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Celecoxib induces hepatic stellate cell apoptosis through inhibition of Akt activation and suppresses hepatic fibrosis in rats
  1. Yong-Han Paik (yhpaik{at}yuhs.ac)
  1. Yonsei University College of Medicine, Korea, Republic of
    1. Ja Kyung Kim
    1. Yonsei University College of Medicine, Korea, Republic of
      1. Jung IL Lee
      1. Inha University College of Medicine, Korea, Republic of
        1. So Hee Kang
        1. Yonsei University College of Medicine, Korea, Republic of
          1. Do Young Kim
          1. Yonsei University College of Medicine, Korea, Republic of
            1. Sang Hoon Ahn
            1. Yonsei University College of Medicine, Korea, Republic of
              1. Se Joon Lee
              1. Yonsei University College of Medicine, Korea, Republic of
                1. Dong Ki Lee
                1. Yonsei University College of Medicine, Korea, Republic of
                  1. Kwang-Hyub Han
                  1. Yonsei University College of Medicine, Korea, Republic of
                    1. Chae Yoon Chon
                    1. Yonsei University College of Medicine, Korea, Republic of
                      1. Sang In Lee
                      1. Yonsei University College of Medicine, Korea, Republic of
                        1. Kwan Sik Lee (leeks519{at}yuhs.ac)
                        1. Yonsei University College of Medicine, Korea, Republic of
                          1. David Brenner
                          1. University of California at San Diego, United States

                            Abstract

                            Background: Activated hepatic stellate cells (HSCs) but not quiescent HSCs express cyclooxygenase-2 (COX-2), suggesting COX-2/prostanoids pathway have an active role in hepatic fibrogenesis. However, the role of COX-2 inhibitors in hepatic fibrogenesis remains controversial.

                            Aims: We investigated the antifibrotic effects of celecoxib, a selective COX-2 inhibitor.

                            Methods: We investigated the effects of various COX inhibitors, including ibuprofen, celecoxib, NS-398, and DFU, in activated human HSCs. Then, we evaluated the anti-fibrotic effect of celecoxib in hepatic fibrosis developed by bile duct ligation (BDL) or peritoneal thioacetamide (TAA) injection in rats.

                            Results: Celecoxib, NS-398, and DFU inhibited PDGF-induced HSCs proliferation, however, only celecoxib (≥50 μM) induced HSCs apoptosis. All COX inhibitors completely inhibited PGE2 and PGI2 production in HSCs. Separately, PGE2 and PGI2 induced cell proliferation and ERK activation in HSCs. All COX inhibitors attenuated ERK activation, but only celecoxib significantly inhibited Akt activation in HSCs. Celecoxib-induced apoptosis was significantly attenuated in HSCs infected with adenovirus containing a constitutive active form of Akt (Ad5myrAkt). Celecoxib had no significant effect on PPAR-γ expression in HSCs. Celecoxib inhibited type I collagen mRNA and protein production in HSCs. Celecoxib (20 mg/kg/day) PO administration significantly decreased hepatic collagen deposition and α-SMA expression in both BDL- and TAA-rats. Celecoxib treatment significantly decreased mRNA expression of COX-2, α-SMA, TGF-£]1, and collagen £\1(I) in both models.

                            Conclusions: Celecoxib shows pro-apoptotic effect on HSCs through Akt inactivation and shows anti-fibrogenic effects in both BDL- and TAA- rats, suggesting celecoxib as a novel anti-fibrotic agent of hepatic fibrosis.

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