High Levels of Vimentin Protein Linked to Lung Fibrosis, Study Shows
Inhibiting vimentin can prevent fibroblasts — the cells responsible for the production and buildup of scar tissue (fibrosis) — from invading the lungs and producing collagen, the major component of fibrotic lesions in IFP, the study showed. Blocking vimentin can also improve autophagy, a “self-cleaning” process that eliminates damaged cells from the lungs.
These findings were in the study, “Vimentin intermediate filament assembly regulates fibroblast invasion in fibrogenic lung injury,” published in JCI Insight.
Lung tissue remodeling is an hallmark of IPF, which is characterized by the invasion of fibroblasts and the accumulation of extracellular matrix (ECM) proteins in lung tissue. Defects in cells’ natural cleaning systems, such as autophagy, which leads to the accumulation of damaged cells in the lungs, has also been linked with IPF.
Researchers at the University of Alabama at Birmingham and their collaborators found in previous studies that IPF patients have increased levels of antibodies that detect their own natural vimentin protein. An antibody is a protein made by plasma cells, a type of white blood cell, in response to harmful substances in the body, called antigens. In addition, vimentin amounts were also linked to poorer lung function.
Vimentin is an intracellular protein commonly found in the cell’s cytoskeleton — the fibers inside cells that give them structure, and sometimes mobility.
However, it was unclear whether vimentin played a role in the invasion of lung tissue by fibroblasts, and whether it affected autophagy in the lungs.
In the new study, researchers looked at lung tissue samples collected from IPF patients, and found that vimentin-rich cells were at the periphery, or outer edges, of the fibrotic lesion. The same finding was detected in experimental 3D lung tissue-derived spheres, called pulmospheres. The pulmospheres were built from cells taken from primary lung biopsies of IPF patients, and developed to mimic in the lab the function of mature lungs.
Compared to fibroblasts collected from age-matched healthy subjects, fibroblasts from the IPF patients were found to have impaired autophagy activation in response to external stimuli. The fibroblasts in IPF patients also had higher-than-usual levels of vimentin. Further experiments revealed that pulmospheres from IPF patients had been subject to more invasions (138.2%) as compared with age-matched controls (83.99%). Similarly, vimentin-positive cells were located at the periphery and in the zone of invasion.
Since vimentin-positive filaments were increased in the autophagy-resistant IPF fibroblasts, the team explored the effects of an inhibitor called withaferin A (WFA) in cells cultured in the lab.
WFA treatment lowered levels of both vimentin and of a type of collagen produced in excess in fibrotic tissue. Moreover, WFA enhanced the autophagy mechanism in IPF fibroblasts.
Researchers also assessed whether the invasiveness of IPF fibroblasts was affected by the activation or inhibition of autophagy. Treatment with approaches that induce natural cell cleansing blocked the cells’ invasiveness; an autophagy inhibitor, or blocker, led to the opposite effect.
To confirm their findings, the team next administrated WFA to mice with bleomycin-induced fibrotic lung injury, an established mouse model of IPF. Treatment with WFA for 11 days prompted autophagy, and decreased vimentin levels in the animal’s lungs when compared to placebo-treated mice.
Pulmospheres prepared from cells collected from these animals also showed that the ones treated with bleomycin and WFA were less invasive.
Finally, researchers tested the effects of WFA in pulmospheres prepared from lung biopsies of 15 IPF patients. Similarly to the mice data, the WFA treatment halted invasion in the pulmospheres of 14 patients.
Overall, this study “expands the role of vimentin as a regulator of fibroblast invasion and cellular autophagy in IPF,” the researchers wrote. These findings suggest that modulating the numbers of vimentin filaments is a potential therapeutic way of treating IPF.