JUL 19, 2018 10:21 AM PDT

Stopping Structural Changes in Collagen may Prevent Lung Fibrosis

WRITTEN BY: Carmen Leitch

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 CliniceLife

About the Author
  • Experienced research scientist and technical expert with authorships on 28 peer-reviewed publications, traveler to over 60 countries, published photographer and internationally-exhibited painter, volunteer trained in disaster-response, CPR and DV counseling.
You May Also Like
MAR 29, 2020
Cell & Molecular Biology
MAR 29, 2020
Investigating How Genetic Variants Impact the Cerebral Cortex
The outermost layer of the brain is called the cerebral cortex, a relatively thin sheet of gray matter that performs a v ...
APR 11, 2020
Cardiology
APR 11, 2020
Cell Transplant Repairs Brain After Stroke
Using cell therapy, researchers from Lund University in Sweden have successfully restored mobility and a sense of touch ...
APR 22, 2020
Immunology
APR 22, 2020
Scientists Engineer Custom Antiviral Receptors to Fight COVID-19
The best offense may be a good defense in the fight against COVID-19. Researchers from the Duke-NUS Medical School are e ...
APR 23, 2020
Cardiology
APR 23, 2020
Arteries Respond in Different Ways in Females and Males
Exploring Arterial Smooth Muscle Kv7 Potassium Channel Function using Patch Clamp Electrophysiology and Pressure Myograp ...
MAY 18, 2020
Cell & Molecular Biology
MAY 18, 2020
Just One Fatty Meal Can Impair Focus
Many tasty and convenient foods are high in fat, and new research has suggested that just one fatty meal may hinder our ...
MAY 22, 2020
Genetics & Genomics
MAY 22, 2020
ALK - The Skinny Gene?
Some people have to count calories and exercise regularly to be skinny while others can consume whatever they want and n ...
Loading Comments...