Cellular and Biochemical Modulation of Inflammation and Fibrosis in the Scleroderma Lung

Vibha Lama, MD, MS and David Pinsky, MD
University of Michigan

Project Summary:

Drs. Lama and Pinsky are examining the mechanisms of inflammation and fibrosis in the lungs of scleroderma patients. Using a novel animal model of graft rejection, they are evaluating the ability of lung-resident mesenchymal (LR-MSC) stem cells to influence inflammation and fibrosis. They will also investigate the roles of certain regulatory molecules which occur naturally in the body, called eicosanoids (as well as their synthetic analogues), in modulating inflammation and fibrosis in the lung.

Research Update:

In the past year, progress was made with a pilot grant from the SRF. With studies done in vitro (test tube), the key result was to show that the LR-MSC can secrete factors including prostaglandin E2 (a member of the eicosanoid family, also known as PGE) that control cytokine production. If secreted, PGE seems to be able to induce immunoregulation and to control tissue injury. However, there seems to be an autoregulatory element to this loop. If the MSC is instead activated to become a fibrocyte, it will elaborate Th2 factors (like Il-13), which are known to be pro-fibrotic.

Future success will focus on determining what the LR-MSC is really doing in SSc (scleroderma) lungs. In the coming year, patients will be studied using BAL (bronchoalveolar lavage) to assess MSC activity and cell number (frequency) and relate those features to pathogenesis.

As a comparison to the scleroderma lung, similar studies will be conducted using MSCs collected by BAL from lung transplant patients.

If it does seem that PGE is a key inhibitory/controlling signal, it would provide a therapeutic avenue. If levels of this key signal can be kept high, the MSC would stay in the immunoregulatory state.

What this project means for people with scleroderma:

Understanding how lung-resident mesenchymal stem cells and eicosanoids modulate fibrosis may lead to therapies to prevent or ameliorate lung disease in scleroderma. In particular, prostaglandins are used therapeutically in SSc today but a better understanding of how they help would be key to more effective therapy with them.

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