Molecular origins of lung diseases discovered

Lungs
Photo by Karen Tian.

An investigation into a mysterious protein has allowed a team of Yale researchers to identify the molecular origins of — and therefore potential solutions to — asthma, pneumonia and metastatic melanoma, a form of cancer that can spread to the lungs.

Jack Elias, formerly the chair of the Yale School of Medicine’s Department of Internal Medicine, looked closely at the protein chitinase 3-like 1 (Chi3l1), which appears at unusually high levels in humans with pulmonary disease. Following a series of experiments on both mice and humans, Elias and his team were able to pinpoint the previously unclear process through which Chi3l1 causes illness. Their studies were published in the August issue of Cell Reports, a medical journal that focuses on life science.

“We knew that, if you took a person with one of these [lung] diseases, and you measured how much of this protein was in their blood, that there would be an abnormal amount compared to a healthy control person’s blood. And so we said, ‘Okay, why are they increased in these diseases? What are they doing?’” said Elias, now the dean of medicine and biological sciences at Brown’s Alpert Medical School.

The study’s main setup involved three types of mice — those with normal or abnormally high levels of Chi3l1, as well as mice bred to have no Chi3l1 protein in their blood. Within each type, some mice were subjected to a diseased lung condition, such as asthma or acute lung injury, while the rest were left unaffected. This experiment allowed Elias and his team to observe the relationship between Chi3l1 level and disease severity.

“We were able to define, in the mice studies, what this particular gene does at baseline, in a normal animal, and what it does in an animal that’s stressed [by disease],” Elias said.

Though the study encompassed several types of lung disease, each disease condition yielded similar and significant results: the mice in which Chi3l1 was inhibited, reduced or withheld demonstrated a lower disease incidence than did the mice in which Chi3l1 was present at normal and increased levels.

Bing Ma, a Yale associate research scientist in pulmonary medicine, worked extensively on the experiments concerning the spread of lung cancer cells. The results of these experiments have helped researchers precisely define the relationship between Chi3l1 and cancer: High levels of Chi3l1 protein prevent the production of cancer-fighting cells. Similarly, high levels of Chi3l1 lead to an increase in cells causing asthma and other lung diseases.

“Cancer can survive in the body — there is an environment that allows cancer cells to grow. If the cancer cells generate a lot of chitinase-like proteins, these proteins can stimulate an inhibitor for some cells that kill the cancer cells,” Ma said.

With this new insight into the development of these related lung diseases, researchers will now be able to find more effective ways to treat them. Charles Dela Cruz, a medical school assistant professor of pulmonary medicine on Elias’ team, said that understanding the specific mechanisms through which these chitinase-like proteins function makes it easier for researchers to develop efficient medical solutions.

“Discoveries do take time to lead to therapeutic options, but the results from these studies are quite encouraging,” Dela Cruz said. “One can envision that knowing these specific receptors and downstream pathways will lead to a targeted approach to controlling this pathway by inhibitors or antibodies that can regulate the levels of these proteins and help in fighting diseases we see.”

In addition to finding more effective cures for asthma, melanoma and these other lung diseases, further research efforts will attempt to identify the pathways taken by similar chitinase-like proteins found in rheumatoid arthritis and diabetes.

“We’re on our way. It looks promising, but it’s early,” Elias said about current and future studies using these findings to guide new investigations into other diseases.

According to the Asthma and Allergy Foundation of America, nearly 25 million Americans currently suffer from asthma.

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