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Fibrosis or scar, defined pathologically as inappropriate repair by connective
tissue, is increasingly recognized as an important feature of many chronic
diseases (Table 1), and as such, represents an enormous health burden. The
United States government estimates that 45% of deaths in the United States
can be attributed to fibrosing disorders. Fibrosis can affect virtually every
tissue and organ system. Traditionally, fibrosis has been viewed as the
irreversible, end-stage sequel to a multitude of diverse disease processes (Table
2). Excessive scarring following physical, thermal, metabolic, ischemic,
infectious, inflammatory, or immunological injury can occur in any part of the
body, and can cause destruction of the affected structures. Fibrotic tissue is
characterized by a loss of normal architecture, paucity of stromal cells, and
replacement of blood vessels and other essential parenchymal structures by
dense, homogeneous, and increasingly stable extracellular matrix. The scar is
composed primarily of type I collagen, but types III and IV collagens,
proteoglycans, fibronectin, glycoproteins, and matricellular proteins are also
prominent. The process leads to progressive distortion of tissue architecture
with consequent dysfunction and ultimate failure of fibrotic organs. Many of
the key morphological features of fibrosis are common to scarring affecting
the lungs, the liver, the kidneys, the heart, or the skin.
Fibrosis is the “dark side” of normal tissue repair. Following injury, a complex
and tightly orchestrated repertoire of cellular responses is called into play,
and normally the wound is rapidly and efficiently repaired. This process is
spatially and temporally self-limited. In contrast, under some conditions repair
is excessive, resulting in pathological scar formation. The pathogenesis of
fibrosis remains poorly understood. Fibrosis involves a “fibrogenic cascade”
integrating multiple molecular pathways and cellular targets. Historically, the
link between inflammation and fibrosis has been emphasized, providing the
rationale for anti-inflammatory or immunosuppressive therapies for fibrosis. It
has become increasingly evident that these types of interventions are generally
ineffective. The lack of effective treatments, and the high mortality and
increasing morbidity attributed to chronic fibrotic diseases, has stimulated an
explosion of research into the cellular, molecular, and genetic basis of fibrosis. |
