rAAV‐mediated stable expression of heme oxygenase‐1 in stellate cells

Heme oxygenase-1 overexpression increases liver injury after bile duct ligation in rats

“…Previous studies could demonstrate HO-1 overexpression as a negative regulator in the control of fibrogenic activities of hepatic stellate cells [57,58] . Therefore it was hypothesized that HO-1 overexpression may prevent fibrosis by inhibiting oxidant-dependent activation and proliferation of stellate cells.…”

Pharmacological and Clinical Aspects of Heme Oxygenase

“…The continuing search to provide this vascular protection is motivated by our findings, accumulated over the past decade, in which we have shown that adenoviral-mediated HO-1 gene therapy prevented hemoglobin toxicity and the generation of inflammatory molecules (Abraham et al, ,b, 2000. Recently, HO-1 gene transfer has been shown to inhibit liver fibrosis (Tsui et al, 2005) and to prevent inflammation (Jian et al, 2005), neointimal hyperplasia (Kong et al, 2004), and ischemic heart injury (Tang et al, 2004). HO-1 gene targeting specifically to endothelial cells, not vascular smooth muscle cells, has been shown to protect endothelial cells from hyperglycemia and TNF-mediated cell death .…”

“…Isolation of different types of cells from CCl 4 -induced fibrotic livers showed the predominant expression of the transgene in hepatic stellate cells after rAAV/HO-1 administration. In addition, HO-1-transduced stellate cells showed reduced transcript levels of type 1 collagen and impaired proliferative ability compared with control animals, suggesting a new approach in the treatment of liver fibrosis using adeno-associated virus-mediated gene transfer (Tsui et al, 2005).…”

“…The authors found that HO plays an important beneficial role in attenuating oxidative stress and inflammation by regulating VEGF (Angermayr et al, 2006). In another study, a recombinant adenovirus carrying rat HO-1 (rAAV/HO-1) was generated, and the virus was injected through the portal vein (Tsui et al, 2005). These data showed that portal hypertension was markedly diminished in rAAV/HO-1-transduced animals compared with controls.…”

Thiazolidinediones and hepatic fibrosis: don't wait too long

“…In most studies, treatment is started at the time of initial damage, as in all studies testing TZDs and liver fibrosis reported so far, or is administered after interruption of the toxin. Obviously, these protocols poorly mimic the condition we face in the clinic where we have to treat a patient with established fibrosis and ongoing damage, a situation much more similar to the protocol employed by Leclercq et al A few recent studies have indeed reported successful treatment of established experimental fibrosis, for example interfering with TGF-b signalling or overexpressing haeme oxygenase 1 in animals undergoing CCl 4 intoxication or bile duct ligation, [19][20][21] indicating that in these models fibrosis may be modulated despite persistent injury. Therefore, trying to extrapolate the available data on TZDs from animal models to the human situation, it might be anticipated that TZD treatment is of limited efficacy in biliary fibrosis, and that treatment of inflammatory and metabolic forms of chronic liver disease would be successful only if the treatment is started very early.…”