Fibrosis is a consequence of injury which is characterized by accumulation of excess collagen and other extracellular matrix components, resulting in the destruction of normal tissue architecture and function. Transforming growth factor-beta, a potent wound healing agent, has also been shown to be an agent that can produce fibrosis because it is a potent stimulator of collagen synthesis. Both glucocorticoids and bleomycin have recently been shown to affect collagen synthesis in opposite directions, by utilizing a common pathway of involving transforming growth factor-beta activator protein binding to the transforming growth factor-beta element. This article presents a mechanistic overview of collagen synthesis regulation by glucocorticoids and bleomycin through the transforming growth factor-beta pathway.

Animals↗

PubMedDate not supplied

Comparison and evaluation of gene therapy and epigenetic approaches for wound healing.

During the past decade considerable evidence has mounted concerning the importance of growth factors in the wound healing process both for cell replication and for stimulating reparative cells to synthesize and secrete extracellular matrix components. During normal wound healing the growth factor concentration has to be maintained at a certain level. If the growth factor concentration is too low, normal healing fails to occur. Whereas if the growth factor concentration is too high due to either over-expression of the growth factor or too much growth factor being applied to the wound, aberrant wound healing will occur. One approach for controlling the amount of growth factor at the wound site during normal healing is through gene therapy and the titration of gene dosage. However if a narrow window exists between the beneficial therapeutic effect and toxic effects with increasing gene dosage, an agent may be necessary to give in combination with gene therapy to regulate the over-expression of growth factor. In addition to genetic approaches to regulate wound healing, epigenetic approaches also exist. Antisense oligodeoxynucleotides have been shown to regulate wound repair in certain model systems and to determine the protein(s) necessary for normal wound healing. A novel approach to regulate the activity of collagen genes, thereby affecting fibrosis, is to use a sense oligodeoxynucleotide having the same sequence of the cis element which regulates the promoter activity of a particular collagen gene. This exogenous oligodeoxynucleotide will compete with the cis element in the collagen gene for the trans-acting factor which regulates promoter activity. These epigenetic approaches afford the opportunity to regulate over-expression of growth factor and therefore preclude the potential toxic effects of gene therapy. Both genetic and epigenetic approaches for regulating the wound healing process, either normal or aberrant wound healing, have certain advantages and disadvantages which are discussed in the present article.

Evaluation Studies as Topic↗

PubMedDate not supplied

A sense phosphorothioate oligodeoxynucleotide containing the transforming growth factor beta regulatory element acts as a novel local nonsteroidal antifibrotic drug.

Fibrosis is a potential response to tissue injury. At present, glucocorticoids with their numerous toxic side effects are the only effective treatment for fibrotic diseases. Granulomas induced by sponge implantation were treated with single-stranded phosphorothioate oligodeoxynucleotides containing the wild type or mutated transforming growth factor-beta response element designed to inhibit the rat proalpha1(I) promoter activity. Single-stranded phosphorothioate oligonucleotides resulted in antifibrotic activity based on their ability to reduce granuloma tissue formation and selectively inhibit collagen synthesis. The mutated single-standed phosphorothioate oligonucleotides or dexamethasone given at an equivalent dose to single-standed phosphorothioate oligonucleotides failed to do so. These data suggest that the phosphorothioate oligodeoxynucleotide containing the transforming growth factor-beta regulatory element has an antifibrotic effect and may be used to inhibit the development of fibrosis.

Animals↗