Novel nanotechnology may help address harmful systemic inflammation.
Many conditions and adverse health events can cause chronic inflammation. This is the body's prolonged response to injury.
Inflammation is meant to help the body heal. However, in some conditions, it can actually cause further damage — for example, if it lasts for too long, if the response is too strong, or if it is misdirected.
Sepsis is a medical emergency in which the body's reaction to damage spins out of control. If a person does not receive treatment immediately, sepsis can lead to organ failure and eventual death.
Although it is unclear how many people sepsis affects, the World Health Organization (WHO) estimate that over 30 million people per year develop it.
Stroke, meanwhile, occurs when the blood supply to the brain becomes obstructed. This means that this crucial organ does not receive the amount of oxygen it needs to function correctly.
According to the Centers for Disease Control and Prevention (CDC), as many as 795,000 people in the United States experience a stroke per year.
After such a cerebrovascular event, inflammatory responses typically take place in the brain, as the organ aims to repair its damaged cells.
However, poststroke inflammation can also lead to further damage. For this reason, researchers have been looking into ways of arresting or moderating the inflammatory response in order to improve the effectiveness of therapy.
Now, a new study in mouse models from Washington State University in Pullman suggests a novel method of preventing damaging inflammatory responses following sepsis or stroke.
In a study paper that now appears in the journal Science Advances, the researchers argue that by using innovative technology, it would be possible to deliver a potent drug straight to the cells responsible for causing harmful inflammation.
Targeting 'good guys' turned bad
In their new study, the investigators turned their attention to neutrophils. These are a type of white blood cell that helps "coordinate" the immune system's response to injury.
"Scientists have started realizing that neutrophils — which were always seen as the 'good guys' for the key role they play in our immune system — are actually also contributing to the pathology of all kinds of diseases."
Senior study author Zhenjia Wang
Though neutrophils normally play a positive role in system maintenance, the researchers explain that sometimes, when they respond to the damage caused by events such as sepsis or stroke, they can actually "go rogue," living past their "best by" date and overaccumulating in healthy tissue. This can lead to further damage.
Wang explains that at this point, "[n]eutrophils don't know who the enemies are. They just attack, releasing all kinds of harmful proteins in the bloodstream."
"They will kill bacteria," he says, "but they will also kill healthy tissue in the body at the same time."
This, the researchers claim, is not the first time that scientists have looked at ways of killing off dangerous activated neutrophils.
However, previous attempts to do so revealed a serious problem: Drugs that killed active neutrophils also attacked neutrophils at rest, which are not dangerous.
Bypassing previous obstacles
To bypass this obstacle, Wang and team came up with a solution: They loaded nanoparticles with doxorubicin, a chemotherapeutic drug able to kill the pro-inflammatory cell.
The nanoparticles will enter neutrophils and, once inside, release the drug. However, they are only able to enter these cells via a receptor present on the surface of neutrophils, called the "Fc-gamma receptor."
Activated neutrophils, the scientists found, express more Fc-gamma receptors. This allows the nanoparticles to target and "stick" to them specifically, without affecting any of the inactive, healthy cells.
"Our experiment found that our doxorubicin albumin nanoparticles can decrease the lifespan of harmful neutrophils in the bloodstream," says Wang.
"More importantly," he adds, "we also found that our nanoparticles don't inhibit the neutrophils' function in the bone marrow."
The researchers tested this method in mouse models of sepsis and ischemic stroke. In both cases, the approach was successful.
In mouse models of sepsis, they note, the doxorubicin-carrying nanoparticles increased survival rates. In models of stroke, they helped lower neurological damage.
Going forward, Wang and team want to continue testing and improving the innovative technology in the hope of refining it to a level that will allow them to confirm its effectiveness and viability in clinical trials involving humans.