A small RNA molecule called miR-133a can prevent tissue scarring (fibrosis) in people with idiopathic pulmonary fibrosis (IPF) by interfering with a pro-fibrotic signaling pathway that is involved in disease progression, a study says.
The findings of the study, “Transforming growth factor (TGF)-β1-induced miR-133a inhibits myofibroblast differentiation and pulmonary fibrosis,” were published in the journal Cell Death & Disease.
IPF is a chronic lung disease of unknown origin, characterized by lung tissue injury that is followed by the abnormal growth of fibroblasts and myofibroblasts (connective tissue cells). These cells produce excessive amounts of proteins from the extracellular matrix (ECM) — the network that surrounds and supports cells — resulting in fibrosis, or tissue scarring, and loss of lung function.
The infiltration of immune cells into the lungs also accompanies IPF. These inflammatory cells produce high quantities of transforming growth factor-beta 1 (TGF-β1), a pro-fibrotic molecule that plays a central role in disease progression.
MicroRNAs (miRNAs) — tiny RNA molecules that control the expression of several genes — have recently been implicated in IPF. However, the mechanisms by which they operate and affect the course of IPF remain largely unknown.
Now, a team led by researchers at the Chinese Academy of Sciences and Creighton University School of Medicine set out to investigate the role of miR-133a — a microRNA — in the development and progression of IPF. Scientists discovered that miR-133a was overproduced in human lung fibroblasts (HFLs) exposed to TGF-β1.
Experiments showed that this miRNA was overproduced in these cells in response to TGF-β1 in a time- and dose-dependent manner.
Importantly, researchers found that miR-133a prevented HFLs from differentiating into myofibroblasts, whereas an inhibitor of this microRNA promoted the differentiation. The differentiation of fibroblasts into myofibroblasts is a hallmark of IPF that is normally triggered by the excessive production of TGF-β1.
Further analyses revealed that miR-133a was able to reduce the number of myofibroblasts by reducing the expression of several components from the pro-fibrotic signaling pathway triggered by TGF-β1. These included classic myofibroblast differentiation markers, such as alpha-smooth muscle actin (ɑ-SMA), connective tissue growth factor (CTGF), and different types of collagen.
Additional experiments also showed that TGF-β receptor 1, CTGF, and collagen type 1-alpha1 (Col1a1) all were directly controlled by miR-133a.
In a final experiment, researchers forced the expression of miR-133a in mice that had been exposed to bleomycin, an anti-cancer drug used to trigger pulmonary fibrosis in rodents. They found that the treatment reduced the severity of fibrotic lesions in the animals’ lungs.
“These data are an exciting breakthrough given the current dismal prognosis associated with IPF in humans,” the researchers said. “Manipulations of miR-133a expression may provide a new therapeutic strategy to halt and perhaps even partially reverse the progression of IPF.”
Nonetheless, the team called attention to the fact that “any therapeutic plan for using miR-133a to treat IPF must include strategies to directly target the fibroblasts due to undesirable off-target effects.”
Regarding future long-term goals, the team said they want to “determine if targeting fibroblast miR-133a expression via local drug application provides an effective strategy for prevention and/or treatment of IPF.”
The researchers noted that the median survival time for people with IPF is 2-3 years from diagnosis.
“At a minimum, our study provides legitimate hope that effective therapies for fibrosis-associated morbidity and mortality, such as that due to IPF, are on the horizon,” the researchers concluded.