Lecture: hepatic fibrogenesis

Today’s lecture featured the fundamental topic of hepatic fibrogenesis. As we all know, fibrogenesis is the common pathway of wound-healing.  The major player is the hepatic stellate cell.  When activated by chemokines (important ones are PDGF and TGF-b) the stellate cell promotes the deposition of collagen type 1, 3 and 4.  It can transform to the shape of a muscle cell, which is why it is refered to as a myofibroblast.  Additionally, it can hug the hepatic sinusoid and cause a rise in sinusoidal pressures. 

The stellate cell, when activated, also loses its internal fatty globules/vitamin A stores.  In addition, it sends out its own chemotactic signals, recruiting more stellate cells and leukocytes, promoting further inflammation and fibrosis. 

Of course, in the course of fibrogenesis, there are also intrinsic pathways of collagen degradation (ie. MMP- matrix metaloproteases).  Over time, however, the pro-fibrogenic pathways overwhelm the others.  Additional pathways/players contribute to shift the balance, like the cannabinoids (CB-1 vs. CB-2), Natural Killer cells (thought to be protective, eventually decrease in number) and some involved with neoangiogenesis (decreased).   

In addition to the stellate cell pathway, there are other important players involved with fibrogenesis.  These include resident portal fibroblasts, bone marrow derived fibrocytes, cholangiocytes and other cells involved with endothelial-to-mesenchymal transition (EMT).  It may be the case that each of these pathways are activated at varying degrees depending on the disease involved (ie. HCV vs alcohol vs PBC). 

With all of this knowlede of fibrosis and its pathways, why is it that we don’t have any good therpeutic targets? Drugs in the pipeline?  One animal model study on statins was reviewed.  Its impetus came from the finding of cardiac fibrosis regression with statin use.  We saw the electron microscopy of a stellate cell that became quiescent after introduction of statin, and active again following removal of statin. 

Hopefully a day will come whereby regression of hepatic fibrosis is addressed with a once a day pill.  Stay tuned.

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