Sepsis is the cause of 1 in 3 hospital deaths in the United States, killing 250,000 people each year according to the CDC. Currently, therapeutic approaches for treating sepsis are largely supportive with no specific drugs available that treat the underlying pathogenesis. A team from the Temple Lung Center, led by Laurie Kilpatrick, PhD, is in pursuit of the first drugs that can protect against the damage septic shock wreaks on the human body.
In sepsis, the immune system’s inflammatory response to bacterial infection can cause damage to organs like the lungs and kidneys. If early treatment with antibiotics doesn’t stave off that inflammatory over-reaction, no available drugs can protect a person’s tissues from the attack. This is partly because of the many immune signaling pathways that are involved—especially when the initial infection includes a mix of gram-negative and gram-positive bacteria. Dr. Kilpatrick’s team is targeting protein kinase C delta (PKC-δ) as a crucial place where many immune-system signaling pathways come together during sepsis. When this enzyme is activated by phosphorylation at a particular site, PKC-δ appears to activate several signaling pathways that intensify the inflammatory immune response and attract neutrophils that cause lung tissue damage. Previous studies from her research group demonstrated that PKC-δ is activated in the lungs of septic animals, and PKC-δ inhibition reduced neutrophil influx and was organ protective.
Dr. Kilpatrick’s team has identified the active site on PKC-δ where the signaling cascade starts, and created a mouse model in which that specific site on PKC-δ is mutated and can’t be activated by phosphorylation. Mice with this mutation in their PKC-δ were largely protected from the effects of induced polymicrobial sepsis, and no negative side effects were observed from turning off the activation site.1 The team has mimicked this effect with in vitro experiments using human tissue and a PKC-inhibitor that blocks phosphorylation of that particular site on PKC-δ. The inhibitor is an excellent candidate for a new sepsis treatment drug.
The next steps, says Kilpatrick, are to understand the mechanism by which PKC-δ regulates the immune response, and to more accurately model the conditions in the human lung; many potential sepsis drugs have not made the jump from mouse to human models. Funded by the NIH, the Kilpatrick lab, in collaboration with Dr. Mohammad Kiani in the Temple College of Engineering, is using SynVivo’s microfluidic chips, creating a 3-D model of lung endothelial tissue structure over which actual human lung endothelial cells are grown; this allows blood flow patterns and other factors to be taken into account. The researchers next plan to model sepsis using blood plasma and neutrophils taken from sepsis patients, to see whether their neutrophils respond differently to the use of the inhibitor drug than those of healthy patients. With the exciting new ability to create more lifelike models, and the identification of an important protective target, there may be new hope for protecting people with sepsis from organ failure. ■