Genetic strain differences in the development of peritoneal fibroproliferative processes in mice

Abstract

Fibroproliferative processes are regulated by a wide variety of tissue components and genetic factors. However, whether there are genetic differences in peritoneal fibroproliferative tissue formation, with consequent differences in response to drug treatment, is unclear. We characterize the influence of the genetic background on peritoneal fibroproliferative tissue induced by sponge implants in DBA/1, Swiss, C57BL/6, and BALB/c mouse strains. In addition, responses to dipyridamole in the implants were evaluated. Angiogenesis, assessed by intra-implant hemoglobin content, was highest in Swiss mice, whereas levels of vascular endothelial growth factor were highest in C57BL/6 mice. The levels of pro-inflammatory cytokines and of inflammatory enzymes (myeloperoxidase- and N-acetyl-β-D-glucosaminidase) were also strain-related. The pro-fibrogenic markers transforming growth factor beta-1 and collagen were lowest in implants placed in DBA/1 mice, whereas those in C57BL/6 mice had the highest levels. Differential sensitivity to dipyridamole was also observed, with this compound being pro-angiogenic in implants placed in DBA/1 mice but antiangiogenic in implants placed in Swiss. An overall anti-inflammatory response was observed in the inbred strains. Antifibrogenic effects were observed only in implants placed in C57BL/6 mice. These important strain-related differences in the development of peritoneal fibrosis and in response to dipyridamole must be considered in the design and analysis of studies on fibrogenesis in mice.

Genomic, microbial and environmental standardization in animal experimentation limiting immunological discovery

“…These investigators observed highly variable responses among the four different groups of mice at 7 days following implantation. For example, angiogenesis and macrophage infiltration were greatest in C57BL/6 mice when compared with the other three inbred strains of mice [47]. Interestingly, fibrogenesis markers, as assessed by implant-derived transforming growth factor beta-1 and collagen were consistently lower in DBA/1 mice when compared with the other three inbred strains.…”

“…Inflammatory angiogenesis Inflammation and angiogenesis are important physiological responses that are required for fibrovascular tissue growth and wound healing. However, dysregulation of this proliferative response may result in the development of chronic inflammatory diseases such as atherosclerosis, rheumatoid arthritis, asthma and inflammatory bowel disease, to name just a few [42][43][44][45][46][47]. Recent studies by Andrade and coworkers examined how host genetic diversity may influence the development and perpetuation of inflammatory angiogenesis and fibrogenesis.…”

“…Interestingly, fibrogenesis markers, as assessed by implant-derived transforming growth factor beta-1 and collagen were consistently lower in DBA/1 mice when compared with the other three inbred strains. In addition to defining the angiogenic and fibrogenic profiles among the different inbred and outbred mice, Marques et al investigated how host genetics affected the anti-platelet activity of dipyridamole (DP) in their peritonitis model [47]. Overall, they found that DP treatment exerted a more generalized anti-inflammatory response in inbred strains vs outbred Swiss mice with significant anti-fibrogenic effects observed only in C57BL/6 mice [47].…”

“…In addition to defining the angiogenic and fibrogenic profiles among the different inbred and outbred mice, Marques et al investigated how host genetics affected the anti-platelet activity of dipyridamole (DP) in their peritonitis model [47]. Overall, they found that DP treatment exerted a more generalized anti-inflammatory response in inbred strains vs outbred Swiss mice with significant anti-fibrogenic effects observed only in C57BL/6 mice [47]. Taken together, these data demonstrate that inflammatory angiogenesis is highly strain dependent and highlight the importance of host genetics in these models of peritonitis.…”

Fibrotic Response to Biomaterials and all Associated Sequence of Fibrosis

“…There are certainly genetic variations in vulnerability to fibrosis (Marques et al, 2014), but genetics are not the whole story. Epigenetics describes functional changes in genome activity while the genetic sequence remains unchanged.…”