Hepatic inflammation is important in the pathogenesis of drug-induced liver injury (DILl), which represents a severe complication to drug therapy and new drug development. Our preliminary studies using a mouse model of acetaminophen (APAP)-induced liver injury have revealed that hepatic macrophages may play an important anti-inflammatory role in addition to their pro-inflammatory effects. Evidence suggests that 15- deoxy-delta 12'14-prostaglandin J2 (15d-PGJ2) is a potent anti-inflammatory mediator that acts directly on macrophages. The proposed studies are to determine whether 15d-PGJ2 acts as an important negative regulator in hepatic inflammation. To attain this objective, we will test the hypothesis that 15d-PGJ2 suppresses inflammatory responses of hepatic macrophages and protects against DILl.
The specific aims of the proposed studies will be the following: 1. Determine whether 15d-PGJ2 represents a negative regulator of inflammatory responses of hepatic macrophages. We will determine the inhibitory effect of 15d-PGJ2 on the production of pro-inflammatory mediators by hepatic macrophages in response to in vitro and in vivo stimulation by lipopolysaccharide (LPS) and APAP, respectively. Moreover, the hepato-protective potential of 15d-PGJ2 will be assessed using a mouse model of APAP-induced liver injury. 2. Determine whether 15d-PGJ2 is functionally related to hepatoprotective mediators: hemeoxygenase-1 (HO-1) and interleukin-1 (IL-10). It is our hypothesis that 15d-PGJ2 might be involved in the hepato-protective effects of other anti-inflammatory mediators, such as HO-1 and IL-10. The induction of HO-1 and IL-10 expression by 15d-PGJ2 will be examined using hepatic macrophages in culture and those isolated from mice treated with exogenous 15d-PGJ2. Furthermore, studies of inhibition of HO-1 and IL-10 will be carried out to determine functional association of 15d-PGJ2 with HO-1 and IL-10.
| Yin, Hao; Cheng, Linling; Langenbach, Robert et al. (2007) Prostaglandin I(2) and E(2) mediate the protective effects of cyclooxygenase-2 in a mouse model of immune-mediated liver injury. Hepatology 45:159-69 |
