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Generation of a mouse model of T-cell lymphoma based on chronic LPS challenge and TGF-β signaling disruption.

Muñoz NM, Katz LH, Shina JH, Gi YJ, Menon VK, Gagea M, Rashid A, Chen J, Mishra L - Genes Cancer (2014)

Bottom Line: asymptomatic steatosis, alcoholic hepatitis and alcoholic cirrhosis, which substantially increase the risk for developing hepatocellular carcinoma.Transforming growth factor (TGF-β) signaling pathway is a major regulator in chronic liver diseases contributing to all liver disease progression from liver injury, inflammation and fibrosis to HCC.In contrast, their liver phenotype was mild as they only developed steatosis but not hepatitis or significant fibrosis.

View Article: PubMed Central - PubMed

Affiliation: Department of Gastroenterology, Hepatology, and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

ABSTRACT

Alcoholic liver disease has various manifestations: asymptomatic steatosis, alcoholic hepatitis and alcoholic cirrhosis, which substantially increase the risk for developing hepatocellular carcinoma. Transforming growth factor (TGF-β) signaling pathway is a major regulator in chronic liver diseases contributing to all liver disease progression from liver injury, inflammation and fibrosis to HCC. With the aim of generating a mouse model of alcoholic liver disease that would rapidly develop steatosis, inflammation as well as fibrosis, we formulated a regimen that combined chronic injections of low dose (2mg/kg) lipopolysaccharide (LPS) with Lieber DeCarli-based diet containing 6.7% ethanol feeding to mice with impaired TGF-β signaling through constitutive disruption of β2-spectrin and/or Smad3. Unexpectedly, the mice treated with chronic low dose LPS and fed the alcohol-containing diet developed very aggressive T-cell lymphomas to which the TGF-β mutant mice succumbed more rapidly than the wild type mice. In contrast, their liver phenotype was mild as they only developed steatosis but not hepatitis or significant fibrosis. To our knowledge, this is the first report of a mouse model of aggressive T- cell lymphoma based on chronic challenge with low dose LPS and TGF-β disruption.

No MeSH data available.


Related in: MedlinePlus

Alcohol- and LPS-treated mice develop liver steatosis but not significant liver fibrosis(A) Histological examination of the liver indicates that alcohol- and LPS-treated mice develop considerable liver steatosis compare with control mice (control diet with saline) (H&E staining and bar graph). (B) Sirius Red staining shows that alcohol- and LPS-treatment have no effect on liver fibrosis (arrow indicates Sirius Red positive cells).
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Figure 4: Alcohol- and LPS-treated mice develop liver steatosis but not significant liver fibrosis(A) Histological examination of the liver indicates that alcohol- and LPS-treated mice develop considerable liver steatosis compare with control mice (control diet with saline) (H&E staining and bar graph). (B) Sirius Red staining shows that alcohol- and LPS-treatment have no effect on liver fibrosis (arrow indicates Sirius Red positive cells).

Mentions: Regarding the liver phenotype, staining of tissue sections with H&E as well as histochemical staining with Sirius red (for histological visualization of collagen I and III fibers) indicated that in spite of the “two hit” protocol, the animals that received alcohol in the diet along with LPS injections and that survived the longest only developed considerable degrees of steatosis, but insignificant fibrosis and no inflammation (Figure 4).


Generation of a mouse model of T-cell lymphoma based on chronic LPS challenge and TGF-β signaling disruption.

Muñoz NM, Katz LH, Shina JH, Gi YJ, Menon VK, Gagea M, Rashid A, Chen J, Mishra L - Genes Cancer (2014)

Alcohol- and LPS-treated mice develop liver steatosis but not significant liver fibrosis(A) Histological examination of the liver indicates that alcohol- and LPS-treated mice develop considerable liver steatosis compare with control mice (control diet with saline) (H&E staining and bar graph). (B) Sirius Red staining shows that alcohol- and LPS-treatment have no effect on liver fibrosis (arrow indicates Sirius Red positive cells).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4209606&req=5

Figure 4: Alcohol- and LPS-treated mice develop liver steatosis but not significant liver fibrosis(A) Histological examination of the liver indicates that alcohol- and LPS-treated mice develop considerable liver steatosis compare with control mice (control diet with saline) (H&E staining and bar graph). (B) Sirius Red staining shows that alcohol- and LPS-treatment have no effect on liver fibrosis (arrow indicates Sirius Red positive cells).
Mentions: Regarding the liver phenotype, staining of tissue sections with H&E as well as histochemical staining with Sirius red (for histological visualization of collagen I and III fibers) indicated that in spite of the “two hit” protocol, the animals that received alcohol in the diet along with LPS injections and that survived the longest only developed considerable degrees of steatosis, but insignificant fibrosis and no inflammation (Figure 4).

Bottom Line: asymptomatic steatosis, alcoholic hepatitis and alcoholic cirrhosis, which substantially increase the risk for developing hepatocellular carcinoma.Transforming growth factor (TGF-β) signaling pathway is a major regulator in chronic liver diseases contributing to all liver disease progression from liver injury, inflammation and fibrosis to HCC.In contrast, their liver phenotype was mild as they only developed steatosis but not hepatitis or significant fibrosis.

View Article: PubMed Central - PubMed

Affiliation: Department of Gastroenterology, Hepatology, and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

ABSTRACT

Alcoholic liver disease has various manifestations: asymptomatic steatosis, alcoholic hepatitis and alcoholic cirrhosis, which substantially increase the risk for developing hepatocellular carcinoma. Transforming growth factor (TGF-β) signaling pathway is a major regulator in chronic liver diseases contributing to all liver disease progression from liver injury, inflammation and fibrosis to HCC. With the aim of generating a mouse model of alcoholic liver disease that would rapidly develop steatosis, inflammation as well as fibrosis, we formulated a regimen that combined chronic injections of low dose (2mg/kg) lipopolysaccharide (LPS) with Lieber DeCarli-based diet containing 6.7% ethanol feeding to mice with impaired TGF-β signaling through constitutive disruption of β2-spectrin and/or Smad3. Unexpectedly, the mice treated with chronic low dose LPS and fed the alcohol-containing diet developed very aggressive T-cell lymphomas to which the TGF-β mutant mice succumbed more rapidly than the wild type mice. In contrast, their liver phenotype was mild as they only developed steatosis but not hepatitis or significant fibrosis. To our knowledge, this is the first report of a mouse model of aggressive T- cell lymphoma based on chronic challenge with low dose LPS and TGF-β disruption.

No MeSH data available.


Related in: MedlinePlus