Mechanism Identified Behind Systemic Fibrotic Disorder

Two of these studies on the disorder were published together in the November 2010 issue of the journal Annals of Rheumatic Diseases. Nephrogenic systemic fibrosis (NSF) is a new disease that was first described in 2000. It manifests as progressive fibrosis in feet, legs, thighs, hands, and forearms. Though initially thought to affect only the skin, it has been shown that NSF can also affect internal organs, including the liver, lungs, muscles, heart, thyroid, and dura mater. The disease appears to affect patients with renal failure who receive specific gadolinium-based imaging agents for MRI.

In the first study, the researchers from the Jefferson Institute of Molecular Medicine of Thomas Jefferson University (Philadelphia, PA, USA) performed cell cultures on fibroblasts obtained from affected skin taken from patients with NSF. They discovered that the fibroblasts from these tissues were continually activated, and expressed an increased amount of collagen and other fibrotic proteins, according to Sergio A. Jimenez, M.D., professor of dermatology and cutaneous biology at Jefferson Medical College of Thomas Jefferson University, and codirector of the Jefferson Institute of Molecular Medicine.

"We also found that the fibroblasts express large amounts of another protein called smooth muscle actin, which indicates that they have transformed to myofibroblasts, which are cells that are a step between fibroblasts and smooth muscle cells,” said Dr. Jimenez, who is also director of the division of connective tissue diseases and director of the Scleroderma Center at Jefferson. "Smooth muscle actin is a protein that is normally present in smooth muscle cells. But these are not muscle cells, they are fibroblasts. Somehow the fibroblasts have changed their features to become an aggressive smooth muscle-like cell that produces large amounts of collagen.”

A significant observation was that the activated features of the fibroblasts were maintained in culture for several generations, indicating that the change in the features of these cells was long lasting, and was probably imprinted in their genetic material.

In a second experiment, Dr. Jimenez and colleagues treated normal fibroblasts with several compounds containing gadolinium, the most typically used imaging agent used for MRI. They found that these agents induced exaggerated production of collagen in the normal fibroblasts. "Normal people excrete gadolinium-containing contrast agents rapidly, but the chemical can stay in the body for prolonged periods of time in people with renal disease,” Dr. Jimenez said.

In the second study, the researchers examined the effects of gadolinium on gene expression of macrophages (white blood cells), production of proinflammatory chemicals called chemokines, and activation of a protein complex (NF [nuclear factor]-kappaB) that regulates immune response. They found that gadolinium-contrast agents caused a profound change in activation of these chemicals and proteins, concluding that these alterations may play a crucial role in development of NSF.

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