A newly discovered pathway of innate immunity may be useful to detect subjects with altered immune responses during critical illness, or to provide a basis for therapeutic intervention targeting tumor necrosis factor receptor–associated factors (TRAF) protein abundance, according to scientists at the University of Pittsburgh School of Medicine.
When mice without the ability to make an ubiquitin E3 ligase component, Fbxo3, were infected with a Pseudomonas bacteria, they had superior lung mechanics and longer survival than mice still able to make the protein.
In blood samples taken from 16 septic patients, researchers identified higher levels of Fbxo3 and other inflammatory proteins and lower levels of Fbxl2 than samples from seven patients who did not have sepsis or lung infection.
Based on the structure of Fbxo3, the researchers developed a family of small molecules with the aim of inhibiting its activity. Administration of one of them, called BC-1215, led to reduced inflammatory markers and improved lung mechanics in mouse models of pneumonia and sepsis.
“The F-box protein Fbxo3, and other related proteins, represent ideal targets for treatment of acute lung injury, because it controls the innate immune response, is upstream of important inflammatory signaling pathways, and is more selective than traditional drugs that regulate protein turnover,” noted Mark T. Gladwin, MD, chief of the Division of Pulmonary, Allergy and Critical Care Medicine at University of Pittsburgh School of Medicine.