Our body has powerful repair mechanisms allowing for wound healing — a complex dynamic process involving a tightly regulated cascade of four physiological events, including coagulation, granulation tissue formation, re-epithelialization, and extracellular matrix (ECM) remodeling. Under certain unfavorable conditions, normal wound healing may transform into fibrosis — a pathological process, also known as fibrotic scarring. It is when normal functioning tissues in our body are gradually replaced by non-functional scar tissue, leading to a loss of function by organs and systems, and potentially — death.
According to one source
published in 2008, 45% of all deaths in Western world were associated with some form of fibrosis. Risks of developing various fibroproliferative diseases, including idiopathic pulmonary fibrosis, liver cirrhosis, cardiovascular disease, and progressive kidney disease, are highly correlated with older age, which means fibrosis is not only a global health problem, but also a growing one — due to the increasingly ageing population.
When our epithelial or endothelial cells are damaged by mechanical impact, or as a result of disease, exposure to aggressive chemicals or microorganisms, the coagulation cascade releases special pro-inflammatory molecules — cytokines, which activate some immune cells, mainly neutrophils and macrophages. The job of activated immune cells is to remove tissue debris and dead cells, which leads to acute inflammation.
Meanwhile, immune cells themselves release a number of bioactive molecules (so-called "factors") — like chemokines and cytokines — to amplify inflammatory reactions. Next, the released factors, such as TGF-β, platelet derived growth factor (PDGF), interleukin-13 and interleukin-4, promote a controlled activation and proliferation of myofibroblasts — a special-purpose cells, which have structural functions and also muscle-like properties. Because of their muscle-like nature, myofibroblasts can generate cell traction force. During wound healing, myofibroblasts migrate to injury sites and render mechanical wound closure.
In the normal process, myofibroblasts render a balance between synthesis and degradation of the extracellular matrix (ECM) — a three-dimensional network consisting of extracellular macromolecules and minerals, which provides structural and biochemical
support to surrounding cells — resulting in ECM homeostasis. At the final stage of normal wound healing, immune cells undergo apoptosis, while epithelial or endothelial cells proliferate to regenerate injury sites, leading to wound repair.
However, the paramount complexity of the wound healing process is also the cause of its fragility. Various factors, like diabetes, venous or arterial disease, infection, and age-related metabolic disruptions may lead to disruptions in normal repair routes. When stimulated persistently, pro-inflammatory cytokines or growth factors may become overexpressed and would overactivate various receptors. On the other hand, other biomolecules may suffer deficiencies. Both overexpression and deficiency can then lead to switching from normal wound healing to a malignant pro-fibrotic process. As a result, there might be the excess of immune cells, overly activated myofibroblast formation and proliferation, and abnormally high production rate of ECM.
Bad comes to worse, such pro-fibrotic process also additionally activates the pro-inflammatory factors, leading to further increase in inflammation and causing chronic inflammation.
Finally, continuous myofibroblasts activation would generate masses of ECM and shift the ECM homeostasis towards fibrosis. Pro-fibrotic process itself can be a cause of secondary injury to the wound and lead to a chronic vicious circle of pathological responses.
Being a systems disease, fibrosis may occur in various tissues and organs, but more often it develops in heart, lung, kidney, liver and skin. Fibrosis in different fibroproliferative diseases has both unique mechanisms, and also common similarities that regulate the process.
Researchers at Insilico Medicine have been focusing on common fibrosis mechanisms, and recently identified a novel pan-fibrotic target which promises to be a useful starting point for a broad range of antifibrotic drug discovery programs. A systems approach to antifibrotic drug discovery, enabled by a sophisticated deep learning (DL)-driven target identification platform PandaOmics, in concert with lead discovery platform Chemistry42, allowed Insilico Medicine to rapidly achieve drug design success with two fibrotic indications — development of novel preclinical drug candidate for IPF
within under 18 month, and more recently a novel milestone in kidney fibrosis.