Epithelial permeability in asthma

Abstract

Our knowledge and understanding of asthma have evolved over time, leading to new and improved treatments for this disease. Despite existing treatments however, there remains to date a significant proportion of asthmatics who remain poorly controlled, with unmet needs. Most existing treatments are based on the Th2-driven inflammation model of asthma, however there is increasing recognition of the importance of the epithelium in asthma pathogenesis. It has been proposed that the asthmatic epithelium is chronically damaged and unable to repair, with increased permeability as a result. Existing treatments do not address the epithelial damage directly, however there are now available recombinant growth factors that have been shown to have beneficial effects on epithelial healing. Our hypothesis was that modification of the epithelium, in effect boosting its repair using recombinant human keratinocyte growth factor (rhKGF), would lead to improvement in clinical parameters.

This was explored in several fashions. Firstly a randomised, double-blind, placebo-controlled clinical trial was performed using 20 poorly controlled, moderate asthmatics, with the active treatment group receiving parenteral rhKGF. Assessments before and after drug administration included objective, clinically relevant, measures of asthma such as airway hyperresponsiveness (AHR) measurements, spirometric measures, exhaled nitric oxide measurements and peak flow recording. Subjective, patient-centred assessments were also made using questionnaires to assess asthma control and quality of life, and bronchoscopy was performed to obtain samples to measure biological effects of the drug. KGF treatment resulted in a significantly greater improvement in the primary outcome of mannitol AHR, together with greater improvements in quality of life in the active treatment group compared to placebo. Other features (such as methacholine AHR, asthma control questionnaire scores, spirometric values, exhaled nitric oxide and peak flow variability) did not differ significantly between the groups, although this may be due to a greater than expected placebo response. Biological outcomes also did not differ significantly between the groups, although this may have been due to the sampling time-point used.

Concurrently to the clinical trial above, in vitro experiments were performed on cell cultures of epithelial cells from asthmatic and healthy donors, to verify and further explore the effects of KGF on an asthmatic epithelium. Specifically mechanical wounds were inflicted on the cultures, with assessment of the repair process using wound imaging, measurement of trans-epithelial electrical resistance (TER) and permeability to FITC-labelled dextran, in the presence and absence of KGF. As a subset of these experiments, some cultures were exposed to mechanical compression using air pressure, as a mimic for bronchoconstriction, to see if KGF was effective in these circumstances. Results confirm a biological effect for KGF on wound repair in the asthmatic epithelium, which can also partially overcome the deleterious effect of compression on wound healing. An intrinsic difference in wound healing between asthmatic and healthy cohorts, as previously reported, was not apparent.

Lastly the potential of nuclear medicine imaging, to assess epithelial permeability, was explored, for its potential use in future studies of asthma treatments addressing the epithelium directly. Unfortunately this was halted after a pilot study suggested potential methodological flaws – the results and conclusions from this pilot study are presented here, with suggestions for future studies in this area.

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