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Microvascular targets for anti-fibrotic therapeutics.

ABSTRACT: Fibrosis is characterized by excessive extracellular matrix deposition and is the pathological outcome of repetitive tissue injury in many disorders. The accumulation of matrix disrupts the structure and function of the native tissue and can affect multiple organs including the lungs, heart, liver, and skin. Unfortunately, current therapies against the deadliest and most common fibrosis are ineffective. The pathogenesis of fibrosis is the result of aberrant wound healing, therefore, the microvasculature plays an important role, contributing through regulation of leukocyte recruitment, inflammation, and angiogenesis. Further exacerbating the condition, microvascular endothelial cells and pericytes can transdifferentiate into matrix depositing myofibroblasts. The contribution of the microvasculature to fibrotic progression makes its cellular components and acellular products attractive therapeutic targets. In this review, we examine many of the cytokine, matrix, and cellular microvascular components involved in fibrosis and discuss their potential as targets for fibrotic therapies with a particular focus on developing nanotechnologies.

SUBMITTER: Pu KM

PROVIDER: S-EPMC3848109 | biostudies-literature | 2013 Dec

REPOSITORIES: biostudies-literature

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Microvascular targets for anti-fibrotic therapeutics.

Pu Kai-Ming T KM Sava Parid P Gonzalez Anjelica L AL

The Yale journal of biology and medicine 20131213 4

Fibrosis is characterized by excessive extracellular matrix deposition and is the pathological outcome of repetitive tissue injury in many disorders. The accumulation of matrix disrupts the structure and function of the native tissue and can affect multiple organs including the lungs, heart, liver, and skin. Unfortunately, current therapies against the deadliest and most common fibrosis are ineffective. The pathogenesis of fibrosis is the result of aberrant wound healing, therefore, the microvas ...[more]

PMID: 24348218

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Project description:Renal fibrosis is the hallmark of virtually all progressive kidney diseases and strongly correlates with the deterioration of kidney function. The renin-angiotensin-aldosterone system blockade is central to the current treatment of patients with chronic kidney disease (CKD) for the renoprotective effects aimed to prevent or slow progression to end-stage renal disease (ESRD). However, the incidence of CKD is still increasing, and there is a critical need for new therapeutics. Here, we review novel strategies targeting various components implicated in the fibrogenic pathway to inhibit or retard the loss of kidney function. We focus, in particular, on antifibrotic approaches that target transforming growth factor (TGF)-β1, a key mediator of kidney fibrosis, and exciting new data on the role of autophagy. Bone morphogenetic protein (BMP)-7 and connective tissue growth factor (CTGF) are highlighted as modulators of profibrotic TGF-β activity. BMP-7 has a protective role against TGF-β1 in kidney fibrosis, whereas CTGF enhances TGF-β-mediated fibrosis. We also discuss recent advances in the development of additional strategies for antifibrotic therapy. These include strategies targeting chemokine pathways via CC chemokine receptors 1 and 2 to modulate the inflammatory response, inhibition of phosphodiesterase to restore nitric oxide-cyclic 3',5'-guanosine monophosphate function, inhibition of nicotinamide adenine dinucleotide phosphate oxidase 1 and 4 to suppress reactive oxygen species production, and inhibition of endothelin 1 or tumor necrosis factor α to ameliorate progressive renal fibrosis. Furthermore, a brief overview of some of the biomarkers of kidney fibrosis is currently being explored that may improve the ability to monitor antifibrotic therapies. It is hoped that evidence based on the preclinical and clinical data discussed in this review leads to novel antifibrotic therapies effective in patients with CKD to prevent or delay progression to ESRD.

Dataset Information

Microvascular targets for anti-fibrotic therapeutics.

Publications

Microvascular targets for anti-fibrotic therapeutics.

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