Fibronectin expression is critical for liver fibrogenesis in vivo and in vitro

Abstract

Increased fibronectin (FN) expression has an important role during liver fibrosis. The present study examined FN expression in rats subjected to carbon tetrachloride (CCl4)-induced liver fibrosis. In addition, the potential mechanisms underlying fibrogenesis were investigated by exposing hepatic stellate cells (HSCs) to transforming growth factor-β (TGF-β), which is a known inducer of myofibroblastic transformation of HSCs. Briefly, a rat model of liver fibrosis was created by administering intraperitoneal injections of CCl4. Furthermore, HSC-T6 cells were stimulated with increasing doses of recombinant TGF-β over 24 h. Hepatic fibrosis gradually increased following CCl4 administration in vivo. Western blotting and immunohistochemistry demonstrated that fibronectin (FN), TGF-β and α-smooth muscle actin (SMA) expression was increased following CCl4 injection, and the maximum expression levels were observed at 8 weeks. Once CCl4 treatment had been terminated, the expression levels of FN, TGF-β and α-SMA progressively declined to near baseline levels. Western blotting and quantitative polymerase chain reaction demonstrated that FN expression was gradually increased in response to TGF-β-stimulation of HSCs; maximum expression was achieved 12 h post-treatment (P<0.01 vs. the baseline). In conclusion, these findings indicated that FN expression is an early and progressive event that occurs during liver fibrogenesis in vivo and in vitro.

Specific Commensal Bacterium Critically Regulates Gut Microbiota Osteoimmunomodulatory Actions During Normal Postpubertal Skeletal Growth and Maturation

“…Cxcl1 , Cxcl11 , Hif1a , Col4a1 , and Fn1 were unexpectedly elevated in the liver of MPF versus EF mice, suggesting that SFB within the complex commensal gut microbiota leads to proinflammatory innate immune response effects in the liver. Astonishingly, these findings are in line with seminal reports demonstrating that CXCL1, CXCL11, HIF1A, COL4A1, and FN1 are implicated in liver fibrosis …”

“…Interestingly, CXCL11 has also been shown to endorse T H 1 cell proinflammatory cytokine production and facilitate T H 17 cell development in an experimental colitis model . Hypoxia inducible factor 1 ( Hif1a ), collagen type IV ( Col4a1 ), and fibronectin ( Fn1 ) are profibrotic factors that promote liver fibrosis . Considering that SFB colonization within a complex gut microbiota increased serum IL17A levels (Fig.…”

“…Astonishingly, these findings are in line with seminal reports demonstrating that CXCL1, CXCL11, HIF1A, COL4A1, and FN1 are implicated in liver fibrosis. (66,(73)(74)(75)(76)(77)(78)(109)(110)(111) The liver is exposed to commensal gut microbiota-derived ligands/metabolites through the portal venous circulation. (112)(113)(114) DCs are critical in presenting antigens to promote T-cell activation in liver-draining lymph nodes.…”

“…(72) Hypoxia inducible factor 1 (Hif1a), collagen type IV (Col4a1), and fibronectin (Fn1) are profibrotic factors that promote liver fibrosis. (73)(74)(75)(76)(77)(78) Considering that SFB colonization within a complex gut microbiota increased serum IL17A levels (Fig. 3F), gene expression studies were carried out in livers from EF and MPF mice to assess chemokines and profibrotic factors implicated in proinflammatory hepatic immune response states (Fig.…”

A bioengineered living cell construct activates metallothionein/zinc/MMP8 and inhibits TGFβ to stimulate remodeling of fibrotic venous leg ulcers

“…The activated inflammatory response consisted of genes involved in signaling pathways of both innate and adaptive immunity (Figure A). The presence of fibrosis was underscored by an enriched network of collagens and secreted matricellular proteins in conjunction with upregulation of many profibrotic factors (Figure B), including fibronectin ( FN1) , tenascin ( TNC) , osteopontin ( SPP1) , connective tissue and hepatocyte growth factors ( CTGF , HGF ), and PAI‐1 ( SERPINE1) . In addition, α‐SMA (alpha‐smooth muscle actin; ACTA2 ), a marker of fibrogenic myofibroblasts, was upregulated ~18‐fold, which correlated with highly positive staining in VLU bed sections in vivo (Figure C).…”