Surfactant as a carrier: influence of immunosuppressive agents on surfactant activity

INTRODUCTION: It has been proposed that exogenous pulmonary surfactant can be used as a drug delivery system for immunosuppressive agents to the alveolar compartment of the lung while reducing the risk of systemic toxicity. Before using this combination, however, alterations in activity of both substances should be examined. Therefore, this study investigated whether the activity of a natural derived surfactant preparation is changed after it is mixed with cyclosporine A (CsA) or rapamycin (RPM). METHODS: A surfactant suspension was mixed with CsA or RPM and minimal surface tension of these mixtures was measured in vitro. Surfactant activity was evaluated in vivo by its capacity to restore gas exchange in an established model of surfactant deficiency in rats. CsA-surfactant, RPM-surfactant or surfactant alone was instilled intratracheally and blood gases were measured under standardized ventilatory conditions. RESULTS: Minimal surface tension of surfactant-CsA was comparable with that of surfactant alone, whereas minimal surface tension of the surfactant-RPM mixture was increased. In vivo partial arterial oxygen pressure levels increased immediately to prelavage values after instillation of CsA-surfactant, RPM-surfactant and surfactant only and were comparable during the entire study period. CONCLUSION: The activity of a naturally derived surfactant was affected when mixed with RPM but not when mixed with CsA at the used concentrations.     

The association of ethnicity with electronically measured adherence to inhaled corticosteroids in children

Purpose

To investigate the association of ethnicity with objectively, electronically measured adherence to inhaled corticosteroids (ICS) in a multicultural population of children with asthma in the city of Amsterdam.

Methods

The study was designed as a prospective, observational multicenter study in which adherence to ICS and potential risk factors for adherence to ICS were measured in a cohort of Moroccan and native Dutch children with asthma. Electronic adherence measurements were performed for 3 months per patient using a Real Time Medication Monitoring (RTMM) system. Ethnicity and other potential risk factors, such as socio-economic status, asthma control and parental medication beliefs, were extracted from medical records or parent interviews. The association between adherence and ethnicity was analysed using multivariate linear regression analysis.

Results

A total of 90 children (aged 1–11 years) were included in the study and data of 87 children were used for analysis. Average adherence to ICS was 49.3 %. Native Dutch children showed higher adherence to ICS than Moroccan children (55.9 vs. 42.5 %, respectively; p?=?0.044, univariate analysis). After correction for confounders (>3 annual visits to the paediatric outpatient clinic, regular use of a spacer during inhalation), the final regression model showed that ethnicity was independently associated with adherence (p?=?0.028).

Conclusions

In our Western European population of inner city children with asthma, poor adherence to ICS was a serious problem, and even somewhat more so in ethnic minorities. Paediatricians involved in asthma treatment should be aware of these cultural differences in medication-taking behaviour, but further studies are needed to elucidate the causal mechanism.

     

IL-23 and IL-12 responses in activated human T cells retrovirally transduced with IL-23 receptor variants

Interleukin-23 (IL-23) is a regulator of cellular immune responses involved in controlling infections and autoimmune diseases. Effects of IL-23 on T cells are mediated via a receptor complex consisting of an IL-12Rbeta1 and a specific IL-23R chain. The R381Q and P310L variants of the IL-23R were recently reported to be associated with autoimmune diseases, suggesting they have an effect on IL-23R function. To investigate this matter, these variants and a newly identified variant, Y173H, were retrovirally transduced into human T cell blasts and functionally characterized by measuring the IL-23-induced signal transduction pathway (i.e., STAT1, STAT3 and STAT4 phosphorylation), and IFN-gamma and IL-10 production. No differences were detected between the genetic variants and wild-type in the function of the IL-23R-chain. Furthermore, while comparing IFN-gamma and IL-10 production in response to IL-23 and IL-12, we found IL-23 to be a more potent IL-10 inducer, and IL-12 a more potent IFN-gamma inducer. In addition, IL-23 also exerted a minor IL-12-like effect by inducing IL-23R-independent, IL-12Rbeta1-dependent STAT4 phosphorylation and IFN-gamma production. In conclusion, the reported association between R381Q and P310L variants of the IL-23R and autoimmune diseases does not depend on differences in functional activity between wild-type and R381Q and P310L variants of the IL-23R.