Liver fibrosis results from dysregulation of normal wound healing, inflammation, activation of myofibroblasts, and deposition of extracellular matrix (ECM). Chronic liver injury causes death of hepatocytes and formation of apoptotic bodies, which in turn, release factors that recruit inflammatory cells (neutrophils, monocytes, macrophages, and lymphocytes) to the injured liver. Hepatic macrophages (Kupffer cells) produce TGFβ1 and other inflammatory cytokines that activate Collagen Type I producing myofibroblasts, which are not present in the normal liver. Secretion of TGFβ1 and activation of myofibroblasts play a critical role in the pathogenesis of liver fibrosis of different etiologies. Although the composition of fibrogenic myofibroblasts varies dependent on etiology of liver injury, liver resident hepatic stellate cells and portal fibroblasts are the major source of myofibroblasts in fibrotic liver in both experimental models of liver fibrosis and in patients with liver disease. Several studies have demonstrated that hepatic fibrosis can reverse upon cessation of liver injury. Regression of liver fibrosis is accompanied by the disappearance of fibrogenic myofibroblasts followed by resorption of the fibrous scar. Myofibroblasts either apoptose or inactivate into a quiescent-like state (e.g., stop collagen production and partially restore expression of lipogenic genes). Resolution of liver fibrosis is associated with recruitment of macrophages that secrete matrix-degrading enzymes (matrix metalloproteinase, collagenases) and are responsible for fibrosis resolution. However, prolonged/repeated liver injury may cause irreversible crosslinking of ECM and formation of uncleavable collagen fibers. Advanced fibrosis progresses to cirrhosis and hepatocellular carcinoma. The current review will summarize the role and contribution of different cell types to populations of fibrogenic myofibroblasts in fibrotic liver.

Transglutaminase 2 (TGase2) is a ubiquitously expressed enzyme that catalyzes irreversible post-translational modification of protein, forming cross-linked protein aggregates. We previously reported that intracellular TGase2 is activated by oxidative stress. To elucidate the functional role of TGase2 activation in cells under the oxidatively stressed condition, we identified the mediator that activates TGase2. In this study, we showed that low levels of oxidative stress trigger the release of TGFbeta, which subsequently activates TGase2 through the nuclear translocation of Smad3. Analysis of substrate proteins reveals that TGase2-mediated protein modification results in a decrease of protein solubility and a collapse of intermediate filament network, which leads to aggregation of proteins. We confirm these results using lens tissues from TGase2-deficient mice. Among several antioxidants tried, only N-acetylcysteine effectively inhibits TGFbeta-mediated activation of TGase2. These results indicate that TGFbeta mediates oxidative stress-induced protein aggregation through activation of TGase2 and suggest that the formation of protein aggregation may not be a passive process of self-assembly of oxidatively damaged proteins but may be an active cellular response to oxidative stress. Therefore, TGFbeta-TGase2 pathway may have implications for both the pathogenesis of age-related degenerative diseases and the development of pharmaceutics.

Vitamin D receptor is a trans-acting transcriptional factor that mediates 1alpha,25-dihydroxyvitamin D3 action in the regulation of target gene expression. Recent studies have shown that clinical response of psoriasis to 1alpha,25-dihydroxyvitamin D3 is correlated with the vitamin D receptor mRNA expression level, which may be influenced by the genotype of the vitamin D receptor. In this study, we have explored a possible association between psoriasis and the polymorphism in the gene encoding the vitamin D receptor. We examined the allelic frequencies of the vitamin D receptor in psoriasis patients (n = 104) and in healthy controls (n = 104) by analyzing the restriction pattern of the polymerase chain reaction products. A significant increase in the frequency of the A allele (absence of the restriction site at intron 8) by ApaI restriction fragment length polymorphism was observed in psoriasis patients compared with that of the control group, and the tendency was more accentuated in early onset psoriasis. Odds ratios (95% confidence interval) for psoriasis of AA and Aa genotypes were 5.0 (1.3-19.1) and 2.4 (1.3-4.3), and odds ratios for early onset of AA and Aa genotypes were 6.4 (1.6-25.0) and 3.1 (1.7-5.9), respectively. Allele frequencies for A and a alleles were 0.317 and 0.683 in the psoriasis group and 0.168 and 0.832 in the control group (p = 0.001). A significant association between vitamin D receptor genotypes and the mean age at onset was observed (p < 0.05). Our findings suggest that allelic variance in the vitamin D receptor gene itself or other genes in linkage disequilibrium with this gene, could predispose to the development of psoriasis.

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