BML-111 Found to Suppress Lung Fibrosis in Mouse Model by Inhibiting Signaling Molecules

BML-111 Found to Suppress Lung Fibrosis in Mouse Model by Inhibiting Signaling Molecules

BML‐111, a potent activator of the natural anti-inflammatory lipoxin A4 receptor, protects lungs from fibrosis by inhibiting fibroblast activation and decreasing the levels of inflammatory signaling molecules, a mouse study shows.

The study “BML-111 suppresses TGF-β1-induced lung fibroblast activation in vitro and decreases experimental pulmonary fibrosis in vivo” was published in the International Journal of Molecular Medicine.

Transforming growth factor-β1 (TGF‐β1) is the potent inducer of fibroblast activation — the main cells responsible for the progression of fibrosis — driving their proliferation and promoting the production of extracellular matrix (the structural and biochemical support for cells). Inhibiting TGF‐β1-mediated signaling is thus a strategy to halt fibroblast activation and prevent fibrosis in the lungs.

In an animal model of skin fibrosis, a member of the lipoxins family — a group of naturally occurring molecules known for their anti-inflammatory properties — called lipoxin A4 receptor inhibited fibroblast activation and proliferation.

BML‐111 is a potent activator of lipoxin A4, and was previously shown to have anti‐inflammatory effects and help resolve different stimuli-induced lung injury. “However, whether BML‐111 affects fibroblast activation and lung fibrosis remains unknown,” researchers said.

To answer this question, the team incubated a lab-grown cell line of mouse embryo lung fibroblasts, called NIH3T3, with TGF‐β1, which activated the cells and induced the production of extracellular matrix proteins, including collagen, alpha-SMA (smooth muscle alpha actin), and fibronectin.

However, pre-treating these cells with BML‐111 led to a marked decrease in their proliferation and expression of the three extracellular matrix proteins.

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Moreover, researchers found that BML‐111’s effects were mediated by suppressing two pathways via which TGF‐β1 induces fibrosis (the Smad‐dependent and ‐independent signaling pathways).

The team then tested the effects of BML-111 in vivo in a PF mouse model.

Researchers injected BML‐111 into the abdomen of the bleomycin‐induced PF mouse model every other day for 21 days. BML‐111 was found to significantly extend the mice’s survival compared with control mice (no BML‐11 treatment). Moreover, BML‐111 lessened the detrimental effects of fibrosis in the lungs, as shown by a reduction of inflammatory cells.

BML‐111 also reduced the levels of inflammatory signaling molecules – namely interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and TGF-β1 itself – and significantly suppressed the production of extracellular matrix proteins.

IL-1β and TNF-α are vital pro‐inflammatory cytokines that cause the further release of fibrosis media and perpetuate the fibrotic cascade,” researchers said. Therefore, reducing the levels of these two proteins eases inflammation and subsequent fibrotic processes.

Overall, this study shows that “BML‐111 inhibits TGF‐β1‐induced fibroblasts’ activation and alleviates BLM [bleomycin]‐induced pulmonary fibrosis,” the team stated. “These results indicate that BML‐111 may be used as a potential agent for the treatment of pulmonary fibrosis.”

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