The Hadassah University Medical Center’s Pulmonary Institute is an innovator in laboratory research aimed at reversal of pulmonary fibrosis, the debilitating formation of excess fibrous connective tissue in the lung:
The Institute is a national referral center for pulmonary fibrosis. Its researchers have developed an animal model that has enabled them to test hypotheses concerning how fibrosis progresses at the molecular and cellular level.
“Pulmonary fibrosis is a special interest of mine,” relates Prof. Raphael Breuer, head of the Institute and Founder and Director of Hadassah’s Laboratory for Lung and Molecular Biology. “Research to better understand the mechanisms of pulmonary fibrosis and to provide the best possible clinical care for patients with this disease has been a primary focus of my professional life over the last 30 years. I think that many scientists and physicians specializing in this field feel that we are beginning to make real headway with this difficult challenge.”
Hadassah’s researchers investigate the genes, proteins, and other molecules that lead fibroblasts to accumulate uncontrollably in patients with fibrosis. Their close link with physicians in the Pulmonary Unit, as well as leading pharmaceutical companies, facilitates rapid patient access to novel therapies that emerge from their work and other laboratories worldwide.
Among their findings are:
- During fibrosis, lung myofibroblasts–the cells that create scars in the lung–acquire an immune-privileged cell phenotype, enabling them to escape from immune surveillance. This mechanism parallels the process that enables cancer cells to escape the immune system and accumulate uncontrollably.
- The Fas molecule–the antigen recognized by antibodies that initiate programmed cell death-plays an important role in myofibroblast accumulation. Fas ligand (FasL-positive) myofibroblasts actually kill the immune cells that might otherwise prevent their uncontrolled accumulation.
- Flice-inhibitory protein (FLIP) diverts Fas signaling and induces the Fas molecule to signal myofibroblasts to accumulate rather than to undergo normal programmed cell death.
Currently, Hadassah researchers are focusing on the role of T lymphocyte immune cells. They have found that, in an animal model, when these T lymphocytes are FasL-positive, they induce myofibroblast cell death and enable clearance of lung myofibroblasts during the resolution of lung fibrosis. The scientists are now seeking to more fully elucidate the roles of Fas molecules, FasL, FLIP, and T lymphocytes in allowing myofibroblast accumulation as well as in the resolution of lung fibrosis.
At present, there is no medication that can reverse or significantly slow the process of lung fibrosis. Based on their findings, however, Hadassah’s researchers are proposing a new approach to treatment of pulmonary fibrosis: Instead of suppressing the immune system, they propose blocking the capability of fibrotic lung myofibroblasts from evading T cell-induced apoptosis (programmed cell death). This would enable lymphocytes to more effectively stop uncontrolled fibroblast accumulation, known to be the cause of lethal lung fibrosis.