Role of extra-oesophageal reflux in the development and severity of non-cystic fibrosis bronchiectasis

Bronchiectasis is a chronic debilitating respiratory disease characterised by severe, recurrent chest infections with resultant high rates of morbidity and mortality, escalating public health costs and profound reductions in productivity and quality of life. In approximately 50% of cases, the cause of bronchiectasis is unknown (idiopathic) and treatment in these patients remains palliative. Gastro-oesophageal reflux has been implicated in the pathogenesis of several respiratory diseases including asthma, chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis and bronchiolitis obliterans post-lung transplant, all of which have been shown to be associated with the development of bronchiectasis in more severe disease. Recent studies have demonstrated persistent and progressive respiratory symptoms and concurrent worsening of pulmonary function severity in bronchiectasis patients despite ongoing medical intervention. Reflux-related pulmonary micro-aspiration has been postulated as a cause of bronchiectasis and is thought to be associated with disease severity. There is a clear need for a better understanding of the underlying pathophysiological mechanisms driving lung inflammation in bronchiectasis and for the identification of biomarkers and new targets of intervention that may allow earlier diagnosis and treatment to prevent or slow disease severity. Further research, therefore, is essential to greater our understanding of the development and severity of this debilitating disease.

Hypothesis: Aspiration of gastric contents into the lung would be anticipated to cause bronchial epithelial cell damage, stimulation of cytokine production and an airway inflammatory/remodelling response, potentially contributing to irreversible airway damage and subsequent disease severity.

Objectives and Methods: The purpose of this proposal is to explore the significance of reflux in the development and severity of non-cystic fibrosis bronchiectasis. The project consists of a clinical and cellular study performed in parallel. In the clinical study, research will be conducted to address the following specific aims: 1) To determine the prevalence of symptomatic and asymptomatic reflux in bronchiectasis patients versus controls; 2) To determine the mechanism of reflux using a multimodal range of diagnostic techniques including 24-hour oesophageal pH-impedance studies in bronchiectasis patients versus controls; 3) To relate the levels of reflux identified in Specific Aims 1 and 2 to measures of lung disease severity and health-related quality of life in bronchiectasis patients versus controls. In the cellular study, research will be conducted to address the following specific aims: 4) To quantify injury in cultured primary bronchial epithelial cells following incubation with varying levels of gastric juices, pepsin and bile acids by measurement of inflammatory cytokine production; 5) To determine the synergistic effect of combined reflux agents and bacterial products using pseudomonas whole cell lysates; 6) To investigate the therapeutic effect of azithromycin on reflux-related bronchial epithelial cell damage in bronchiectasis patients versus controls. The clinical study is a prospective, observational, cross-sectional, case-control study outlining the effects of reflux in bronchiectasis patients versus controls. The cellular study consists of laboratory-based bench research which will form the basis for further randomised clinical trials to translate these findings into clinical practice.

Significance: The proposed research project will have direct relevance to a highly important clinical condition that imposes a significant societal burden in Ireland and worldwide. It will involve an experimental strategy incorporating ex vivo observations in human primary bronchial epithelial cells and will enable this and other research techniques to be introduced to Ireland. It will also have high potential for identifying new strategies for intervening in reflux-related inflammatory events that contribute to the onset or severity of bronchiectasis and other forms of chronic respiratory disease.

Award Date
04 April 2013
Award Value
€389,921.00
Principal Investigator
Dr Melissa McDonnell
Host Institution
National University of Ireland, Galway
Scheme
National SpR/SR Academic Fellowship Programme