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Protection effect of kallistatin on carbon tetrachloride-induced liver fibrosis in rats via antioxidative stress.

Huang X, Wang X, Lv Y, Xu L, Lin J, Diao Y - PLoS ONE (2014)

Bottom Line: Furthermore, residual hepatic functional reserve was improved by kallistatin treatment.CCl4 induced elevation of malondialdehyde level and reduced superoxide dismutase activity in the liver, while kallistatin reduced these oxidative parameters.We also investigated the effects of kallistatin on rat primary HSC and LX-2, the human HSC cell line.

View Article: PubMed Central - PubMed

Affiliation: Institute of Molecular Medicine, Huaqiao University, Quanzhou, China.

ABSTRACT
Prolonged inflammation and oxidative stress are emerging as key causes of pathological wound healing and the development of liver fibrosis. We have investigated the effects of recombinant human kallistatin, produced in Pichia. pastoris, on preventing carbon tetrachloride (CCl4)-induced liver fibrosis in rats. Daily administration of kallistatin prevented development of CCl4-induced liver fibrosis, which was evidenced by histological study. In all kallistatin treated rats, activation of hepatic stellate cells (HSC) as assessed by s-smooth muscle actin staining was attenuated, TGF- β1 expression was inhibited, class I serum biomarkers associated with the process of fibrogenesis, such as hyaluronic acid, laminin, and procollagen III, were lowered, compared with that in the model control group. Furthermore, residual hepatic functional reserve was improved by kallistatin treatment. CCl4 induced elevation of malondialdehyde level and reduced superoxide dismutase activity in the liver, while kallistatin reduced these oxidative parameters. We also investigated the effects of kallistatin on rat primary HSC and LX-2, the human HSC cell line. Kallistatin scavenged H2O2-induced ROS in the LX-2 cells, and suppressed the activation of primary HSC. These results suggest recombinant human kallistatin might be a promising drug candidate for therapeutic intervention of liver fibrosis.

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Kallistatin prevents CCl4–induced injury to hepatic structure in rats.(A) Representative images of H&E or Sirus red stained sections (original magnifications ×40). Hyperplastic proliferation of hepatocytes in nodular formations (arrowheaded) surrounded by fibrotic septa (arrowed). Scale bars = 100 µm. (B) Collagen deposition was evaluated by Sirius red staining and quantitated by image analysis. Data are expressed as mean±SD (n = 8). ## p<0.01 vs. negative control; * p<0.01 vs. model control group.
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pone-0088498-g001: Kallistatin prevents CCl4–induced injury to hepatic structure in rats.(A) Representative images of H&E or Sirus red stained sections (original magnifications ×40). Hyperplastic proliferation of hepatocytes in nodular formations (arrowheaded) surrounded by fibrotic septa (arrowed). Scale bars = 100 µm. (B) Collagen deposition was evaluated by Sirius red staining and quantitated by image analysis. Data are expressed as mean±SD (n = 8). ## p<0.01 vs. negative control; * p<0.01 vs. model control group.

Mentions: A rat hepatic fibrosis model with chronic CCl4 injection was established, the degree of liver fibrosis was assessed by H&E and Sirius red staining (Figure 1A). Negative control (oil-injected without CCl4) rats did not show any liver damage. Following CCl4 administration, histological examination of the livers by H&E staining demonstrated a distorted architecture with extensive fibrosis combined with development of micronodules throughout the liver parenchyma. Liver injury was attenuated in the kallistatin-treated groups. Fibrillar collagen deposition as an indicator of liver fibrosis was determined by Sirius red staining. Repeated injection of CCl4 induced bridging fibrosis. In contrast, by addition of kallistatin, the pathological progression was attenuated showing fewer and smaller fibrotic nodules. Quantification of Sirius red staining showed obvious increase in collagen accumulation in CCl4-induced fibrotic rats compared with the negative control group, while combined administration of kallistatin resulted in a dose-response decrease in staining positive area (Figure 1B). These data supported that kallistatin administration was efficient in reducing pathological collagen deposition and structure damage in the CCl4-induced rat hepatic fibrosis model.


