What is fibrosis?

Fibrosis is a pathological process characterized by the excessive accumulation of fibrous connective tissue, primarily collagen, in an organ or tissue. This fibrous tissue replaces normal functional tissue and disrupts the normal structure and function of the affected organ. Fibrosis can occur in various organs and tissues throughout the body and is associated with many chronic diseases and conditions.


The process of fibrosis involves several key steps:


  • Injury or Insult: Fibrosis often begins with tissue injury, inflammation, or chronic irritation caused by various factors such as infection, toxins, autoimmune reactions, ischemia (lack of blood flow), mechanical injury, or exposure to environmental pollutants. The initial injury triggers an inflammatory response, leading to the recruitment of immune cells and the release of pro-inflammatory cytokines and growth factors.


  • Activation of Fibroblasts: In response to tissue injury and inflammation, resident fibroblasts and other precursor cells in the affected tissue are activated and undergo transformation into myofibroblasts. Myofibroblasts are specialized cells that play a central role in the production and deposition of extracellular matrix components, particularly collagen, which forms the structural framework of fibrous tissue.


  • Extracellular Matrix Deposition: Activated myofibroblasts secrete excessive amounts of extracellular matrix proteins, including collagen, fibronectin, and proteoglycans. These proteins accumulate in the extracellular space and form a dense network of fibrous tissue, leading to the formation of scar tissue or fibrosis. The excessive deposition of collagen disrupts the normal architecture and function of the affected tissue, impairing its elasticity, flexibility, and function.


  • Tissue Remodeling and Scarring: Over time, the deposited fibrous tissue undergoes remodeling, maturation, and cross-linking, leading to the formation of mature scar tissue. The scar tissue replaces the normal functional tissue and impairs its ability to perform its physiological functions. In some cases, the fibrosis may progress and become irreversible, leading to organ dysfunction, impaired organ function, and ultimately organ failure.


Fibrosis can affect virtually any organ or tissue in the body, including the lungs (pulmonary fibrosis), liver (cirrhosis), heart (cardiac fibrosis), kidneys (renal fibrosis), skin (dermal fibrosis), and joints (fibrosis associated with arthritis). In addition to chronic diseases, fibrosis can also occur as a complication of surgical procedures, radiation therapy, or certain medications.


What is the relationship between fibrosis and oxidative stress?

The relationship between fibrosis and oxidative stress is significant and plays a central role in the pathogenesis and progression of fibrotic diseases. Oxidative stress refers to an imbalance between the production of reactive oxygen species (ROS) and the body’s antioxidant defenses, leading to cellular damage and dysfunction. Fibrosis is characterized by the excessive accumulation of fibrous connective tissue, primarily collagen, in an organ or tissue, leading to tissue scarring and disruption of normal structure and function.


Several mechanisms underlie the relationship between fibrosis and oxidative stress:


  • Activation of Fibroblasts: Oxidative stress can directly activate fibroblasts, the primary cells responsible for producing collagen and extracellular matrix proteins during fibrosis. ROS can stimulate signaling pathways involved in fibroblast activation and proliferation, leading to increased synthesis and deposition of collagen in the affected tissue. Activated fibroblasts are more sensitive to oxidative stress and produce higher levels of ROS, perpetuating a cycle of oxidative stress and fibrosis.


  • Induction of Inflammation: Oxidative stress promotes inflammation in the affected tissue, contributing to the initiation and progression of fibrosis. ROS can activate pro-inflammatory signaling pathways, stimulate the production of pro-inflammatory cytokines and chemokines, and recruit immune cells to the site of tissue injury. Chronic inflammation exacerbates oxidative stress and promotes the activation of fibroblasts, leading to the deposition of fibrous tissue and fibrosis.


  • Collagen Cross-linking and Maturation: Oxidative stress can promote the cross-linking and maturation of collagen fibers in the extracellular matrix, leading to the formation of mature scar tissue. ROS can modify collagen molecules by cross-linking amino acid residues, increasing the stability and stiffness of collagen fibers. Cross-linked collagen fibers are less susceptible to degradation and turnover, contributing to the persistence of fibrous tissue and fibrosis.


  • Mitochondrial Dysfunction: Oxidative stress can impair mitochondrial function in fibroblasts and other cells involved in fibrosis, leading to increased ROS production and energy depletion. Mitochondria are a major source of ROS in cells, and oxidative damage to mitochondrial DNA, proteins, and lipids can disrupt mitochondrial function and promote ROS generation. Mitochondrial dysfunction exacerbates oxidative stress and cellular damage, contributing to fibrotic tissue deposition and fibrosis.


  • Activation of Fibrogenic Signaling Pathways: Oxidative stress activates fibrogenic signaling pathways involved in fibroblast activation, extracellular matrix deposition, and tissue remodeling. ROS can stimulate transforming growth factor-beta (TGF-β) signaling, a key regulator of fibrosis, leading to increased collagen synthesis and fibroblast differentiation. Activation of TGF-β and other profibrotic pathways by oxidative stress promotes the progression of fibrosis and tissue scarring.


Overall, oxidative stress plays a critical role in the pathogenesis and progression of fibrosis by promoting fibroblast activation, inflammation, collagen cross-linking, mitochondrial dysfunction, and activation of fibrogenic signaling pathways.