Fibrosis is a significant component of many age-related conditions, a failure of the normal regenerative process that leads to the formation of increasing amounts of scar-like, fibrous connective tissue in organs. This disrupts normal tissue structure and degrades proper function. It features prominently in common forms of heart disease, kidney failure, and liver disease, among others. As is the case for many specific aspects of aging, there is no good treatment for fibrosis, if by this we mean a reliable way to turn back its progression and restore failing tissues to their former state.
The causes of fibrosis lie somewhere downstream of the fundamental forms of cell and tissue damage outlined in the SENS view of aging. Insofar as it is cells that work to produce fibrotic structures, built from the same materials as the normal extracellular matrix, the proximate causes of fibrosis are thus altered cell signaling and behavior, such as that related to the increased chronic inflammation that accompanies aging. The nature of these signals is much debated, and likely varies considerably from tissue to tissue.
Given the importance of fibrosis to the progression of age-related disease, there is considerable interest in finding ways to reverse its progression, not just slow it down. Most such research, as is the case in the paper linked below, is focused on the proximate causes of fibrosis, the altered cellular signaling and behavior. Researchers hope that by forcing a change here, through the use of small molecule drugs and the like, they can change cellular behavior for the better despite the continued existence of underlying damage that causes dysfunction, and set cells to removing fibrosis and correctly regenerating tissue. Or at last tilt the balance somewhat in that direction.
Cardiac fibrosis, an abnormal thickening of the heart wall leading to congestive heart failure, was not only halted but also reversed by a caveolin-1 surrogate peptide (CSD) in a preclinical model, report researchers. CSD was able to decrease the fibrotic ventricular wall thickness and improve heart function, all with apparently no toxicity and minimal off-target effects. More than a decade ago, researchers noted that the skin and lung cells producing excess collagen in scleroderma, leading to fibrosis, were deficient in caveolin-1. Supplementing these cells with a caveolin-1 surrogate peptide (CSD; caveolin-1 scaffolding domain peptide), a truncated version of the original compound, showed a reversal of fibrosis.
Hypertrophic overgrowth and profibrogenic signaling of the cardiac muscle occurs under pressure overload. Fibrosis that develops under these conditions is detrimental to the heart's pumping efficiency as it causes a stiffer and less compliant cardiac muscle, leading to the progression of congestive heart failure. To mimic the cardiac fibrosis typical of heart failure, researchers used a transverse aortic constriction mouse model to create pressure overload hypertrophy that then led to the development of fibrosis. Treatment with CSD not only halted the progression of the cardiac fibrosis but also led to its reversal with improved ventricular function.
Although promising, these findings are preliminary - only reflecting outcomes in mice. The researchers plan to run larger preclinical studies using the same approach to generate more definitive data, and if all goes as expected, to move forward to the large-animal studies necessary to take a compound forward into clinical trial. They also note that they are testing CSD in a different congestive heart failure model, the angiotensin II infusion model, which also affects the kidneys. CSD is showing promising anti-fibrotic effects on both the heart and the kidneys in this model. "Fibrotic diseases are related to each other no matter the affected organ. In our case, we were studying lung and skin fibrosis. We had the opportunity to test the same reagent in heart fibrosis and, lo and behold, it worked even better than in lung and skin fibrosis models. And there are plenty of other diseases with a fibrotic element to them where we think the CSD peptide might be useful."
Chronic ventricular pressure overload (PO) results in congestive heart failure (CHF) in which myocardial fibrosis develops in concert with ventricular dysfunction. Caveolin-1 is important in fibrosis in various tissues due to its decreased expression in fibroblasts and monocytes. The profibrotic effects of low caveolin-1 can be blocked with the caveolin-1 scaffolding domain peptide (CSD, a caveolin-1 surrogate) using both mouse models and human cells.
We have studied the beneficial effects of CSD on mice in which PO was induced by trans-aortic constriction (TAC). Beneficial effects observed in TAC mice receiving CSD injections daily included: improved ventricular function (increased ejection fraction, stroke volume, and cardiac output; reduced wall thickness); decreased collagen I, collagen chaperone HSP47, fibronectin, and CTGF levels; decreased activation of non-receptor tyrosine kinases Pyk2 and Src; and decreased activation of eNOS. To determine the source of cells that contribute to fibrosis in CHF, flow cytometric studies were performed that suggested that myofibroblasts in the heart are in large part bone marrow-derived. Two CD45+ cell populations were observed. One (Zone 1) contained CD45+/HSP47-/macrophage marker+ cells (macrophages). The second (Zone 2) contained CD45moderate/HSP47+/macrophage marker- cells often defined as fibrocytes. TAC increased the number of cells in Zones 1 and 2 and the level of HSP47 in Zone 2. These studies are a first step in elucidating the mechanism of action of CSD in heart fibrosis and promoting the development of CSD as a novel treatment to reduce fibrosis and improve ventricular function in CHF patients.