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Abstract
Liver fibrosis is defined as excessive extracellular matrix deposition in the hepatic parenchyma as a consequence of complex interactions among matrix-producing hepatic stellate cells (HSCs) and liver-resident and infiltrating cells. In addition to the liver, the process of fibrosis may represent end-stage disease of several diseases including kidneys, lungs, spleens, heart, muscles and at certain extent, the central nervous system and the peripheral nerves. To date, antifibrotic treatment of fibrosis represents an unconquered area for drug development. The aim of the present study was to test the efficacy of a new drug combination for the treatment of hepatic fibrosis in order to provide a proof-of-concept for the use of therapeutic agents in clinical practice. For this purpose, we have studied the effects of the PDGF inhibitor imatinib and the angiogenesis inhibitor sorafenib, administered alone or in combination, in reducing the progression of the fibrogenetic process in a pre-clinical model of liver damage induced in mice by repeated administration of Concanavalin A (ConA), resembling long-tern autoimmune hepatitis. Our results suggest that treatments with imatinib and sorafenib can modulate potently and, in a superimposable fashion, the fibrinogenic process when administered alone. However, and in agreement with the computational data presently generated, they only exert partial overlapping antifibrotic effects in modulating the main pathways involved in the process of liver fibrosis, without significant additive or synergist effects, when administered in combination.
Highlights
Fibrosis represents an intrinsic response to chronic injury, maintaining organ integrity when extensive necrosis or apoptosis occurs
We have studied the effectiveness of the platelet-derived growth factor (PDGF)-inhibitor, imatinib, and of the angiogenesis inhibitor, sorafenib, administered alone or in combination, in reducing the progression of the fibrogenetic process in a pre-clinical model of liver damage induced in mice by repeated administration of Concanavalin A (ConA)
Our results suggest that imatinib and sorafenib exert only a partial overlapping effect in inhibiting the main pathways involved in the process of liver fibrosis
Summary
Fibrosis represents an intrinsic response to chronic injury, maintaining organ integrity when extensive necrosis or apoptosis occurs. Fibrosis may progress toward excessive scarring and organ failure. Fibrosis occurs in most human organs including the liver, lung, heart, and kidney, and is crucial for the progression of most chronic diseases [1]. Fibrotic scar formation through fibroblasts and pericytes may contribute to abnormal functioning and lack of recovery of the blood–brain barrier (BBB) during acute and chronic pathologies of the central nervous system such as traumatic spinal cord injury and multiple sclerosis [2,3]. Fibrosis may represent a common hallmark with common and subtle pathogenetic differences among different organs that jeopardizes organ functionality and often represents an end-stage disease of the affected organ.
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