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New Findings on Idiopathic Pulmonary Fibrosis

Cedars-Sinai investigators have made significant progress in identifying the mechanisms behind idiopathic pulmonary fibrosis, a deadly disease that scars the lungs and impairs breathing. The findings appeared in a study published this summer in the journal Science Advances.

New Findings on Idiopathic Pulmonary Fibrosis

Idiopathic pulmonary fibrosis affects more than 100,000 people in the U.S. The condition results in a buildup of fibrosis–fibrous scar tissue–that blocks the lungs from performing their primary function of transporting oxygen to the bloodstream. Although the disease progresses at variable rates, most patients die within five years after being diagnosed unless they are a candidate for and receive a lung transplant, according to the National Institutes of Health. 

"This research is an important step forward in really understanding what causes disease progression in idiopathic pulmonary fibrosis and how we can better treat it," said Paul Noble, MD, professor of Medicine and chair of the Department of Medicine, director of the Women's Guild Lung Institute and the Vera and Paul Guerin Family Distinguished Chair in Pulmonary Medicine at Cedars-Sinai. Noble is the corresponding author of the study.

In a normal lung, a specialized cell known as a type 2 alveolar epithelial cells (ATII) function as progenitor cells, or stem cells, meaning that they regenerate to support the renewal and overall health of the lung. Other cells, known as mesenchymal cells, support the progenitor function of the ATII cells, secreting growth factors that promote the ATII renewal.

Paul Noble, MD

Paul Noble, MD

The interactions between the mesenchymal cells and ATII cells can either deter or promote cell renewal in the lung. When functioning properly, the two cell types work together to maintain healthy alveoli, air sacs where gas exchange occurs. For reasons not fully understood, that protective and regenerative mechanism is lost in idiopathic pulmonary fibrosis. Instead, the mesenchymal cells become invasive fibroblasts and destroy the progenitor cell niche, resulting in fibrous scars. In this capacity, they behave similarly to cancer cells that invade tissues.

This process inhibits the function of the lungs, as ATII cells are needed to provide the environment where oxygen can be transferred to the bloodstream. The fibrous scar that forms supplants them and can't perform this function.

"This communication is essential for normal repair after injury, and if it’s lost, your lungs will progressively fibrose," Noble said.

Investigators in the study created a mouse model of pulmonary fibrosis in which they eliminated the growth hormone receptor in the mesenchymal cells. They found that the mice without the receptors were more prone to developing fibrosis. The results suggest that the growth hormone receptors have a key role to play in maintaining healthy lung tissue. Interestingly, the prevalence of IPF dramatically increases with age–most patients are over 60 at the time of diagnosis–and it is well known that growth hormone levels decrease with age.

"So, communication matters, and when it's lost, disarray happens," Noble said. "We think that's one of the mechanisms for idiopathic pulmonary fibrosis progression, but it is not the only one."

Further, investigators found that in mice that received injections of growth hormone receptor-enriched extracellular vesicles, the hormone receptor-enriched vesicles were readily taken up by the ATII cells and used effectively within the lung.

"These findings provide evidence that mesenchymal growth hormone receptor deficiency contributes to pulmonary fibrosis. They also demonstrate that a vesicle mechanism of communication between mesenchymal cells and ATII cells can benefit ATII renewal and work against pulmonary fibrosis in mice," said Ting Xie, PhD, lead author of the study.

Their data suggest that vesicles, nano-sized carriers that transport molecular substances within or between cells, can carry functional growth hormone receptor that originated outside of the ATII cells, and that treatment with growth hormone receptor may improve lung function.

Noble said that while treatment with growth hormone receptor using a vesicle delivery mechanism may eventually prove to be an option for patients with pulmonary fibrosis, more study is needed.

"Our next step will be to better understand how this communication works and to explore whether restoring the growth hormone receptor would be a possible treatment option," Noble said.