Study finds immunity protein that ramps up inflammation, and agents that can block it

March 31, 2013, University of Pittsburgh Schools of the Health Sciences

Scientists at the University of Pittsburgh School of Medicine have discovered a new biological pathway of innate immunity that ramps up inflammation and then identified agents that can block it, leading to increased survival and improved lung function in animal models of pneumonia. They reported their findings today in Nature Immunology.

Pneumonia and other infections sometimes provoke an inflammatory response from the body that is more detrimental than the disease-causing bacteria, said senior author Rama Mallampalli, M.D, professor and vice chair for research, Department of Medicine, and director of the Acute Lung Injury Center of Excellence at Pitt.

"In our ongoing studies of pneumonia, we found infecting bacteria activate a previously unknown protein called Fbxo3 to form a complex that degrades another protein called Fbxl2, which is needed to suppress the inflammatory response," said Dr. Mallampalli, who is also chief of the pulmonary division of the VA Pittsburgh Healthcare System. "The result is an exaggerated inflammatory response that can lead to further damage of the lung tissue, multi- and shock."

The research team, led by Bill B. Chen, Ph.D., associate professor, Division of Pulmonary, Allergy and Critical Care Medicine, conducted experiments in which mice that lacked the ability to make Fbxo3 were infected with a strain of Pseudomonas bacteria, and found that they had better lung mechanics and longer survival than mice that still made the protein.

Research team members Bryan J. McVerry, M.D., and Yingze Zhang, Ph.D., both of the Acute Lung Injury Center of Excellence, found that blood samples from 16 people who had sepsis, a condition of systemic inflammation, revealed higher levels of Fbxo3 and other and lower levels of Fbxl2 than samples from seven patients who did not have sepsis or .

Based on the structure of Fbxo3, the researchers developed a family of small molecules with the aim of inhibiting its activity. Administration of one of them, called BC-1215, led to reduced inflammatory markers and improved lung mechanics in mouse models of pneumonia and sepsis.

"The key is to find ways to help the body temper its inflammatory response so that it's able to kill the infectious agent without causing injury to healthy tissue," Dr. Mallampalli said.

"The F-box protein Fbxo3, and other related proteins, represent ideal targets for treatment of , because it controls the innate immune response, is upstream of important inflammatory signaling pathways, and is more selective than traditional drugs that regulate protein turnover," noted Mark T. Gladwin, M.D., chief of the Division of Pulmonary, Allergy and , Pitt School of Medicine.

The team is beginning to study the effects of BC-125 on other conditions of , such as colitis and arthritis.

Explore further: Bio-hybrid device acts as 'thermostat' to control systemic inflammation in sepsis

More information: Paper: dx.doi.org/10.1038/ni.2565

Related Stories

Bio-hybrid device acts as 'thermostat' to control systemic inflammation in sepsis

May 14, 2012
A small, external bioreactor holding human cells pumped out an anti-inflammatory protein to prevent organ damage and other complications in a rat with acute inflammation caused by bacterial products in a model of sepsis, ...

Scientists uncover liver's role in preventing dissemination of lung infection

April 2, 2012
Researchers at Boston University School of Medicine (BUSM) have discovered the regulation and functional significance of the acute phase response during a lung infection. The findings, which will be published in the May edition ...

A boost in microRNA may protect against sepsis and other inflammatory diseases

May 24, 2012
Acute inflammatory diseases, such as sepsis, as well as chronic inflammatory diseases like diabetes and arthritis, develop as a result of sustained inflammation of the blood vessel wall. Researchers at Brigham and Women's ...

Stem cells from bone marrow save the day

May 13, 2011
New research, published in BioMed Central's open access journal Stem Cell Research & Therapy, investigates the therapeutic use of human stem cells from bone marrow against acute lung injury and identifies TNF-α-induced ...

Recommended for you

A bad influence—the interplay between tumor cells and immune cells

October 16, 2018
Research at Huntsman Cancer Institute (HCI) at the University of Utah (U of U) yielded new insights into the environment surrounding different types of lung tumors, and described how these complex cell ecosystems may in turn ...

Function of neutrophils during tumor progression unraveled

October 15, 2018
Researchers at The Wistar Institute have characterized the function of neutrophils, a type of white blood cells, during early stages of tumor progression, showing that they migrate from the bone marrow to distant sites and ...

Immune health maintained by meticulously ordered DNA

October 15, 2018
Walter and Eliza Hall Institute researchers have revealed how immune health is maintained by the exquisite organisation skills of a protein called Pax5.

New immunotherapy targeting blood-clotting protein

October 15, 2018
Normally, the blood protein fibrin does not enter the brain. But in several neurological disorders, the blood-brain barrier—which keeps large molecules in the blood from entering the brain—becomes abnormally permeable, ...

Enzyme that triggers autoimmune responses from T-cells in patients with MS found

October 11, 2018
A team of researchers from Switzerland, the U.S. and Spain has isolated an enzyme that triggers an autoimmune response from T-cells in patients with MS. In their paper published in the journal Science Translational Medicine, ...

Scientists reveal new cystic fibrosis treatments work best in inflamed airways

October 11, 2018
A new UNC School of Medicine study shows that two cystic fibrosis (CF) drugs aimed at correcting the defected CFTR protein seem to be more effective when a patient's airway is inflamed. This is the first study to evaluate ...

1 comment

Adjust slider to filter visible comments by rank

Display comments: newest first

rfw
not rated yet Mar 31, 2013
Might this kind of mechanism be a way to describe the often-alleged effectiveness of homeopathy?

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.