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A Breath of Fresh Air: Targeting the Immune System to Treat Pulmonary Fibrosis

Signaling Molecules Involved in Allergic Diseases May Be the Key

illustration of a Fibrotic Lung compared with a healthy lung
Figure A shows the location of the lungs and airways in the body. The inset image shows a detailed view of the lung’s airways and air sacs in cross-section. Figure B shows idiopathic pulmonary fibrosis (scarring) in the lungs. The inset image shows a detailed view of the fibrosis and how it damages the airways and air sacs.
Credit: National Heart, Lung and Blood Institute

A team of NIAID researchers is examining the role of the immune system in the development of idiopathic pulmonary fibrosis (IPF), a life-threatening condition in which the lungs become scarred or thickened. There is no cure for IPF, and current treatments work only to prevent additional tissue scarring and to alleviate symptoms. These treatments also can have serious side effects.

Although the cause(s) of IPF is unknown, groups of cytokines, signaling molecules secreted by immune cells, have been shown to play a role in tissue repair and fibrosis in models of asthma, skin fibrosis, IPF, and drug-induced pulmonary fibrosis. These findings prompted a team from the NIAID laboratory of Tom Wynn, Ph.D., who had identified a critical role for the cytokine interleukin-13 (IL-13) in parasite-induced liver fibrosis, to examine the signaling molecules involved in IPF.

“Being diagnosed with IPF is similar to being diagnosed with cancer: Many people live only 3 to 5 years once disease is discovered,” says Dr. Wynn. “Understanding how IPF develops may help us identify new targets for treatment.”

micrograph of mouse lung
5-μm sections of lung tissue taken from normal mice on day 21 after bleomycin administration. The blue stained areas reveal the development of pulmonary fibrosis

Mouse Model Reveals Possible Cause of Disease

The team used three different mouse models of pulmonary fibrosis—parasite egg-induced, drug-induced, and cytokine-induced—to determine which cytokines may play a role in the development of the disease. Among the models they employed, the drug-induced pulmonary fibrosis closely resembles IPF disease. The drug they used, bleomycin, is a chemotherapeutic drug used to treat lymphomas, head and neck cancers, and Hodgkin’s disease.

In mice, the team found that bleomycin- and cytokine-induced pulmonary fibrosis were both mediated by another cytokine, IL-17A.  IL-17A is associated with allergic diseases and tissue injury and has been implicated in autoimmune diseases such as rheumatoid arthritis and multiple sclerosis. Mice that cannot make IL-17A did not display the same scarring and tissue thickening as mice with IL-17A. Blocking IL-17A activity also reduced fibrosis. 

Signaling Molecule in Mouse Disease Also Found in Humans

The investigators looked for evidence of IL-17A in lung tissue of people with IPF. The research team identified regions of inflammation in diseased lung tissue and found elevated levels of IL-17A in bronchoalveolar lavage fluid—fluid injected into the lungs and then collected for examination—suggesting that IL-17A may play a role in human IPF disease.

micrograph of a human lung
5-μm lung sections were cut from lung biopsies obtained from a patient with IPF. The section reveals marked inflammatory foci within the parenchyma (arrowheads), surrounded by dense collagen deposits (arrows)

In contrast, parasite egg-induced pulmonary fibrosis was mediated by IL-13, and IL-17A did not play a significant role in IL-13-dependent fibrosis. Additionally, IL-13 did not play a significant role in IL-17A-dependent disease.

IPF Involves Two Signaling Pathways

“These data indicate that two distinct signaling pathways are involved in pulmonary fibrosis,” says Mark Wilson, Ph.D., one of the project leads. “It is possible that IL-17A plays a role in the early stages of fibrosis, and then as the condition progresses, IL-13 becomes more important.”

More research is needed to determine just how these two signaling molecules may interact in the development and progression of pulmonary fibrosis.

“We show that without IL-17A, fibrosis is reduced in the mouse model system,” comments Dr. Wynn. “This work merges the fields of fibrosis research and immunology, opening the door to new treatment targets for a disease that currently has very few therapeutic options.”

Reference: MS Wilson et al. Bleomycin and IL-1beta-mediated pulmonary fibrosis is IL-17A-dependent. Journal of Experimental Medicine. DOI: 10.1084/jem.20092121 (2010).

Last Updated July 08, 2010

Last Reviewed July 02, 2010