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PD is characterized by fibrosis of the tunica albuginea secondary to aberrant wound healing. Typically, no predisposing trauma is recollected by the patient. However, biochemical examination of acutely diseased tunical tissue shows a typical cascade of wound-healing pathways leading to eventual fibrosis. This process can be subdivided into the acute proliferative phase and subsequent remodeling phase characterized by maturation of fibrosis and scar formation.

The cascade begins with exposure of platelets to collagen, thus activating the coagulation cascade and leading to the release of potent chemoattractant molecules, such as transforming growth factor beta (TGF-beta), platelet-derived growth factor (PDGF), tumor necrosis factor alpha (TNF-alpha), and interleukin-1 (IL-1). Fibrin is deposited to act as a matrix for subsequent repair. Inflammatory cells, beginning with neutrophils and followed by macrophages, infiltrate the area.

These cells not only perpetuate the inflammatory signaling cascade but also stimulate the release of growth factors, such as vascular endothelial growth factor (VEGF). The proliferative phase involves the influx of fibroblasts and deposition of collagen types I and III. The remodeling phase involves the tightly regulated interaction of profibrotic and antifibrotic substances, such as matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs), that are responsible for final scar formation.

Recent research into the etiology of PD implies an imbalance between profibrotic and antifibrotic substances. Overexpression of TGF-beta1 has been shown to induce penile plaques in the rat model. TGF-beta1 has also been shown to be overexpressed in PD plaques as compared with patients without evidence of PD. Another group of profibrotic proteins includes fibrin and plasminogen activator inhibitor-1 (PAI-1). Like TGF-beta1, fibrin has been shown to induce plaque formation in an animal model; levels of PAI-1 are elevated in these plaques.

Plasmin serves to degrade fibrin as well as to activate other antifibrotic proteins, including MMPs. Several types of MMP, a class of molecules primarily responsible for collagen degradation, have been identified and have been shown to have different specificities. For example, MMP-1 and -13 are mostly involved in the degradation of collagen type I, whereas MMP-3 and -10 are more specific for collagen type III. TIMPs act as profibrotic molecules by inhibiting the activity of MMPs and decreasing collagen degradation. TIMPs are upregulated after stimulation with TGF-beta1. Several TIMPs with varying degrees of activity (TIMPs 1-4) have been identified.

Recent research implicates these molecules involved in the regulation of fibrosis as being key components in the pathogenesis of PD. It has been demonstrated that targeted inhibitors of TGF-beta1 in a rat model can improve curvature and fibrosis. Likewise, future therapies may be directed toward increasing tissue expression of MMPs or inhibition of TIMP activity. This area of research is evolving rapidly as the molecular mechanisms underlying PD are further elucidated.