In PF Mice, Fibroblast Activation Protein Seen to Speed Collagen Clearance from Lungs
A potentially important new study, published in the Journal of Biological Chemistry, identified fibroblast activation protein (FAP) as a crucial factor in collagen fragment clearance in the lungs. Clearing collagen fragments is a key step in reducing tissue scarring and restoring lung function following injury, making FAP an interesting target for new idiopathic pulmonary fibrosis (IPF) treatments.
The process of lung tissue scarring in IPF is dependent on an array of molecular factors promoting the accumulation of collagen in the tissue. Scientists have previously observed that FAP levels are increased in the lungs of IPF patients, assuming FAP to be part of the process leading to disease. The new study, however, shows that FAP protects the lungs from fibrosis.
The first author of the study, Dr. Ming-Hui Fan from the University of Pittsburg, was joined by researchers from a large number of centers, including the National Institute of Health (NIH). By approaching the question of increased FAP in IPF from several angles, the study, entitled “Fibroblast Activation Protein (FAP) Accelerates Collagen Degradation and Clearance from Lung in Mice,” was able to answer many important questions about lung fibrosis.
The multicenter team used a knockout mouse unable to produce FAP and, by inducing experimental lung injury, generated two different mouse models of pulmonary fibrosis. Studying the two mouse types in both models, researchers were able to reach several conclusions regarding the role FAP plays in lung tissue scarring.
The team observed that normal mice start producing more FAP following lung injury, a finding that resembles the increased FAP levels in patients. However, mice lacking FAP did not survive as long as their normal counterparts, indicating that FAP was protecting the lungs from damage. Next, looking at the lungs of the experimental animals, researchers found that mice lacking FAP had more collagen and more fibrosis, irrespective of the lung fibrosis model used.
The cytokine TGF-β is a signaling molecule described as the master switch of fibrosis development. It stimulates normal lung fibroblasts to turn into reactive myofibroblasts involved in wound healing and scar formation. While the team did not detect a higher number of myofibroblasts in cells cultured from the lungs of FAP-deficient mice, they did find that the myofibroblasts displayed more pronounced characteristics after exposure to TGF-β.
Based on further molecular investigations, the team believes that FAP is important for clearance of shorter collagen fragments that are first cleaved by other factors known as MMPs. In contrast to normal mice, FAP-deficient mice had short collagen fragments present in the lungs before they acquired lung injury. The most important piece of evidence in the study was that when researchers re-introduced FAP into the deficient mice, the changes were reversed. Therefore, the team proposed that FAP plays an important role in the clearance of collagen both in healthy and injured lungs.
The researchers argue that fibrosis can be seen as an imbalance between the production and the clearance of collagen. They hope these new findings will inspire the generation of a new class of therapeutics favoring the breakdown of fibrotic tissue. The only approved drugs for IPF available today — OFEV (nintedanib) and Esbriet (pirfenidone) — act by decreasing the formation of fibrotic tissue.