We all experience it from time to time: a low-grade, annoying pain or inflammation. Some tend to ignore it or put off seeing a doctor until it gets worse. But these seemingly benign symptoms could be precursors to the onset of major diseases.
Liwu Li, a professor of biological sciences in the College of Science at Virginia Tech, and his research team are exploring the connections between low-grade chronic inflammations and the development of major diseases such as diabetes, atherosclerosis, and Parkinson’s disease.
“Our body tends to respond and adjust well to major challenges,” said Li, director of the Inflammation Center at Virginia Tech. “After a robust response, our body has a compensatory mechanism to resolve ourselves and bring ourselves back to a resting state. But with low-grade chronic inflammatory challenges, our body tends to elicit a mild yet sustained response, without the compensatory mechanism to bring us back to the resting state.”
One of the key inflammatory agents is microbial endotoxin, which can shed from commensal bacteria – harmless bacteria found in the body that help with things such as food digestion -- and slowly enter the blood stream. Mildly elevated levels of endotoxin exist in people who are aging or who have adverse health conditions or lifestyles such as chronic infections, obesity, chronic smoking, and alcohol consumption. For example smokers tend to have lung damage, enabling endotoxin to spread into the circulatory system. This can allow the progression of chronic and low-grade inflammation that leads to the development of atherosclerosis or other inflammatory diseases.
“In recent years, we began to realize that even without a major infection, we can still have endotoxin in our system in low doses,” Li said. “In contrast to high-dose endotoxin that induces a robust inflammatory response, these low-dose (subclinical) endotoxin cause low-grade, yet persistent inflammatory responses.
“Given the prevalence of low-dose endotoxemia and low-grade inflammation in humans at various stages of life, the economic and health tolls are reaching pandemic levels,” Li said. “Consequently, strategies that target chronic states of endotoxemia and low-grade inflammation may hold significant promise in not only the treatment, but also the prevention or reversal of some debilitating diseases.”
Given its significance, Li’s research group has been working on defining the cellular and molecular mechanism that maintains low-grade inflammation induced by subclinical endotoxin, an endotoxin infection that doesn’t show any symptoms.
“We have found that subclinical endotoxin can affect the behavior of white blood cells such as macrophages and T helper cells,” he said. “Specifically, a distinct molecular circuit in response to low-dose endotoxin can skew our immune cells into a preferentially pro-inflammatory state and allow these cells to persistently express low levels of inflammatory mediators in our bodies.”
The discovery of such novel molecular circuits for low-dose endotoxin holds significant promise in the early detection, prevention, and treatment of chronic inflammatory diseases. Li and his team are studying ways to identify blood markers to identify low-grade inflammation and early disease risks.
“I think by determining the markers for low-grade inflammation, can be very telling,” he said. “By monitoring the blood endotoxin levels, we may evaluate the potential risks for chronic diseases. “
In addition, the group is exploring compounds that can specifically target this novel molecular circuit as a potential way to stop the inflammation. Instead of the conventional practice of creating another new drug, Li said, the better approach may be the optimum combination of existing drugs that jointly reset the cellular circuit.
“It’s all a matter of recipes,” Li said. “We want to find the right ratio and combination of drugs that already exist in the market.” This is particularly relevant to personalized medicine, as the endotoxin levels as well as the cellular circuits from different individuals may be slightly different.
“There is still a long way to go for finding the actual cure for these diseases,” Li said. “That is why our research combines expertise from various disciplines, including experimental biology and computational simulation.” Li’s interdisciplinary partners include researchers at the Institute for Critical Technology and Applied Science, the Fralin Life Science Institute, Wake Forest University, the Carilion School of Medicine and Research Institute, and partnerships with various pharmaceutical industries.
Excessive inflammation is the common mechanism for almost all human disease.
Inflammation research conducted in Virginia Tech emphasizes on system network analyses of human inflammatory processes using biological, chemical, computational, and clinical approaches.
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