Targeting PAD4 Reduces Age-Related Fibrosis

Fibrosis is the inappropriate formation of scar-like tissue, and it is an important component in the pathology of a range of age-related diseases. Fibrosis causes loss of function where it disrupts the normal tissue structure of organs, and at present there is little in the medical toolkit that can be used to help. Better known examples of conditions in which fibrosis is significant include the progression of chronic kidney disease and damage to aged heart tissue. Here researchers note the possibility for an intervention that slows down the progression of fibrosis in mice, and may form the basis for a human therapy:

The wear and tear of life takes a cumulative toll on our bodies. Our organs gradually stiffen through fibrosis, which is a process that deposits tough collagen in our body tissue. Fibrosis happens little by little, each time we experience illness or injury. Eventually, this causes our health to decline. Ironically, fibrosis can stem from our own immune system's attempt to defend us during injury, stress-related illness, environmental factors and even common infections. But a team of scientists thinks preventative therapies could be on the horizon. "We've documented in mice how deletion of a single gene, PAD4, has a drastic effect on curbing the complex process of fibrosis." Looking to the future, they envision that the development of a once-daily pill, capable of inhibiting PAD4, could one day be used as a preventative measure.

The PAD4 gene controls an enzyme of the same name. In times of infection or bodily stress, the PAD4 enzyme activates a strange, primitive immune defense that ends up doing more harm than good. White blood cells, called neutrophils, self-combust and eject their own DNA strands outward like javelins. Sacrificing themselves, the exploded neutrophils and their outreaching DNA tentacles form so-called neutrophil extracellular traps (NETs), which nature perhaps intended to use as webs for catching foreign invaders and plugging up injury-related bleeding. Even though NETs try to help us, they counteractively set off a chain reaction that deposits an insidious type of collagen amidst our organs' hard-working cells. This collagen-laced fibrosis keeps piling up each time our body's immune system releases NETs. Over a lifetime, cumulative fibrosis is a far more important factor in health than any possible benefits imparted by NET release.

Whereas young hearts in mice and humans contain thin layers of connective tissue, older hearts typically have too much connective collagen built up between heart muscle cells. This reduces the heart's ability to pump blood efficiently. To investigate PAD4's effects on age-related cardiac fibrosis, researchers compared heart tissue of normal mice with another group of mice that had the PAD4 gene deleted. They observed that old mice without PAD4 had much less fibrosis than the normal mice. In fact, these mice had heart tissue that looked strikingly similar to heart tissue of young mice, and they kept up remarkably "young" levels of systolic and diastolic heart function as they aged. Researchers then looked at collagen deposition in mouse lungs. They found that deleting the PAD4 gene also significantly reduced lung fibrosis as mice aged. The researchers believe these observations show that deleting the PAD4 gene in mice protected their organs from age-related fibrosis and dysfunction. "If we could inhibit PAD4 or otherwise stop NET release in humans, we might be able to greatly reduce age-related fibrosis and improve our quality of life."

Link: https://www.eurekalert.org/pub_releases/2017-01/bch-faf012717.php

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