Combo Therapy Seen to Enhance Anti-Fibrotic Activity in Lung Cells from IPF Patients in Early Study
A combined treatment, pirfenidone and rapamycin, worked to prevent fibrosis in lung fibroblasts from patients with idiopathic pulmonary fibrosis, new research showed, suggesting a possibly more effective way of treating IPF.
The study, “Anti-fibrotic effects of pirfenidone and rapamycin in primary IPF fibroblasts and human alveolar epithelial cells” was published in the journal BMC Pulmonary Medicine.
Pirfenidone, marketed as Esbriet by Genentech, is an oral anti-inflammatory and anti-fibrotic drug approved in the U.S. and Europe (among other countries) to treat mild to moderate IPF.
It inhibits collagen synthesis, fibroblast proliferation, fibrosis induced by transforming growth factor β1 (TGF−β), and works to mediate tissue repair. All these activities prevent progression of the fibrotic process and the inflammation associated with it.
The treatment has been shown to prolong survival without disease worsening, slow down the decline in the levels of forced expiratory volume (a measure of lung function), reduce fibrosis and normalize the secretion of pro-inflammatory mediators in IPF patients.
Despite the important contributions that anti-fibrotic drugs such as Esbriet have brought to managing IPF, the ultimate goal is a treatment that completely halts fibrosis.
With this in mind, researchers investigated if a combined of pirfenidone and rapamycin, another inhibitor of fibroblast proliferation, could improve the effects of pirfenidone alone.
Rapamycin is currently being evaluated in clinical trials as a potential IPF therapy.
The team studied pirfenidone and rapamycin in lung fibroblasts from IPF patients and human lung epithelial cells grown in the laboratory. Both cell lines were treated with this combination, and in the presence or absence of TGF−β, a major player in fibrosis progression.
The combination significantly inhibited the conversion of fibroblasts into myofibroblasts, an important step in the fibrotic process. But such anti-fibrotic activity was mainly due to the action of pirfenidone.
Since uncontrolled migration of fibroblasts to the injury site is also a main contributor to the formation of scar tissue in the lungs, researchers also investigated the treatment’s effects on this process.
Using a cell migration assay, they found that both pirfenidone and rapamycin, alone or in combination, reduced the migration of fibroblast cells from IPF patients. Importantly, the slowing of this process was increased by combining pirfenidone with rapamycin, compared with pirfenidone alone.
The combination treatment also inhibited the synthesis of key proteins involved in the fibrotic process, including collagen. Interestingly, each drug inhibited different proteins, indicating that both compounds working together could increase the anti-fibrotic range of action.
Pirfenidone plus rapamycin also did not result in any significant toxicity to the cells.
“These findings indicate that the combination of pirfenidone and rapamycin widen the inhibition range of fibrogenic markers and prevents fibroblast migration,” the researchers concluded. “These findings reveal the importance for a combined therapy that may result in a more efficient treatment.”