The discovery of a new metabolic pathway has upended a long-held belief of how fibrosis occurs and offers hope for a new treatment target in PF.

The results of a recent study point to new players in pulmonary fibrosis (PF) that may be important for a better understanding of the disease and developing novel treatment.

Accumulating evidence suggests that PF is a disease associated with the fibrotic process resulting from recurrent injury to lung alveolar epithelial tissues. These tissues line the outer side of lung alveoli, or air sacs where gas exchange takes place. An important role in the repair of the lung injury exists for macrophages, which are a distinct type of white blood cell and the lungs’ first line of defense within the lung. In fibrosis (scarring), macrophages have a vital role in repairing lung injury. Yet, this new study shows how macrophages can induce abnormal scarring without recurrent alveolar epithelial injury—the long-held teaching.

In experimentation on mice, researchers at the University of Alabama at Birmingham (UAB) found a new avenue for macrophage involvement in lung repair: the “mevalonate metabolic pathway.”*

  • The researchers looked at localization of a small protein implicated in fibrosis called Rac1 in lung cells from fluid samples called bronchoalveolar lavage (BAL). These cells represent a convenient model for PF research, since BAL cells of PF patients keep some disease hallmarks that set them apart from those of healthy individuals.
  • They then found that Rac1 in mitochondria (cellular organelles producing energy) is significantly increased in BAL cells of PF patients. The transition of Rac1 from cytosol (a liquid inside cells) is initiated by addition of a small “tag” called geranylgeranyl to Rac1 protein in a process called post-translational modification.
  • Adding this tag to Rac1, causing it to activate and move to mitochondria of lung macrophages, contributes to fibrosis.
Fibrotic Pathway Suggests New Target for Treating PF

The study also found that Rac1 relocation to mitochondria is associated with generation of ROS (mtROS), a reactive form of oxygen produced by mitochondria.

  • High mtROS levels may induce cell death (apoptosis).
  • Generation of mtROS also induces macrophages to switch to a profibrotic mode, promoting scar formation.
  • Prior experiments have shown that the deletion of Rac1 from macrophages protected against fibrosis, whereas treatment with the tag geranylgeranyl increased collagen deposition (scarring).
  • These new results demonstrate that the addition of a tag to Rac-1 in macrophages is a critical regulator of fibrotic repair.

It is believed that PF is an abnormal response to lung injury that involves several cell types: epithelial cells, fibroblasts, and immune cells. While models of pulmonary fibrosis have focused on abnormal epithelium-fibroblast interactions, the new experimental data show a model shift, indicating a critical role for macrophages and their communication (“crosstalk”) with fibroblasts in the development and progression of fibrosis.

In a press release by UAB, lead study author A. Brent Carter, MD said, “Here, we show a paradigm shift that indicates a critical and essential role for monocyte-derived macrophage/fibroblast crosstalk in the development and progression of fibrosis in the absence of epithelial injury. Although alveolar epithelial cell dysfunction may initiate the development of IPF, our findings suggest that repeated epithelial cell injury is not required for the progression of fibrosis.”

“We propose that monocyte-derived macrophage/fibroblast crosstalk can induce fibrosis without epithelial cell injury and is the primary driver in mediating disease progression. These observations suggest that targeting the mevalonate pathway may abrogate the role of macrophages in dysregulated fibrotic repair.”

The research article can be found at:

*Larson-Casey, J.L.; Vaid, M.; Gu, L. et al. (2019). Increased flux through the mevalonate pathway mediates fibrotic repair without injury. Journal of Clinical Investigation129(11), 4962-4978.