Cellular and Biochemical Modulation of Inflammation and Fibrosis in Systemic Scleroderma

Vibha Lama, MD, MS
University of Michigan

Project Summary:

Dr. Lama is examining the mechanisms of inflammation and fibrosis in the lungs of scleroderma patients. Dr. Lama's laboratory is investigating the contributions of an adult stem cell, termed lung-resident mesenchymal stem cells (LR-MSC), to human lung scarring accompanying scleroderma. 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:

Dr. Lama's laboratory continued to make progress with studies done in vitro, their key result was showing that the LR-MSC are able to 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 auto-regulatory element to this loop. If the LR-MSC loses its ability to produce or respond to this vital anti-fibrotic molecule, it can instead become activated and become a scar-producing cell called a myofibroblast. This pro-fibrotic change was shown to contribute to lung fibrosis.

Future success will focus on determining the role of LR-MSC in scleroderma lungs. In the coming year, scleroderma patients will be studied using BAL (bronchoalveolar lavage) to assess LR-MSC activity and cell number (frequency) and they will relate those features to pathogenesis. For comparison purposes, similar studies will be conducted using MSCs collected by BAL from lung transplant patients. If it appears that PGE is a key inhibitory/controlling signal, this would provide a therapeutic avenue; if levels of PGE can be kept high, the MSC would stay in the immunoregulatory state and would not progress to a myofibroblast.

What this project means for people with scleroderma:

Understanding how LR-MSC and eicosanoids modulate fibrosis may lead to therapies to prevent or ameliorate lung disease in scleroderma. In particular, prostaglandins are used therapeutically in scleroderma today, but a better understanding of how they work is key to developing more effective therapies. Another highly significant aspect of this proposal is that it provides a basis for applying the various treatment agents in an individualized fashion to patients with scleroderma.

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