Artificial organ bioreactor stops out-of-control inflammation

Inflammation brought on by an influx of white blood cells and proteins helps the human body to heal when it’s faced with an acute infection or injury. But, at the same time, that inflammatory process can cause cellular damage, leading to a potential cascade of inflammation and damage that's tough to stop once it takes hold. Ultimately, this inflammation can cause organ failure, leading to serious complications or death.

To counter this inflammatory cascade, scientists at the University of Pittsburgh School of Medicine are experimenting with what they call a small, external bioreactor -- in essence, an artificial external organ -- containing cells that help to control inflammation by making and dispensing an anti-inflammatory protein. The researchers used the bioreactor in an experiment involving a rat with acute sepsis, and found it did help control inflammation.

Eventually, this bioreactor may be useful to help patients fight acute bacterial infections on their own while holding the associated inflammation -- and therefore organ and tissue damage -- in check, said said Yoram Vodovotz, Ph.D., director of the university’s Center for Inflammation and Regenerative Modeling at the McGowan Institute for Regenerative Medicine.

“In sepsis, for example, the inflammatory response evolves almost too quickly, but the available treatment strategies aim to prevent inflammation entirely,” Dr. Vodovotz said in a statement. “A better approach would be to turn down the response when it’s too strong, yet still have appropriate inflammation signaling to promote tissue repair.”

In theory, the bioreactor created at the university would do just that. If medical studies show it can control the inflammatory response while allowing the body’s immune system to do its job fighting the acute infection, it could prove a valuable weapon in the fight against sepsis.

Sepsis strikes about 750,000 Americans each year and kills 28 to 50 percent of them; it accounts for nearly 10 percent of total US deaths each year and costs more than $17 billion. In addition, sepsis cases are on the rise in the US, although it’s not quite clear why this is happening -- researchers have blamed the aging population, the growth of drug-resistant bacteria, and immune-suppressing chemotherapy and other medical treatments for the increase.

Dr. Vodovotz and his colleagues described their biohybrid reactor and experiments in the inaugural issue of the journal Disruptive Science and Technology, which was published May 14. In their rat model, the researchers loaded their bioreactor with human liver cells designed to continuously manufacture soluble tumor necrosis factor-alpha receptor (sTNFR) cells, which limit the inflammatory response. Frequently, people suffering from sepsis don’t make enough sTNFR.

With the bioreactor loaded with sTNFR-producing cells and hooked into the rat’s own circulation system, the rat’s sTNFR levels rose above “natural” levels. Meanwhile, other signs of inflammation -- including markers of organ damage and findings of abnormal blood pressure -- improved.

The bioreactor device developed at the university is first-generation and would need considerable further study in animals before it even could be tested in humans. However, its inventors envision the eventual possibility of loading it with different types of cells that produce sTNFR at different rates, which would allow them to customize the bioreactor to treat different forms of infection.

“Ultimately, therefore, this type of device should produce sTNFR, or any other therapeutic molecule, in a manner that adapts to an individual’s inflammatory dynamics,” the researchers concluded. The device also is portable, meaning it could be used in acute care situations, such as on a battlefield, to combat raging systemic infection.

Plenty of other researchers also are exploring different ways to combat inflammation-induced organ damage brought on by sepsis and other acute infections. In addition, scientists are focusing on ways to treat chronic inflammation, such as that found in conditions like asthma and rheumatoid arthritis.

For example, on May 14 researchers at Princeton University announced they had developed novel inflammation-fighting peptides that target the complement component 3a receptor (C3aR), an innate immune system receptor.

The complement system works in tandem with the body’s immune system to control infection, and either can ramp up or calm down an inflammatory response. C3aR itself can either promote or suppress inflammation, depending on the cellular system it’s operating within. Therefore, researchers have been focused on developing both C3aR agonists and antagonists in order to attempt to regulate inflammation.

In the Princeton study, published in the Journal of Medicinal Chemistry, researchers using leukemia cells in rats reported that they have identified four peptides, two of which act as prominent agonists and two which act as partial agonists of C3aR. The next research step involves animal model experiments to determine whether the peptides continue to have anti-inflammatory properties.

The researchers used a novel process that allows them to carefully tailor the peptides to fit specific parts of the C3aR molecule.

In theory, the peptides could be used to treat a wide range of conditions, including sepsis, asthma, rheumatoid arthritis, stroke, organ transplant and reperfusion injuries, all of which involve inflammation-related damage.

Sources:

Bellows-Peterson M., et al. De Novo Peptide Design with C3a Receptor Agonist and Antagonist Activities: Theoretical Predictions and Experimental Validation. Journal of Medicinal Chemistry. 2012. 55(9), 4159-4168.

Namas R., et al. A Biohybrid Device for the Systemic Control of Acute Inflammation. Disruptive Science and Technology. 2012. 1(1).

National Institute of General Medical Sciences. Sepsis Fact Sheet. Accessed May 16, 2012.