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.
It turned out that the inhibitor worked even more broadly than the researchers expected. The peptide blocks a "shuttle" that ferries not only NF-kappa-B to the nucleus, but also a group of additional stress-responsive proteins. The nuclear shuttle protein represents a new intracellular target for anti-inflammatory therapy, Hawiger said.
The researchers tested the effectiveness of this cell-penetrating peptide therapy against inflammation in a mouse model of acute lung injury.
They exposed mice to staphylococcal enterotoxin B (SEB), an immunotoxin produced by methicillin-resistant S. aureus (MRSA). SEB generates a "storm" of inflammatory signals that damages the lungs and causes ARDS and multiple organ dysfunction. Airborne SEB caused fatal ARDS in non-human primates.
Treatment of SEB-exposed mice with the nuclear transport inhibitor suppressed the inflammatory storm in the lungs. Inflammatory cells, whose numbers increase 2.5-fold after SEB exposure, remained normal in peptide-treated mice. Peptide therapy also suppressed the levels of chemokines and cytokines and prevented injury to the lung's blood vessels.
"It's very reassuring to us that this single agent, which targets the nuclear import shuttle, suppressed the production of all of these harmful mediators of excessive inflammation," Hawiger said.
The investigators are pursuing pre-clinical studies of the peptide therapy with hopes that it will lead to improved adjunctive therapies for life-threatening pneumonia caused by multiple germs.
Leigh MacMillan | EurekAlert!
Further reports about: > ARDS > Lung inflammation > Molecular Therapy > NF-kappa-B > SEB > Staphylococcus aureus > Staphylococcus aureus infections > acute respiratory distress syndrome > anti-inflammatory therapy > blood vessel > cell cytoplasm > chemokines > cytokines > immune system > inflammatory signals > lung infection > microbial agents > runaway inflammation > therapeutic peptide
Satellites, airport visibility readings shed light on troops' exposure to air pollution
09.12.2016 | Veterans Affairs Research Communications
Oxygen can wake up dormant bacteria for antibiotic attacks
08.12.2016 | Penn State
Physicists of the University of Würzburg have made an astonishing discovery in a specific type of topological insulators. The effect is due to the structure of the materials used. The researchers have now published their work in the journal Science.
Topological insulators are currently the hot topic in physics according to the newspaper Neue Zürcher Zeitung. Only a few weeks ago, their importance was...
In recent years, lasers with ultrashort pulses (USP) down to the femtosecond range have become established on an industrial scale. They could advance some applications with the much-lauded “cold ablation” – if that meant they would then achieve more throughput. A new generation of process engineering that will address this issue in particular will be discussed at the “4th UKP Workshop – Ultrafast Laser Technology” in April 2017.
Even back in the 1990s, scientists were comparing materials processing with nanosecond, picosecond and femtosesecond pulses. The result was surprising:...
Have you ever wondered how you see the world? Vision is about photons of light, which are packets of energy, interacting with the atoms or molecules in what...
A multi-institutional research collaboration has created a novel approach for fabricating three-dimensional micro-optics through the shape-defined formation of porous silicon (PSi), with broad impacts in integrated optoelectronics, imaging, and photovoltaics.
Working with colleagues at Stanford and The Dow Chemical Company, researchers at the University of Illinois at Urbana-Champaign fabricated 3-D birefringent...
In experiments with magnetic atoms conducted at extremely low temperatures, scientists have demonstrated a unique phase of matter: The atoms form a new type of quantum liquid or quantum droplet state. These so called quantum droplets may preserve their form in absence of external confinement because of quantum effects. The joint team of experimental physicists from Innsbruck and theoretical physicists from Hannover report on their findings in the journal Physical Review X.
“Our Quantum droplets are in the gas phase but they still drop like a rock,” explains experimental physicist Francesca Ferlaino when talking about the...
16.11.2016 | Event News
01.11.2016 | Event News
14.10.2016 | Event News
09.12.2016 | Life Sciences
09.12.2016 | Ecology, The Environment and Conservation
09.12.2016 | Health and Medicine