Fibrosis is Harmful, and Varied Approaches to Suppress it are Under Development

Fibrosis is one of the major age-related failures of mammalian regenerative processes. Instead of reconstructing or maintaining the correct form of tissue, scar-like structures are deposited, disrupting organ function. Enough of this is fatal in organs such as the heart, liver, kidney, or lungs. Rising levels of fibrosis, and particularly following trauma such as infection or structural failure of aged blood vessels, are a significant component of loss of organ function and mortality in the old. Worse, the medical community has little in the way of therapies that can treat fibrosis; those that do exist are marginal in their benefits.

The causes of fibrosis are thought to be complex and tissue specific because regeneration is complex and tissue specific. Considered at the high level, it is a coordinated dance carried out between stem and progenitor cells of various types, the somatic cells already present in the tissue to be worked on, and immune cells, with many and varied signals passing back and forth between all of these types. The lower level details vary considerably by tissue type and structure.

In recent years, however, investigation of senescent cells - and the ability to slow aging by targeted removal of those cells - has revealed that a fair amount of fibrosis appears secondary to cellular senescence. Senescent cells generate chronic inflammation, as well as signals related to construction and destruction of the extracellular matrix, so it seems almost obvious in hindsight that they would be involved. A range of supporting evidence makes it seem plausible that inflammation causes disarray in the role of immune cells in regeneration and tissue maintenance, and comparisons between highly regenerative and less regenerative species suggest that immune cells strongly determine the quality of regeneration. Fibrosis in the lungs and other organs can be reversed through the use of senolytic treatments that destroy some fraction of senescent cells, a result so far demonstrated in animal studies only.

The research noted here is an example of bypassing all of these consideration in favor of outright sabotage of a crucial mechanism in tissue maintenance that is needed for fibrosis to occur. Unfortunately, this will also sabotage other important forms of normal regeneration, which may well limit its application to the treatment of critical cases after the fact, rather than as a form of prevention to keep the damage of fibrosis to a low level. Other forms of medicine with similar downsides have done well - think of the biologics for autoimmune disease that work through blanket suppression of parts of the immune system, for example - but I would hope that the research community can do better than this class of approach in the years ahead.

Blocking Matrix-Forming Protein Might Prevent Heart Failure

Researchers tested a manufactured peptide called pUR4 to block the fibronectin protein in human heart cells donated by heart failure patients. The treatment prevented the human heart cells from failing and restored their function. The treatment also reduced fibrosis and improved heart function after a simulated heart attack in mice.

Fibronectin is normally a good actor in the body. It helps form a cell-supporting matrix for the body's connective tissues, aiding tissue repair after injury. But after a heart attack, fibronectin overreacts, it polymerizes and helps produce too much connective matrix. It also causes hyperactive production of clogged and dysfunctional cardiac myofibroblast cells that damage the heart. The pUR4 compound is designed so it will attach to surface points on fibronectin, effectively inhibiting its effects in injured heart cells.

The pUR4 molecular treatment used in the current study is one of several compounds that show promise in preliminary preclinical research data. A key question in the current study was verifying the results of pUR4 targeted molecular therapy in both the mouse models and human heart failure cells. In mice with simulated heart attack that as a control experiment received a placebo therapy, the animals developed significant fibrosis and heart failure. When researchers treated mice with pUR4 for just the first seven days after heart attack, or genetically deleted fibronectin activity from the heart cells of mice, these reduced fibrosis and improved cardiac function. Treatment of human failing heart cells with pUR4 also reduced their fibrotic behavior.

The researchers emphasize it's too early to know whether the experimental therapy in this study can one day be used to treat human heart patients clinically. Extensive additional research is needed first, including proving pUR4's safety in larger animal models and then moving on to establish proof-of-principal effectiveness treating heart failure in those models.

Inhibiting Fibronectin Attenuates Fibrosis and Improves Cardiac Function in a Model of Heart Failure

Fibronectin (FN) polymerization is necessary for collagen matrix deposition and is a key contributor to increased abundance of cardiac myofibroblasts (MF) following cardiac injury. We hypothesized that interfering with FN polymerization or its genetic ablation in fibroblasts would attenuate MF, fibrosis, and improve cardiac function following ischemia/reperfusion (I/R)-injury.

Mouse and human MF were utilized to assess the impact of the FN polymerization inhibitor (pUR4) in attenuating pathologic cellular features such as proliferation, migration, extracellular matrix (ECM) deposition, and associated mechanisms. To evaluate the therapeutic potential of inhibiting FN polymerization in vivo, wild-type (WT) mice received daily intraperitoneal injections of either pUR4 or control peptide immediately after cardiac surgery, for seven consecutive days.

pUR4 administration on activated MF reduced FN and collagen deposition into the ECM and attenuated cell proliferation, likely mediated through decreased c-myc signaling. pUR4 also ameliorated fibroblast migration. In vivo, daily administration of pUR4 for seven days post-I/R significantly reduced MF markers and neutrophil infiltration. This treatment regimen also significantly attenuated myocardial dysfunction, pathologic cardiac remodeling, and fibrosis up to 4 weeks post-I/R. Finally, inducible ablation of FN in fibroblasts post-I/R resulted in significant functional cardioprotection with reduced hypertrophy and fibrosis.

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I already mentioned this news in older comment on this blog, but Janko Nikolich-Zugich, who presented at the SENS 5 conference, recently got a 10 million grant to rejuvenate the Thymus, and he thinks it will also be necessary to rejuvenate or reverse the fibrosis of the lymph nodes:

https://uanews.arizona.edu/story/ua-lab-seeks-holy-grail-gerontology

"Although T-cells still enter the lymph system in older people, the scant T-cells that are produced can't readily enter the lymph nodes. "The reason for that is the lymph nodes are undergoing profound changes with aging," Nikolich-Zugich says.

In fact, researchers see a lot of fibrosis in the lymph node, meaning the connective bundles are starting to get thicker, less organized and less flexible.

"Lymph nodes aren't able to effectively call in the cells from the outside, so fewer cells arrive," he says. "Moreover, when the cells arrive, they don't move inside like they should. Inside the lymph node is a superhighway meshwork, and we have found that this really gets messed up in aging."

Scientists have tried rejuvenating only the thymus by blocking the body's androgen production to increase its T-cell production, but increased, long-lasting immunity has proved elusive for the very reason that T-cells can't gain entrance to the lymph nodes.

So, Nikolich-Zugich and his collaborators are formulating a novel plan of attack.

"There is one important part of this grant that is different from the approaches that people have been taking from the past," Nikolich-Zugich says. "The novel idea here is that we want to rejuvenate both the thymus and the peripheral lymph organs, so both the factory that makes the cells and sites where the T-cells go to do the real work of defense against infection can once again work together.

"We feel like we will never get to rejuvenation if we work only on the thymus."

In fact, the grant, sponsored by the National Institutes of Health, is a program project grant, which by design includes several interrelated individual projects, each run by Nikolich-Zugich and his collaborators. Some of the projects look at the thymus, others at the lymph nodes."

Posted by: Jim at April 18th, 2018 8:19 AM

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