May 3, 2019

WSU researchers publish discovery of sarcoidosis inflammation mechanism

A team of Wayne State University School of Medicine researchers has published results of their work that have, for the first time, identified the underlying mechanisms that lead to the persistent inflammation in sarcoidosis, a disease that attacks between 20 and 50 of every 100,000 Americans each year.

The findings established in “HIF-1α regulates IL-1β and IL-17 in sarcoidosis,” published in eLife magazine’s April edition by Lobelia Samavati, M.D., F.C.C.P., associate professor of Internal Medicine and director of the WSU Sarcoidosis/Interstitial Lung Disease Center, should open new avenues for drug discovery, not only for sarcoidosis, but for other inflammatory diseases.

The condition affects African-Americans at least 10 times more often than Caucasians, and more women than men. Sarcoidosis has a high incidence rate in Michigan, especially in Detroit. Common symptoms include chest pain, a dry cough and shortness of breath.

Researchers have not yet identified a cure for sarcoidosis, an inflammatory disorder of unknown origin. The condition, which manifests as abnormal clumps of immune cells called granulomas, can affect a number of organs such as lungs, brain, eyes and the skin. In some cases, the condition can go into remission without treatment. Extreme cases can require a heart or lung transplant.

Sarcoidosis is most frequently treated with steroids or other immune suppressive medications. According to the National Heart, Lung and Blood Institute, many patients recover with few or no long-term problems. More than half experience remission within three years of being diagnosed, but the disease can reappear or lead to slow and progressive lung damage requiring lung transplantation. Organ damage occurs in about one-third of patients. While rarely fatal, death from sarcoidosis is generally caused by advanced lung disease, heart failure or brain damage.

The research conducted by Dr. Samavati and her colleagues set out to identify the protein/genetic markers involved in the development of sarcoidosis and its sustained inflammation.

“We showed for the first time that sarcoidosis patients exhibit an enhanced expression and activity of a protein called the hypoxia inducible factor 1α (HIF)-1α in the sarcoidosis immune cells,” she said. This protein/ factor is very important in all mammals and regulates oxygen uptake by the cells, metabolism and inflammation by the cells. The expression of this factor is affected in cancer cells promoting the cancer growth.

Dr. Samavati said, “For the first time, we discovered that this factor is highly expressed in the immune cells of sarcoidosis patients. We also found an increased expression of HIF-1α in lung biopsies of patients with sarcoidosis. The abundance of HIF isoforms was mechanistically linked to elevated production of pro-inflammatory cytokines, IL-1β and IL-17. Both of these cytokines are potent inflammatory cytokines that can damage end organs, such as lungs and heart.”

The research team includes Jaya Talreja, Ph.D., Internal Medicine research associate; Harvinder Talwar, Ph.D., Internal Medicine research associate; Christian Bauerfeld, M.D., assistant professor of Pediatrics; Lawrence Grossman, Ph.D., professor of Molecular Medicine and Genetics, and the Henry L. Brasza director of the Center for Molecular Medicine and Genetics; Kezhong Zhang, Ph.D., professor of the Center for Molecular Medicine and Genetics, and of Biochemistry, Microbiology and Immunology; and Paul Tranchida, M.D., assistant professor of Pathology.

The research was supported by a grant (R01HL113508) and the American lung Association, as well as the WSU Department of Internal Medicine and the WSU Center for Molecular Medicine and Genetics.