LEADERSHIP IN FIBROSIS: Groundbreaking Discoveries

Fibrosis is the harmful build-up of scar tissue leading to loss of tissue and organ function. A pathology common to a number of serious and chronic diseases, fibrosis is a leading cause of morbidity and mortality and can affect any tissue and organ system. This scar tissue, which physically and biologically blocks healthy tissue and organ function, is made up of extracellular matrix (ECM) proteins such as collagens and fibronectin. Despite the high prevalence of fibrosis and its enormous adverse impact on human health, there currently are no FDA-approved anti-fibrotic drug therapies.

Monocytes Are The Master Controller: Tissue damage generated by disease or injury stimulates the recruitment of monocytes from the blood stream. Once recruited to the site of injury, these monocytes are stimulated to differentiate into either profibrotic M2 macrophages and fibrocytes or regulatory macrophages, depending upon the cytokines and growth factors found in conjunction with the damaged tissue. In normal healing, an equilibrium is reached that facilitates the replacement of damaged cells with new cells in the absence of significant scar tissue. However, in fibrotic disease a disequilibrium develops in which monocytes predominantly differentiate into fibrocytes and profibrotic M2 macrophages. These pathogenic cells recruit and activate large numbers of myofibroblasts to produce the proteins that make up scar tissue and a molecule called TIMP that inhibits scar breakdown as the immune system attempts to wall off the injury. MMP, matrix metalloproteinase; TIMP, tissue inhibitor of MMP.

Breakthrough research by Promedior and its collaborators has identified the cellular source and control mechanisms for the initiation and progression of fibrotic and inflammatory diseases. In particular, a specific white blood cell population called monocytes has been shown to be the key regulator and master controller of fibrotic disease. Monocytes can either promote progression of fibrotic disease through differentiation into fibrocytes and profibrotic M2 macrophages or can promote resolution of fibrotic disease through differentiation into regulatory macrophages that produce interleukin-10.

Many individual and redundant stimuli, including cytokines, growth factors and chemokines, contribute to the disequilibrium present in fibrosis that activates the differentiation of monocytes into the downstream fibrocyte and profibrotic M2 macrophage cell populations. In addition, once activated the fibrocytes and profibrotic macrophages amplify the level and number of profibrotic cytokines and growth factors produced, driving and accelerating myofibroblast activation. Although fibrosis has been an area of active research for many years, the inherent biological complexity underlying fibrosis has, in the past, created a significant challenge for drug development. With a large number of individual and redundant stimuli attempting to wall off the injury through production of fibrotic scar tissue, it has been difficult to effectively reverse the fibrotic process and stimulate resolution, until now.

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