Fibroblast proliferation and increased synthesis of connective tissue matrix occurs as part of wound healing and other forms of repair. In some circumstances, this normal fibrotic response is initiated in the absence of a significant need for repair. Alternatively, a normal reparative response becomes persistent or exaggerated, leading to pathological fibrosis. Excess accumulation of connective tissue and loss of normal tissue architecture interferes with organ function. The consequences of such processes can vary from the localized damage seen in tissue scars and keloids to complete organ failure in the lungs or kidneys.

The interstitial fibroblast is the cell responsible for deposition of connective tissue matrix proteins and other components, including collagen, fibronectin, and proteoglycans. Fibrotic response may be characterized by increased numbers of fibroblasts, increased matrix synthesis per cell or both factors acting in concert. The factors that initiate pathological fibroblast proliferation and activation and the excessive synthesis and deposition of collagen and other extracellular matrix proteins include acute or ongoing tissue injury, chronic inflammation, toxic agents or irradiation. Because fibrosis per se can be a disease state, it is important to have an understanding of the events and processes leading to fibroblast activation and fibrosis. Much of the work in this field has focused on defining the immune-derived and other factors that might activate fibroblasts and play a role in the process. In some cases, however, there is fibroblast activation that persists beyond the acute stimulus, or in the absence of a known stimulus. Furthermore, in some of these cases, abnormal fibroblast behavior is manifest by cultured lesional cells in vitro. Thus, while initiating events are important, pathology intrinsic to the fibroblast plays a role in some forms of fibrosis. Because fibroblasts are ultimately responsible for the excessive extracellular matrix synthesis and deposition, this review will focus on fibroblasts and their importance in the development of fibrosis. Systemic sclerosis (SSc), a disease characterized by cutaneous and visceral fibrosis, as well as vascular damage and immune cell activation will be used as a model system.