treatment with the anti-IL4Rα nanoparticles significantly decreased pro-inflammatory cytokine expression and release in BALF and airway lung tissue in mice. The numbers of lung tissue lymphocytes, neutrophils and eosinophils were also decreased. Interestingly, anti-IL4Rα nanoparticles deactivated CD4 and CD8 T cells in lung tissue and inhibited their ability to produce pro-inflammatory cytokines to a significantly lower level than the treatment with free anti-IL4Rα. Moreover, they induced a sustained low level of lung inflammation for 1 week following the last instillation compared with the treatment with free anti-IL4Rα antibodies. Together, this data suggested that the enhanced tissue penetrability and sustainability of these nanoparticles improved the strength and durability of the immunosuppressive effects of anti-IL4Rα.

Poor asthma education and medication compliance are associated with increased emergency department visits by asthmatic children

Acute exacerbations of bronchial asthma remain a major cause of frequent Emergency Department [ED] visits by pediatric patients. However, other factors including psychosocial, behavioural and educational, are also reportedly associated with repetitive ED visits. Therefore, it is necessary to determine whether such visits are justifiable. The objective of this cross-sectional study was to identify risk factors associated with visits to ED by asthmatic children. Asthmatic children [n= 297] between 1-17 years old were recruited and information collected at the time of visiting an ED facility at two major hospitals. Asthmatic patients visited the ED 3.9 3.2 times-per-year, on average. Inadequately controlled asthma was perceived in 60.3% of patients. The majority of patients [56.4%] reported not receiving education about asthma. Patients reflected misconceptions about the ED department, including the belief that more effective treatments are available [40.9%], or that the ED staff is better qualified [27.8%]. About half of patients [48.2%] visited the ED because of the convenience of being open 24 hours, or because they are received immediately [38.4%]. Uncontrolled asthma was associated with poor education about asthma and/or medication use. Patients educated about asthma, were less likely to stop corticosteroid therapy when their symptoms get better [OR:0.55; 95% CI:0.3-0.9;P= 0.04]. This study reports that most patients had poor knowledge about asthma and were using medications improperly, thus suggesting inefficient application of management action plan. Unnecessary and frequent visits to the ED for asthma care was associated with poor education about asthma and medication use. Potential deficiencies of the health system at directing patients to the proper medical facility were uncovered and underline the necessity to improve education about the disease and medication compliance of patients and their parents/guardians

IL-4 receptor alpha single-nucleotide polymorphisms rs1805010 and rs1801275 are associated with increased risk of asthma in a Saudi Arabian population

The IL-4 receptor alpha subunit [IL-4Ralpha], when associated with the common gamma chain receptor, or the IL-13Ralpha1 subunit, transduces signals to STAT6 in response to IL-4 and IL-13 stimulations. This results in a number of cell-specific responses including Th2 differentiation, lymphocyte proliferation and IgE production. Given the prominent role of IL-4Ralpha in allergic disorders, several single-nucleotide polymorphisms [SNPs] have been found associated with asthma and other atopic disorders, including rs1805010 [I75V] and rs1801275 [Q576R] SNPs; however, lack of significant association have also been reported for some ethnic groups. The objective of this study was to determine whether IL-4Ralpha rs1805010 and rs1801275 polymorphisms are associated with asthma in patients from Saudi Arabia. One hundred and ninety severe asthmatic patients [11-70 years old] and 194 healthy subjects of equivalent age range were recruited for blood donation. DNA was purified and genotyping for rs1801275 and rs1805010 polymorphisms in the IL-4Ralpha gene was performed by PCR amplification, followed by cycle sequencing of the purified PCR fragments using BigDye chain terminator and capillary electrophoresis. Pearson's Chi-square tests showed that the minor alleles, G, for both rs1805010 and rs1801275 SNPs, were significantly more frequent in asthmatics than in the healthy group [Yates' P < 0.05]; conversely, the major alleles, A, were significantly more frequent in healthy than in asthmatics [P < 0.05]. Concerning association analysis, odds for A/G-G/G genotypes were significantly higher to be associated with asthma predisposition [rs1801275: OR = 2.12; 95% CI = 1.39-3.22; P < 0.001*; rs1805010: OR = 1.6; 95% CI = 1.01-2.53; P < 0.05*; dominant model]. Analysis of gender-genotype interactions, with genders nested within A/G-G/G, indicated higher odds for females than males of significant association with asthma [rs1801275: OR = 5.19, 95% CI = 2.09-12.94*; rs1805010: OR = 3.73, 95% CI = 2.06-6.74*]. Rs1805010 and rs1801275 were in linkage disequilibrium [D' = 0.27; P < 0.0004*], with G-G haplotype being more frequent in asthmatics than in healthy subjects [OR = 2.43, 95% CI = 1.59-3.71*].The risk alleles, G, of IL-4Ralpha rs1805010 and rs1801275 SNPs and corresponding A/G-G/G genotypes were significantly associated with asthma predisposition in asthmatics from Saudi Arabia.

T1 and T2 ADAM33 single nucleotide polymorphisms and the risk of childhood asthma in a Saudi Arabian population: a pilot study

Genetic association studies have demonstrated that over 100 variants in target genes [including ADAM33] are associated with airway remodeling and hyper-responsiveness in different ethnic groups; however, this has never been evaluated in Arabic populations. The objective of this study was to determine whether ADAM33 polymorphisms that are associated with asthma in a population of asthmatic children from Saudi Arabia. A cross-sectional pilot study comparing the polymorphisms of normal subjects and asthmatic patients from Saudi Arabia over a period of 1 year. One hundred and seven Saudi asthmatic children and 87 healthy Saudi children of 3-12 years old were assessed for allelic association of ADAM33 T1 [rs2280091], T2 [rs2280090], ST+4 [rs44707] and S1 [rs3918396] SNPs to asthma. Genotyping was done by real-time PCR, multiplex ARMS and PCR-RFLP. T1 and T2 SNP genotype frequencies in asthmatic children were significantly different compared to controls [P<.05], indicating allelic association with asthma. The T1 A/G and G/G and the T2 A/G and A/A genotypes [P=0.0013 and P=.008, respectively] but not S1 and ST+4, increased the risk of asthma when using the best fit dominant model. Strong linkage disequilibrium between T1 [rs2280091] and T2 [rs2280090] was observed [r2=0.83; D'=0.95; P<.001]. The haplotype G-A-A-C was significantly more frequent in asthmatics, thus supporting the association of T1 G-allele and T2 A-allele with increased predisposition to asthma [P=.007]. T1 A/G and T2 G/A ADAM33 polymorphisms, but not S1 or ST+4, were significantly associated with asthma development in Saudi children, like those reported for white and Hispanic population in the United States