Neonatal endotoxin stimulation is associated with a long-term bronchiolar epithelial expression of innate immune and anti-allergic markers that attenuates the allergic response.
- 作者列表："García LN","Leimgruber C","Nicola JP","Quintar AA","Maldonado CA
:Allergic asthma is the most common phenotype of the pathology, having an early-onset in childhood and producing a Th2-driven airways remodeling process that leads to symptoms and pathophysiological changes. The avoidance of aeroallergen exposure in early life has been shown to prevent asthma, but without repeated success and with the underlying preventive mechanisms at the beginning of asthma far to be fully recognized. In the present study, we aimed to evaluate if neonatal LPS-induced boost in epithelial host defenses contribute to prevent OVA-induced asthma in adult mice. To this, we focused on the response of bronchiolar club cells (CC), which are highly specialized in maintaining the epithelial homeostasis in the lung. In these cells, neonatal LPS administration increased the expression of TLR4 and TNFα, as well as the immunodulatory/antiallergic proteins: club cell secretory protein (CCSP) and surfactant protein D (SP-D). LPS also prevented mucous metaplasia of club cells and reduced the epidermal growth factor receptor (EGFR)-dependent mucin overproduction, with mice displaying normal breathing patterns after OVA challenge. Furthermore, the overexpression of the epithelial Th2-related molecule TSLP was blunted, and normal TSLP and IL-4 levels were found in the bronchoalveolar lavage. A lower eosinophilia was detected in LPS-pretreated mice, along with an increase in phagocytes and regulatory cells (CD4+CD25+FOXP3+ and CD4+IL-10+), together with higher levels of IL-12 and TNFα. In conclusion, our study demonstrates stable asthma-preventive epithelial effects promoted by neonatal LPS stimulation, leading to the presence of regulatory cells in the lung. These anti-allergic dynamic mechanisms would be overlaid in the epithelium, favored by an adequate epidemiological environment, during the development of asthma.
: 过敏性哮喘是最常见的病理表型，在儿童时期具有早期发作，并且产生导致症状和病理生理变化的Th2-driven气道重塑过程。在生命早期避免吸入性过敏原暴露已被证明可以预防哮喘，但没有反复成功，并且在哮喘开始时的潜在预防机制远未得到充分认识。在本研究中，我们旨在评估新生LPS诱导的上皮宿主防御增强是否有助于预防成年小鼠中OVA诱导的哮喘。为此，我们关注细支气管俱乐部细胞 (CC) 的反应，其高度专门化于维持肺中的上皮稳态。在这些细胞中，新生儿LPS施用增加了TLR4和tnf α 以及免疫调节/抗过敏蛋白: 俱乐部细胞分泌蛋白 (CCSP) 和表面活性蛋白D (sp-d) 的表达。LPS还防止了俱乐部细胞的粘液化生，并减少了表皮生长因子受体 (EGFR) 依赖性粘蛋白的过度产生，其中小鼠在OVA攻击后显示正常的呼吸模式。此外，上皮Th2-related分子TSLP的过度表达减弱，并且在支气管肺泡灌洗中发现正常的TSLP和IL-4水平。在LPS预处理的小鼠中检测到较低的嗜酸性粒细胞增多，以及吞噬细胞和调节细胞 (CD4 + CD25 + FOXP3 + 和CD4 + IL-10 +) 的增加，以及较高水平的IL-12和tnf α。总之，我们的研究证明了新生儿LPS刺激促进的稳定的哮喘预防上皮作用，导致肺中存在调节细胞。在哮喘的发展过程中，这些抗过敏动力学机制将被覆盖在上皮中，受到足够的流行病学环境的青睐。
METHODS::There is emerging evidence for the role of posaconazole in the management of Aspergillus-related cystic fibrosis (CF) lung disease. The tolerability and efficacy of posaconazole in paediatric CF is not well established. We report a prospective study over a fifty-three month period evaluating the safety, tolerability, and efficacy of posaconazole in pediatric CF. Fourteen children (seven males, median age 13 years, range 3-17 years) received a total of twenty-three courses of posaconazole (13 oral suspension and 10 tablet formulation). Of these patient episodes, nine received posaconazole for emerging or active allergic bronchopulmonary aspergillosis (ABPA) and two required a combination of posaconazole and systemic corticosteroids for difficult-to-treat ABPA. A subgroup of patients (n = 12) with persistent isolates of Aspergillus fumigatus, in the absence of serological markers of ABPA, received posaconazole monotherapy for pulmonary exacerbations not responding to conventional broad-spectrum antibiotic treatment. Posaconazole levels, full blood count, electrolytes, and liver function were monitored on day 7 of treatment and then monthly. Posaconazole was well tolerated in all but three patients. Therapeutic plasma levels >1 mg/l were achieved in all receiving the tablet formulation in comparison to 60% on the liquid preparation. There was a modest but significant improvement in FEV1 (% predicted) demonstrated for the cohort as a whole (p = 0.015) following posaconazole therapy. Posaconazole is well tolerated in children as young as six years old, improvements in lung function are observed, and therapeutic plasma levels are readily achieved in patients taking the tablet formulation and in adherent patients taking the liquid formulation.
METHODS::The relationship between the cellular immune response during Trichuris trichiura infection and asthma has not yet been established. In this study, the cytokines interleukin (IL)-2, IL-4, IL-6, IL-10, TNF-α, IFN-γ and IL-17A were evaluated in asthmatic children harboring T. trichiura. For this assessment, asthmatic and non-asthmatic children (ISAAC questionnaire) were submitted to parasitological tests and blood samples were cultured (mitogen stimulation) for cytokine measurements in the supernatant. Asthma frequencies were similar in infected and uninfected children, but IL-4, IL-6, TNF-α and IL-10 levels were high in the infected asthmatic children. Additionally, infected non-asthmatic children exhibited high levels of these cytokines in relation to uninfected non-asthmatic children; however, cytokine levels were lower when compared with infected and asthmatic children. Therefore, T. trichiura infection positively modulated the pro- and anti-inflammatory cytokines in asthmatic children, but a background of asthma seemed to narrow the production of cytokines induced by this helminth.
METHODS::In a recent meta-analysis, we found that atopic diseases, like asthma and allergic rhinitis, occur more frequently prior to the onset of attention-deficit/hyperactivity disorder (ADHD). Our aim was to determine the temporal order of the association between daily fluctuations in atopic disease symptoms and in ADHD symptoms in individual participants. In this observational study among 21 participants, age 7-16 years, we performed a replicated time-series analysis of symptom fluctuations in asthma and/or allergic rhinitis and ADHD. Data were collected through parents who filled in a daily online questionnaire during up to 50 days. In each individual, we investigated the temporal order of fluctuations in atopic disease symptoms and ADHD symptoms using a vector autoregressive (VAR) model while using sleep problems and medication use as covariates. For 16 out of 21 participants, we constructed a VAR model. For a majority of the participants, significant associations were detected between atopic disease symptoms and ADHD symptoms. The results were heterogeneous; the direction, sign, and timing of the relationship between ADHD, atopy, sleep problems, and medication use varied between individuals. This study provides additional evidence that the symptom expression of atopy and ADHD are related. However, the connection between both diseases in children is found to be heterogeneous within our study population.