A novel anti-inflammatory therapy designed by Vanderbilt University Medical Center investigators prevents acute lung injury in mice exposed to an inflammation-causing toxin, the researchers report in the journal Molecular Therapy.
The new therapy may offer a way to protect the lungs from the "runaway inflammation" that can accompany bacterial or viral pneumonia, said Jacek Hawiger, M.D., Ph.D., the leader of the research team that has pioneered the new approach.
"Lung inflammation is an extremely perplexing problem," noted Hawiger, chair of the Department of Microbiology & Immunology.
The immune system sometimes overreacts to lung infection and produces excessive concentrations of inflammatory signals (cytokines and chemokines), which can damage the fine architecture of the lungs and lead to life-threatening acute respiratory distress syndrome (ARDS). Such damage is most likely when pneumonia has both viral and bacterial causes - for example from combined influenza and Staphylococcus aureus infections.
"We believe that in addition to controlling the infection with antibacterial and antiviral agents, we need therapies that reduce this inflammation-induced collateral damage to the lung tissue," Hawiger said. "This would allow both faster clearance of the infecting organisms and faster healing of the lung."
Several years ago, Hawiger and colleagues began searching for new targets for anti-inflammatory therapy. They reasoned that a protein called NF-kappa-B - the "master regulator" of genes that encode mediators of inflammation - might make a good target.
The researchers knew that NF-kappa-B moves from the cell cytoplasm to the nucleus (where it is active) in response to cellular injury or microbial agents, and they decided to try to block this nuclear translocation.
They designed a small protein fragment - a peptide - that mimicked the nuclear transport "signal," hoping that it would compete with, and block, NF-kappa-B's movement to the nucleus. To get the peptide into cells, the team took advantage of the cellular mechanism that proteins use to cross membranes and engineered a membrane-crossing motif onto the therapeutic peptide.
"To our delight, we found that this peptide crossed the cell membrane and stopped NF-kappa-B in its tracks, blocking it from going to the nucleus in response to conditions which cause inflammation," Hawiger said.