Lung fibrosis is a serious condition that thickens tissues in the lungs and makes it hard to breathe. It can be caused by a variety of environmental factors, including exposure to coal or grain dust. New work has shown that it may be possible to prevent the disease with a drug that can block structural changes to collagen. It has been suggested that it is not the amount, but rather the structure of collagen that can lead to lung fibrosis. This research, reported in eLife, has also revealed how drugs can protect against those changes.
The architecture of our tissues is called the extracellular matrix (ECM) and it had been thought that when that ECM accumulates, tissues get stiff and fibrosis can happen. Recent work has suggested, however, that the increase in stiffness causes more ECM material to build up, feeding a cycle that is constantly generating new scar tissue.
"We knew that stiffness is an important factor in the build-up of scar tissue in the lung," explained the lead author of this study, Mark Jones, NIHR Clinical Lecturer in Respiratory Medicine at the NIHR Southampton Biomedical Research Centre and University of Southampton, UK. "But we didn't understand what specifically causes increased stiffness in diseased human tissue. Given that excessive build-up of collagen is considered a hallmark of fibrosis, we wanted to see whether this molecule has a role in tissue stiffness."
The research team began by assessing lung tissue taken from healthy people and those with lung fibrosis to learn more about the biological and structural changes the disorder causes in that organ. The lung samples taken from fibrosis patients turned out to be far stiffer than what was taken from healthy people, but the levels of collagen were startlingly similar.
Next, the scientists analyzed enzymes that help crosslink collagen, which imparts its unique structure. The LOXL family is one such group of these enzymes; they were found at much higher levels in the fibrosis lung samples.
Digging deeper, the researchers looked at collagen structure within the fibrosis samples, finding that stiffness was present wherever so-called mature cross-linked collagen levels were high. The collagen building block, called fibril, was also found to be altered in these samples. This work suggests that tissue stiffness is determined by collagen structure, which is regulated by he LOXL family.
A movie demonstrating how the effect of different treatments on tissue stiffness can be tested using patient cells which have been grown in 3D.
Knowing that, the team wanted to see if they could change collagen structure with the LOXL enzymes, and whether that could prevent lung fibrosis. LOXL-2 and LOXL-3 are blocked by an enzyme, PXS-S2A in lung cells harvested from fibrosis patients. Exposure to that drug reduced the level of cross-linked molecules in those cells. It also lowered stiffness, even at low drug concentrations. When applied to a rat model of lung fibrosis, treated rats showed no adverse impacts and had improvement in lung function and reduced fibrosis.
"Together, our results identify that treatment approaches which maintain normal collagen architecture may prevent tissue stiffening and limit the mechanisms that drive progressive fibrosis," noted Donna Davies, Professor of Respiratory Cell and Molecular Biology at the University of Southampton. "Our findings suggest the need to conduct studies in patients with lung fibrosis to see whether these approaches would be of benefit."
Sorces: AAAS/Eurekalert!, Mayo Clinic, eLife
