Thomas Murray, MD, PhD

Pulmonary infection in cystic fibrosis (CF): Prevention, pathogenesis and treatment

Global Aim: Identify optimal methods to prevent and treat pulmonary infections in children with CF. There are two arms of the research program:1) Understanding the host/pathogen interaction and inflammation in CF; 2) Disinfection and infection prevention in the CF home and in the community

1) Understanding the host/pathogen interaction and inflammation in CF.

Increased inflammation in the CF lung contributes to premature patient morbidity and mortality. Both chronic infection and underlying dysfunction of the immune system in CF are fundamental to this increased inflammation. Heme-oygenase (HO), an enzyme that activates anti-inflammatory and anti-microbial cellular responses, is reduced in CF. Dr. Emanuela Bruscia and I are leading a team that is testing potential therapies (see below) to restore HO activity and reduce inflammation to normal levels. Furthermore, we are studying the interaction between Pseudomonas aeruginosa, a common CF pulmonary pathogen, and CF host cells to understand how chronic infection prevents the resolution of inflammation.

This work involves a novel drug, Sanguinate (Prolong pharmaceuticals), bovine hemoglobin saturated with carbon monoxide, as a potent anti-inflammatory and anti-microbial drug that, in vitro, can reduce the hyper-inflammation observed in CF macrophages via correcting the reduced expression of the

HO pathway. Future work will study whether Sanguinate has in vivo antimicrobial and anti-inflammatory properties in animal models of pulmonary infection. If successful, these studies will lay the groundwork for potential clinical trials partnering with the Cystic Fibrosis Foundation Therapeutic Drug Network.

2) Disinfection and infection prevention in the CF home and community.

The burden of home care for children and families with CF is extensive, requiring multiple daily treatments. Home respiratory equipment can be contaminated with lung pathogens, providing a potential source of re-infection with each nebulization. I have studied how different home disinfection techniques kill common CF bacterial pathogens on nebulizers and whether repeated disinfection with these methods changes nebulizer function. Recently, this disinfection research has extended beyond CF to the community, studying bacterial contamination from hand dryers in bathrooms to determine optimal hand drying techniques.

Future questions regarding infection prevention that my team is working on include: 1) What is the risk to patients for aerosolizing bacteria on home nebulizer equipment? Few studies have examined the factors, (e.g. biofilm formation, hydration) that impact bacterial dispersion during nebulization. 2) Do all disinfection methods work equally well on clinical isolates? We will test clinical CF bacterial isolates under different disinfection conditions to determine the preferred method. 3) Do user friendly disinfection methods result in improved patient quality of life? We will measure compliance and the burden of home care for different disinfection methods. We anticipate that the results of these studies will be generalizable beyond the CF population and impact families with other diseases that require home nebulizers. I continue to study infection prevention in the community comparing bacterial contamination from different hand drying methods, forced air hand dryers or paper towels, with a focus on anaerobic bacteria including Clostridium difficile. This work will help determine best practice hand drying techniques.