Central to the mechanism of cold
Central to the mechanism of cold I/R-associated liver injury is the activation of the pro-inflammatory cascade resulting in the release of pro-inflammatory cytokines. In agreement with the present study, serum and hepatic mRNA levels of TNF-α, IL-6, and ICAM-1 were all significantly up-regulated early post-OLT following 18 h cold liver graft storage.37, 38 PGI2 analogs have been shown to inhibit leukocyte activation by inhibiting TNF-α production, neutrophil activation and adhesion to endothelial cells39, 40 and, in particular, treprostinil inhibited the mRNA SCH 527123 of multiple cytokines including TNF-α, IL-6, and IL-1β by blocking the translocation of NF-kB. In a separate study, we measured CYP450 induction in primary cultured hepatocytes and found that treprostinil did not induce CYP450 mRNA, thereby eliminating the possibility that treprostinil improved CYP450 activity by enzyme induction (Ghonem et al, in review).
Considering the many factors involved in I/R injury and the role of PGs in maintaining vascular and cellular homeostasis, PGI2 has a particular relevance in the setting of hepatic I/R injury associated with OLT. Since the late 1980s, PG analogs have been tested for their ability to reduce I/R-induced liver injury in several animal models and in clinical liver transplantation. Early studies using epoprostenol and iloprost were promising in minimizing primary liver graft non-function, however, clinical application has been limited by their inherent instability and short half-life, thus requiring intolerable doses. While the principle pharmacological effects of PG analogs are similar, there are notable differences in the pharmacokinetics and metabolism, with a wide range in half-lives. Treprostinil has favorable characteristics, including longer stability in the delivery system (48 h at room temperature) and a longer half-life, which enables lower doses to achieve therapeutic efficacy with lower potential for side effects.
The current study demonstrated that I/R injury post-OLT resulted in a significant decrease in hepatic CYP450 activity, secondary to increased pro-inflammatory cytokines in liver graft post-OLT. Noteworthy findings are that treprostinil protected the liver graft against I/R injury, suppressed the pro-inflammatory response, and improved CYP450-mediated drug metabolism. From the clinical perspective, donor + recipient treatment may not always be possible. Therefore, to determine whether recipient only treatment yields protection, we treated recipient animals with treprostinil or matching placebo (100 ng/kg/min) prior to transplantation and until the time of sacrifice. The significant reduction in serum ALT and AST levels post-OLT confirms treprostinil as a viable therapy to protect patients against I/R injury during OLT (Supplemental Material 3).
Conflicts of interest
Introduction Kaempferia parviflora, a herbal plant belonging to the family Zingiberaceae, is found primarily in the North and Northeast of Thailand. Its rhizome has been widely used as a traditional medicine for centuries and is claimed to have many pharmacological activities. These include use as anti-peptic ulcer (Rujjanawate et al., 2005), anti-inflammation (Tuchida et al., 2002), anti-allergy (Tewtrakul et al., 2008), anti-mutagenic (Sripanidkulchai et al., 2004, Azuma et al., 2011), antibacterial (Kummee et al., 2008), anti-fungal, anti-mycobacterium, anti-plasmodium (Yenjai et al., 2004), anti-viral (Phurimask and Leardkamolkarn, 2005), and anti-depression agents (Wattanathorn et al., 2007). Other reported activities include anti-cholinesterase activity for Alzheimer\'s disease (Sawasdee et al., 2009), cardioprotective effects (Malakul et al., 2011), aphrodisiac effects (Sudwan et al., 2006, Wattanapitayakul et al., 2007, Chaturapanich et al., 2008) and anti-tumor activity (Banjerdpongchai et al., 2008, Banjerdpongchai et al., 2009, Leardkamolkarn et al., 2009). The major components of Kaempferia parviflora that demonstrated pharmacological effects are methoxyflavones, in particular 5,7-dimethoxyflavone (DMF), 5,7,4′-trimethoxyflavone (TMF), and 3,5,7,3′,4′-pentamethoxyflavone (PMF) (Sutthanut et al., 2007). DMF is an effective chemoprotectant in chemical-induced liver cancer (Wen et al., 2005) while DMF and PMF exhibited inhibition of multidrug resistance associated-protein (Patanasethanont et al., 2007a). TMF was shown to possess anti-cholangiocarcinoma action (Leardkamolkarn et al., 2009), and PMF was also demonstrated to inhibit P-glycoprotein function (Patanasethanont et al., 2007b). Due to these broad pharmacological activities, Kaempferia parviflora has been increasingly used as an alternative medicine. Because many patients ingest a wide range of herbal health products in combination with conventional drugs, the potential number of incidences of herbal–drug or herbal–herbal interactions is increased.