The effect of macrolide therapy on sub-clinical infection and inflammation in human lung transplantation.
Lead Research Organisation:
Newcastle University
Department Name: Clinical Medical Sciences
Abstract
For many chronic lung diseases, such as cystic fibrosis in young people, lung transplantation can be the only present treatment for advanced disease. This can extend life expectancy and quality, and allows resumption of day to day activities, but chronic rejection is a major problem.
We will carry out research into how small amounts of infection, which do not cause immediate clinical problems, might cause subsequent chronic rejection. This has previously not been considered significant, and therefore has not been studied. This area of research has been chosen because it is a strength of respiratory medicine in the UK. The Freeman Hospital is one of the worlds largest transplant centres, making the work feasible. The question of why lung transplants develop chronic rejection is of national and international importance.
To do our work we will be using very sensitive molecular methods to quantify low levels of infection, to see if there is evidence to suggest that this may cause inflammation and scarring of the airways. We believe that this causes progressive shortness of breath and chronic transplant rejection.
New antibiotic therapies have been used in chronic rejection and this seems to help some people, but no one knows how this works. We will perform a formal scientific study of this approach to improve the available evidence. We will also perform experiments with lung samples from transplant patients that aim to investigate potential mechanisms, and why some people do well but others do not. To allow these experiments we will grow transplant cells from small samples to give the larger numbers of cells needed. All of our work will be done using human samples because these are the most appropriate for our research.
It is expected that our results will show that even low levels of infection are a problem to lung transplant patients and that antibiotic treatment helps this. This would change how chronic rejection is treated and we think this may help to protect transplanted lungs and extend life expectancy.
We will carry out research into how small amounts of infection, which do not cause immediate clinical problems, might cause subsequent chronic rejection. This has previously not been considered significant, and therefore has not been studied. This area of research has been chosen because it is a strength of respiratory medicine in the UK. The Freeman Hospital is one of the worlds largest transplant centres, making the work feasible. The question of why lung transplants develop chronic rejection is of national and international importance.
To do our work we will be using very sensitive molecular methods to quantify low levels of infection, to see if there is evidence to suggest that this may cause inflammation and scarring of the airways. We believe that this causes progressive shortness of breath and chronic transplant rejection.
New antibiotic therapies have been used in chronic rejection and this seems to help some people, but no one knows how this works. We will perform a formal scientific study of this approach to improve the available evidence. We will also perform experiments with lung samples from transplant patients that aim to investigate potential mechanisms, and why some people do well but others do not. To allow these experiments we will grow transplant cells from small samples to give the larger numbers of cells needed. All of our work will be done using human samples because these are the most appropriate for our research.
It is expected that our results will show that even low levels of infection are a problem to lung transplant patients and that antibiotic treatment helps this. This would change how chronic rejection is treated and we think this may help to protect transplanted lungs and extend life expectancy.
Technical Summary
Introduction
Five year mortality following lung transplantation is 50%, with chronic rejection, manifested functionally by bronchiolitis obliterans syndrome (BOS), the major cause of death. Current treatments have little impact on BOS, but we have recently shown that an open trial of the macrolide antibiotic azithromycin led to a clinically significant gain in lung function. The mechanisms for this improvement are not known.
Hypothesis
Sub-clinical airway infection and inflammation are key precursors of BOS. Macrolide antibiotics disrupt infection and are anti-inflammatory, leading to clinical benefit.
Methods
A longitudinal study of infection, airway inflammation and remodeling in lung transplantation, The effect of azithromycin therapy will be tested in a placebo controlled, parallel group design. Ex-vivo mechanistic studies will be made in primary bronchial epithelial cells from the same patients. All the proposed methods and the ability to recruit the required patient cohort are available to our laboratory.
Significance
This study will immediately impact on patient management.
Five year mortality following lung transplantation is 50%, with chronic rejection, manifested functionally by bronchiolitis obliterans syndrome (BOS), the major cause of death. Current treatments have little impact on BOS, but we have recently shown that an open trial of the macrolide antibiotic azithromycin led to a clinically significant gain in lung function. The mechanisms for this improvement are not known.
Hypothesis
Sub-clinical airway infection and inflammation are key precursors of BOS. Macrolide antibiotics disrupt infection and are anti-inflammatory, leading to clinical benefit.
Methods
A longitudinal study of infection, airway inflammation and remodeling in lung transplantation, The effect of azithromycin therapy will be tested in a placebo controlled, parallel group design. Ex-vivo mechanistic studies will be made in primary bronchial epithelial cells from the same patients. All the proposed methods and the ability to recruit the required patient cohort are available to our laboratory.
Significance
This study will immediately impact on patient management.
