The model of asthma as a single entity has now been replaced by a much more complex biological network of distinct and interrelating inflammatory pathways. The term asthma is now considered an umbrella diagnosis for several diseases with distinct mechanistic pathways (endotypes) and variable clinical presentations (phenotypes). The precise definition of these endotypes is central to asthma management due to inherent therapeutic and prognostic implications. This review presents the molecular mechanisms behind the heterogeneity of airway inflammation in asthmatic patients. Asthma endotypes may be broadly regarded as type 2 (T2) high or T2-low. Several biologic agents have been approved for T2-high asthma, with numerous other therapeutics that are incipient and similarly targeted at specific molecular mechanisms. Collectively, these advances have shifted existing paradigms in the approach to asthma to tailor novel therapies.

In pharmaceutical research, an adequate cell-based assay scheme to efficiently screen and to validate potential drug candidates in the initial stage of drug discovery is crucial. In order to better predict the clinical response to drug compounds, a cell culture model that is faithful to in vivo behavior is required. With the recent advances in microfluidic technology, the utilization of a microfluidic-based cell culture has several advantages, making it a promising alternative to the conventional cell culture methods. This review starts with a comprehensive discussion on the general process for drug discovery and development, the role of cell culture in drug research, and the characteristics of the cell culture formats commonly used in current microfluidic-based, cell-culture practices. Due to the significant differences in several physical phenomena between microscale and macroscale devices, microfluidic technology provides unique functionality, which is not previously possible by using traditional techniques. In a subsequent section, the niches for using microfluidic-based cell culture systems for drug research are discussed. Moreover, some critical issues such as cell immobilization, medium pumping or gradient generation in microfluidic-based, cell-culture systems are also reviewed. Finally, some practical applications of microfluidic-based, cell-culture systems in drug research particularly those pertaining to drug toxicity testing and those with a high-throughput capability are highlighted.

Background IL-17A has been implicated in severe forms of asthma. However, the factors that promote IL-17A production during the pathogenesis of severe asthma remain undefined. Diesel exhaust particles (DEP) are a major component of traffic related air pollution and are implicated in asthma pathogenesis and exacerbation. Objective To determine the mechanism by which DEP exposure impacts asthma severity using human and mouse studies. Methods Balb/c mice were challenged with DEP +/− house dust mite extract (HDM). Airway inflammation and function, BALF cytokine levels, and flow cytometry of lung T cells were assessed. The impact of DEP exposure on frequency of asthma symptoms and serum cytokine levels was determined in children with allergic asthma. Results In mice, exposure to DEP alone did not induce asthma. DEP and HDM co-exposure markedly enhanced AHR compared to HDM alone and generated a mixed Th2 and Th17 response, including IL-13+IL-17A+ double producing T-cells. IL-17A neutralization prevented DEP-induced exacerbation of AHR. Among 235 high DEP-exposed children with allergic asthma, 32.2% had more frequent asthma symptoms over a 12 month period, compared to only 14.2% in the low DEP-exposed group (p=0.002). Additionally, high DEP-exposed children with allergic asthma had nearly six times higher serum IL-17A levels compared with low DEP-exposed children. Conclusions Expansion of Th17 cells contributes to DEP-mediated exacerbation of allergic asthma. Neutralization of IL-17A may be a useful potential therapeutic strategy to counteract the asthma promoting effects of traffic related air pollution especially in highly exposed severe allergic asthmatics.

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