School of Medicine

Wayne State University School of Medicine

WSU researcher secures NIH grant to study inflammation pathways in sarcoidosis

Lobelia Samavati, M.D., F.C.C.P.

Lobelia Samavati, M.D., F.C.C.P.

A Wayne State University School of Medicine physician-researcher has secured a substantial grant from the National Institutes of Health to study the inflammatory regulation process involved in the lungs of those suffering from sarcoidosis.

Lobelia Samavati, M.D., F.C.C.P., assistant professor of Internal Medicine and director of the WSU Sarcoidosis/Interstitial Lung Disease Center, will use the $389,681 grant for her study, “The Role and Regulation of MKP-1 in Sarcoidosis.” The grant from the National Heart, Lung and Blood Institute is part of a larger overall $1,906,944 NIH grant.

Sarcoidosis affects between 20 and 50 of every 100,000 Americans, most between 20 and 40 years of age. The disease attacks African-Americans at least 10 times more often than Caucasians, and more women than men. Sarcoidosis has a high incidence rate in Michigan and especially in Detroit. Common symptoms include chest pain, a dry cough and shortness of breath.

Researchers have not yet identified a cause or 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 NHLBI, 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.

Dr. Samavati and her research group will study the mechanisms underlying signaling pathways that lead to continued inflammation in sarcoidosis.

“Immune cells in the body recognize and react to microbes and produce substances to kill them. These immune cells are equipped with specific receptors, which recognize these invaders and trigger an inflammatory response in an attempt to kill the invading pathogens,” she explained. “If the inflammation continues to be active and does not shut down as it usually does when an infection is fought off, it may lead to inflammatory disorder such as sarcoidosis. Specific proteins called kinases initiate such inflammatory responses. We have discovered that several protein kinases are involved in continued inflammation in sarcoidosis. Using direct drugs inhibiting these kinases in cells derived from patients, we can develop potential therapy for this disease.”

A different class of proteins called phosphatases has the opposite effect and control inflammation in healthy people. Dr. Samavati’s team has discovered that one of these phosphatases, called MKP-1, does not work properly in people with sarcoidosis, so that inflammation remains unchecked. Her team will investigate why these immune proteins work differently in people with sarcoidosis, with an eye toward determining how to decrease sustained activation of inflammatory pathways. The findings may lead to more effective drug therapies not only for sarcoidosis, but also for other inflammatory disorders such as lupus and inflammatory bowel disease.

Among the three well-defined MAPK pathways, p38 activation plays an essential role in the induction of several inflammatory genes. Dr. Samavati has recently shown that bronchoalveolar lavage cells and alveolar macrophages of patients with sarcoidosis exhibit p38 at a constant rate but lack active extracellular signal-regulated kinase, or ERK, to regulate the P38. This lack of regulation, or the inability or insufficiency to “turn off” the inflammation signaler, may result in the persistent inflammation that is the hallmark of sarcoidosis, Dr. Samavati said.

“We hypothesize that the heightened inflammatory response in sarcoidosis is due, at least in part, to impaired negative feedback regulation of p38 as a result of MKP-1 induction and a defective ERK activation in response to microbial stimulation,” she said. “We further hypothesize that resolution of inflammation in response to corticosteroid therapy is dependent on induction and function of MKP-1. Additionally, we hypothesize that failure of MKP-1 induction is due to aberrant regulation of transcription factors required for MKP-1 transcription.”

The study, she explained, has three goals: to test the hypothesis that defective ERK activation in response to microbial stimuli in sarcoidosis leads to failure of MKP-1 induction; to determine the frequency of active p38 in patients with sarcoidosis; and to test the hypothesis that sarcoid alveolar macrophages respond to microbial stimuli with aberrant expression transcription factors involved in MKP-1 expression and that effective drug treatment targets MKP-1 induction through modification of those transcription factors.

Dr. Samavati’s grant is supported by the National Heart, Lung, Blood Institute (NHLBI) #1R01HL113508.

In addition to her recent grant, Dr. Samavati’s laboratory works on developing arrays for diagnosis of sarcoidosis, which is also supported by the NHLBI (#R21HL104481). The ongoing grant started in 2012.

Dr. Samavati said that her research team developed a protein library derived from patients affected with sarcoidosis. This project will identify a panel of predictive antigens able to classify and differentiate sarcoidosis patients from healthy subjects and from subjects affected by different inflammatory diseases. Her team has immune-screened more than 100 patients with sarcoidosis and healthy individuals. The results can be used to develop a diagnostic tool in sarcoidosis and provide new and specific targeted therapies.
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