Mechanisms of spontaneous resolution of rat liver fibrosis. Hepatic stellate cell apoptosis and reduced hepatic expression of metalloproteinase inhibitors.

Abstract

Liver fibrosis results from the excessive secretion of matrix proteins by hepatic stellate cells (HSC), which proliferate during fibrotic liver injury. We have studied a model of spontaneous recovery from liver fibrosis to determine the biological mechanisms mediating resolution.Livers were harvested from rats at 0, 3, 7, and 28 d of spontaneous recovery from liver fibrosis induced by 4 wk of twice weekly intraperitoneal injections with CCl 4 . Hydroxyproline analysis and histology of liver sections indicated that the advanced septal fibrosis observed at time 0 (peak fibrosis) was remodeled over 28 d of recovery to levels close to control (untreated liver). ␣ -Smooth muscle actin staining of liver sections demonstrated a 12-fold reduction in the number of activated HSC over the same time period with evidence of HSC apoptosis. Ribonuclease protection analysis of liver RNA extracted at each recovery time point demonstrated a rapid decrease in expression of the collagenase inhibitors TIMP-1 and TIMP-2, whereas collagenase mRNA expression remained at levels comparable to peak fibrosis. Collagenase activity in liver homogenates increased through recovery.We suggest that apoptosis of activated HSC may vitally contribute to resolution of fibrosis by acting as a mechanism for removing the cell population responsible for both producing fibrotic neomatrix and protecting this matrix from degradation via their production of TIMPs.

Adenosine reverses a preestablished CCl4-induced micronodular cirrhosis through enhancing collagenolytic activity and stimulating hepatocyte cell proliferation in rats

“…In a model of spontaneous resolution of CCl 4 -induced liver fibrosis, it was shown that an increased collagenase activity was associated with a rapid and significant decrease in the level of expression of TIMP-1 and -2, an effect correlating with enhanced apoptosis in activated myofibroblast-like stellate cells. 48 Then, the differential diminution of collagenase activity and the changes in collagen types I/III ratio in the cirrhotic liver agreed with the fact that interstitial collagenase and other MMPs were differently regulated in sinusoidal and/or parenchymal cells by the presence of increased levels of TIMPs. Adenosine treatment increased net collagenase activity when tested with both endogenous and exogenous (type I) collagens.…”

“…In any case, it could be expected that increased collagenolytic activity could oppose collagen accumulation and promote resolution of an established cirrhosis, because it occurs at early stages of liver fibrosis when spontaneous recovery is allowed. 48 Free hydroxyproline is derived mainly from the intracellular degradation of newly synthesized collagen and can be formed through nonenzymatic hydroxylation by reduced oxygen derivates. 49 This could imply that cell management of reactive oxygen species might be involved in collagen metabolism by normal or diseased livers.…”

Soluble CD74 Reroutes MIF/CXCR4/AKT‐Mediated Survival of Cardiac Myofibroblasts to Necroptosis

“…However, the mechanisms that induce activation of regulated cell death in myofibroblasts are poorly understood. Although induction of apoptosis‐dependent mechanisms has been repeatedly demonstrated as a trigger of myofibroblast death,63, 64 we are the first to demonstrate an activation of a caspase‐3–independent (ie, apoptosis‐independent) death pathway in myofibroblasts. We found that myofibroblasts undergo necroptosis in a RIP1/RIP3‐dependent manner, which is consistent with previous studies demonstrating that activation of RIP1 and RIP3 are key pathway elements of necroptosis 65, 66.…”

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

“…It was reported that this kind of model could undergo spontaneous resolution of fibrosis after CCl4 challenging was stopped [15] . So it is necessary to establish a cirrhosis model to unceasingly inject CCl4.…”