Cirrhosis: new research provides a basis for rational and targeted treatments

Iredale, John P.

doi:10.1136/bmj.327.7407.143

Cited by 173 publications

(117 citation statements)

References 24 publications

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“…30 Of potential importance here is the fact that TIMP-1 is a poor inhibitor of MMP-14, MMP-15, MMP-16, and MMP-24. 10 Because expression of MMP14 and MMP16 is significantly increased in the DD nodule, these proteinases might escape inhibition from TIMP-1.…”

Section: Discussionmentioning

confidence: 99%

“…Again, drawing on the analogy with liver fibrosis, a treatment that downregulates TIMPs but increases the activity of MMPs may be an appropriate therapy for DD. 30 One such possibility is relaxin, an insulin-like growth factor hormone reported to decrease collagen expression, increase MMP, and decrease TIMP expression in a variety of in vitro and in vivo models. 39 -42 It also may be possible to target collagen biosynthesis via blockade of ADAMTS-14.…”

Section: Discussionmentioning

confidence: 99%

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A Complete Expression Profile of Matrix-Degrading Metalloproteinases in Dupuytren’s Disease

Johnston

Chojnowski

Davidson

et al. 2007

The Journal of Hand Surgery

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Purpose: Dupuytren's disease (DD) is a common fibrotic condition of the palmar fascia, leading to deposition of collagen-rich cords and finger contractions. The metzincin superfamily contains key enzymes in the turnover of collagen and other extracellular matrix macromolecules. A number of broad-spectrum matrix metalloproteinase inhibitors, used in cancer clinical trials, caused side effects of DD-like contractures. We tested the hypothesis that changes in the expression of specific metalloproteinases underlie or contribute to the fibrosis and contracture seen in DD. Methods: We collected tissue from patients with DD and used normal palmar fascia as a control. We profiled the expression of the entire matrix metalloproteinase (MMP), tissue inhibitor of metalloproteinases (TIMP), and a disintegrin and metalloproteinase domain with thrombospondin motif (ADAMTS) gene families in these tissues using real-time reversetranscription polymerase chain reaction. Results: A number of metalloproteinases and inhibitors are regulated in DD. The expression of 3 key collagenases, MMP1, MMP13, and MMP14 is increased significantly in the DD nodule, as is the expression of the collagen biosynthetic enzyme ADAMTS14. The expression of MMP7, an enzyme with broad substrate specificity, is increased in the DD nodule and remains equally expressed in the DD cord. TIMP1 expression is increased significantly in DD nodule compared with normal palmar fascia. Conclusions: This study measured the expression of all MMP, ADAMTS, and TIMP genes in DD. Contraction and fibrosis may result from: (1) increased collagen biosynthesis mediated by increased ADAMTS-14; (2) an increased level of TIMP-1 blocking MMP-1-and MMP-13-mediated collagenolysis; and (3) contraction enabled by MMP-14 -mediated pericellular collagenolysis (and potentially MMP-7), which may escape inhibition by TIMP-1. The complete expression profile will provide a knowledge-based approach to novel therapeutics targeting these genes. (J Hand Surg 2007;32A:343-351.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

A Complete Expression Profile of Matrix-Degrading Metalloproteinases in Dupuytren’s Disease

Johnston

Chojnowski

Davidson

et al. 2007

The Journal of Hand Surgery

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“…Cirrhosis leads to hepatocellular dysfunction and increases intrahepatic resistance to blood flow, resulting in hepatic insufficiency and portal hypertension [2] , and often requires liver transplantation. However, donor livers are limited [3,4] . Cell transplantation has become the better choice of treatment for liver regeneration.…”

Section: Introductionmentioning

confidence: 99%

Contribution of mononuclear bone marrow cells to carbon tetrachloride-induced liver fibrosis in rats

Cao

Lin²,

Zhong³

et al. 2007

WJG

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AIM:To study the inhibitory effect of mononuclear bone marrow cell (BMC) transplantation on carbon tetrachloride (CCl4) -induced liver fibrosis in rats. METHODS:Rat liver fibrosis models were induced by CCl4 and alcohol administration. After 8 wk, twenty rats were randomly allocated into treatment group (n = 10) and control group (n = 10). BMC were infused into the rats in treatment group via the portal vein, while heparinized saline was infused in control group. CCl4 was hypodermically injected into the rats twice a week for 4 wk. At the end of wk 12, all rats were humanely sacrificed. Liver samples were taken and stained with HE or Masson trichrome. The general conditions, liver fibrosis (hydroxyproline and collagen fibre) and liver pathological grades in rats were evaluated. RESULTS:The general conditions of the rats in treatment group improved markedly, but not in control group. Hydroxyproline was 504.6 ± 128.8 mg/g in treatment group, and 596.0 ± 341.8 mg/g in control group. The percentage of collagen fibre was 3.75% ± 0.98% in treatment group and 5.02% ± 0.44% in control group. There was a significant difference between the two groups (P < 0.05). Liver pathological grade decreased from grade Ⅳ to grade Ⅲ partially i n t r e a t m e n t g r o u p (P < 0 . 0 5 ) w i t h n o o b v i o u s improvement in control group (P > 0.05). There was a significant difference between treatment group and control group (P < 0.05). World

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“…As examples of chronic liver injury, liver fibrosis and cirrhosis are intractable diseases with high mortality rates throughout the world (Iredale, 2003). Oxidative stress, i.e., the status of excessive reactive oxygen species (ROS) and free radicals, plays a crucial role in the initiation and progression of various hepatic pathologies (Waris & Ahsan, 2006).…”

Section: Introductionmentioning

confidence: 99%

Hepatoprotective effect ofAmomum xanthoidesagainst dimethylnitrosamine-induced sub-chronic liver injury in a rat model

Wang

Choi

et al. 2013

Pharmaceutical Biology

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Son (2013) Hepatoprotective effect of Amomumxanthoides against dimethylnitrosamine-induced sub-chronic liver injury in a rat model, Pharmaceutical Biology, 51:7, 930-935, DOI: 10.3109/13880209.2013 and 100 mg/kg) was given once a day for 3 weeks. Results and conclusion: WAX (100 mg/kg) significantly attenuated the DMN-induced excessive release of alanine aminotransferase (123.6 IU/L), aspartate aminotransferase (227.9 IU/L), alkaline phosphatase (820.9 IU/L) and total bilirubin (0.50 g/dL) in serum (p50

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Cirrhosis: new research provides a basis for rational and targeted treatments

Cited by 173 publications

References 24 publications

A Complete Expression Profile of Matrix-Degrading Metalloproteinases in Dupuytren’s Disease

A Complete Expression Profile of Matrix-Degrading Metalloproteinases in Dupuytren’s Disease

Contribution of mononuclear bone marrow cells to carbon tetrachloride-induced liver fibrosis in rats

Hepatoprotective effect ofAmomum xanthoidesagainst dimethylnitrosamine-induced sub-chronic liver injury in a rat model

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