Protection effect of kallistatin on carbon tetrachloride-induced liver fibrosis in rats via antioxidative stress.

Huang X, Wang X, Lv Y, Xu L, Lin J, Diao Y - PLoS ONE (2014)

Kallistatin prevents CCl4–induced injury to hepatic structure in rats.(A) Representative images of H&E or Sirus red stained sections (original magnifications ×40). Hyperplastic proliferation of hepatocytes in nodular formations (arrowheaded) surrounded by fibrotic septa (arrowed). Scale bars = 100 µm. (B) Collagen deposition was evaluated by Sirius red staining and quantitated by image analysis. Data are expressed as mean±SD (n = 8). ## p<0.01 vs. negative control; * p<0.01 vs. model control group.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3928242&req=5

pone-0088498-g001: Kallistatin prevents CCl4–induced injury to hepatic structure in rats.(A) Representative images of H&E or Sirus red stained sections (original magnifications ×40). Hyperplastic proliferation of hepatocytes in nodular formations (arrowheaded) surrounded by fibrotic septa (arrowed). Scale bars = 100 µm. (B) Collagen deposition was evaluated by Sirius red staining and quantitated by image analysis. Data are expressed as mean±SD (n = 8). ## p<0.01 vs. negative control; * p<0.01 vs. model control group.
Mentions: A rat hepatic fibrosis model with chronic CCl4 injection was established, the degree of liver fibrosis was assessed by H&E and Sirius red staining (Figure 1A). Negative control (oil-injected without CCl4) rats did not show any liver damage. Following CCl4 administration, histological examination of the livers by H&E staining demonstrated a distorted architecture with extensive fibrosis combined with development of micronodules throughout the liver parenchyma. Liver injury was attenuated in the kallistatin-treated groups. Fibrillar collagen deposition as an indicator of liver fibrosis was determined by Sirius red staining. Repeated injection of CCl4 induced bridging fibrosis. In contrast, by addition of kallistatin, the pathological progression was attenuated showing fewer and smaller fibrotic nodules. Quantification of Sirius red staining showed obvious increase in collagen accumulation in CCl4-induced fibrotic rats compared with the negative control group, while combined administration of kallistatin resulted in a dose-response decrease in staining positive area (Figure 1B). These data supported that kallistatin administration was efficient in reducing pathological collagen deposition and structure damage in the CCl4-induced rat hepatic fibrosis model.

Bottom Line: Furthermore, residual hepatic functional reserve was improved by kallistatin treatment.CCl4 induced elevation of malondialdehyde level and reduced superoxide dismutase activity in the liver, while kallistatin reduced these oxidative parameters.We also investigated the effects of kallistatin on rat primary HSC and LX-2, the human HSC cell line.

View Article: PubMed Central - PubMed

Affiliation: Institute of Molecular Medicine, Huaqiao University, Quanzhou, China.

ABSTRACT
Prolonged inflammation and oxidative stress are emerging as key causes of pathological wound healing and the development of liver fibrosis. We have investigated the effects of recombinant human kallistatin, produced in Pichia. pastoris, on preventing carbon tetrachloride (CCl4)-induced liver fibrosis in rats. Daily administration of kallistatin prevented development of CCl4-induced liver fibrosis, which was evidenced by histological study. In all kallistatin treated rats, activation of hepatic stellate cells (HSC) as assessed by s-smooth muscle actin staining was attenuated, TGF- β1 expression was inhibited, class I serum biomarkers associated with the process of fibrogenesis, such as hyaluronic acid, laminin, and procollagen III, were lowered, compared with that in the model control group. Furthermore, residual hepatic functional reserve was improved by kallistatin treatment. CCl4 induced elevation of malondialdehyde level and reduced superoxide dismutase activity in the liver, while kallistatin reduced these oxidative parameters. We also investigated the effects of kallistatin on rat primary HSC and LX-2, the human HSC cell line. Kallistatin scavenged H2O2-induced ROS in the LX-2 cells, and suppressed the activation of primary HSC. These results suggest recombinant human kallistatin might be a promising drug candidate for therapeutic intervention of liver fibrosis.

Show MeSH
Related in: MedlinePlus