A study recently published in The Journal of Pathology led by researchers at the University of Southern California and the Saban Research Institute at Children’s Hospital Los Angeles revealed the mechanism underlying the multiplication of fibrous tissue cells in the lungs of patients with idiopathic pulmonary fibrosis (IPF). The study is entitled “A novel profibrotic mechanism mediated by TGF-β-stimulated collagen prolyl hydroxyls expression in fibrotic lung mesenchymal cells.”
IPF is a progressive fatal lung disease in which the lung tissues and alveoli are damaged, becoming thick and scarred, compromising oxygen transfer between the lungs and the bloodstream. The generation of this scar tissue is known as fibrosis and a rapid growth of fibrous tissue is observed in IPF patients, leading to severe breathing difficulties, a persistent cough, and problems in performing daily tasks. IPF has no cure and respiratory failure is the main cause of death associated with the disease. IPF has a poor prognosis and around two-thirds of the patients succumb within five years after being diagnosed.
Signaling of the growth factor TGF-β is known to be important for diverse functions, including an appropriate immune response. Excessive TGF-β signaling, however, has a pro-fibrotic effect, playing a key role in the development of lung fibrosis both in IPF patients and experimental models, although the mechanism underlying this effect remains unclear. Blocking the TGF-β signaling pathway is not a viable therapeutic strategy due to the importance of this key molecule in other cellular mechanisms. “This is a very complicated signaling pathway, which promotes mesenchymal stem cell proliferation, while also acting as a tumor suppressant,” explained the study’s senior author Dr. Wei Shi. “Our goal was to find a way to target specific cells that result in fibrosis without affecting other cells.”
Researchers used a unique transgenic mouse model to inhibit TGF-β signaling in mouse lung mesenchymal cells at different stages of lung fibrosis. They found that fibrosis development was attenuated by TGF-β inhibition and that this was independent of altered early inflammatory processes. Furthermore, the team identified a novel gene called prolyl 4-hydroxylase (P4HA3) downstream of the TGF-β signaling pathway, which is involved in collagen synthesis and is crucial for the overabundant collagen accumulation associated with IPF. P4HA3 was found to be significantly expressed in fibrotic mouse lungs and in the lungs of IPF patients. Inhibition of P4HA3 reduced the TGF-β-stimulated collagen production in both cultured connective tissue cells and mouse models of lung fibrosis.
The research team concluded that excess activation of TGF-β signaling results in upregulation of P4HA3 that subsequently leads to an increased collagen production. “Our data indicate that increased expression of collagen prolyl hydroxylase is one of the important mechanisms underlying the proliferation of fibrous tissue that is mediated by TGF-β. Inhibiting this enzyme appears to be a promising therapy to interfere with excessive collagen production and deposition in IPF patients,” concluded Dr. Shi in a news release.