Skin flap‐induced regression of granulation tissue correlates with reduced growth factor and increased metalloproteinase expression

Abstract

Previous studies have shown that covering granulation tissue of a full-thickness skin wound by a vascularized skin flap induces tissue remodeling, with a rapid loss of granulation tissue cells by apoptosis. In the present study, in situ hybridization has been used to examine mRNA expression for several factors that may be implicated in the apoptosis seen in this tissue. Skin wounds were made on the dorsal skin of 8-week-old rats. Ten days after wounding, skin flaps were created surgically and sutured over the granulation tissue. Tissue sections of granulation tissue from various times after addition of the skin flap were hybridized with 33P-labelled cRNA probes for transforming growth factor-beta1 (TGF-beta1), beta-inducible gene H3 (beta-ig-h3), alpha1 (1) procollagen, alpha-smooth muscle actin, matrix metalloproteinase-13 (MMP-13) and -2 (MMP-2), tissue inhibitor of metalloproteinase-1 (TIMP-1), and inducible nitric oxide synthase (iNOS). Control granulation tissue prior to addition of the skin flap showed high levels of TGF-beta1, beta-ig-h3, alpha1 (1) procollagen, alpha-smooth muscle actin, and TIMP-1 expression. MMP-13, MMP-2, and iNOS mRNA were low in 10-day granulation tissue. Addition of a skin flap resulted in a decrease in the expression of TGF-beta1, beta-ig-h3, alpha1 (I) procollagen, alpha-smooth muscle actin, and TIMP-1, but increased expression of MMP-13 and MMP-2. Similarly, an increase in iNOS mRNA expression was observed in the granulation tissue after addition of the skin flap. Addition of a vascularized skin flap may result in rapid remodelling of granulation tissue due to a decrease in expression of the trophic growth factor TGF-beta1 and increased degradation of extracellular matrix due to an alteration in the balance between MMPs and their inhibitor, TIMP-1. Additionally, increased iNOS expression may also favour apoptosis through the generation of free radicals. The additive effect of reduced growth factor expression, increased extracellular matrix turnover, and nitric oxide generation may result in the fibroblast and vascular cell apoptosis seen during the rapid remodelling of this tissue.

Suppressed TGF-?1 expression is correlated with up-regulation of matrix metalloproteinase-13 in keloid regression after flashlamp pulsed-dye laser treatment

“…In humans, there are three distinct collagenases: MMP-1 (collagenase 1 or interstitial collagenase), MMP-8 (neutrophil collagenase or collagenase 2), and MMP-13 (collagenase 3). MMP-1 and MMP-13 are distinct in their capacity to degrade fibrillar collagens matrix of wound healing [17,18,20,[28][29][30]. Thus far, little is known about the collagenase in these abnormal keloid tissues.…”

Evolving Concepts of Apoptosis in Idiopathic Pulmonary Fibrosis

“…The combined effects of reduced growth factor expression, increased extracellular matrix turnover, and nitric oxide generation were proposed as the mechanism for fibroblast apoptosis seen during remodeling of skinflap-induced regression of granulation tissue (51). Moroever, strong correlation between declining levels of TGF-␤1 expression, reduced myofibroblast presence, and histopathological improvement in fibrosis is observed later in the course of bleomycininduced pulmonary fibrosis in rodents (52,53).…”

Wound Repair and Regeneration

“…Changes in the ECM and the epithelium seem to be involved in excessive scarring also [65,66,67]. A neurogenic inflammation hypothesis has been suggested [68]: mechanical stress stimulates mechanosensitive nociceptors in skin sensory fibers that release neuropeptides involved in vessel modifications and fibroblast activation.…”