Molecular Mechanisms Elucidating Why Old Stomach Is More Vulnerable to Indomethacin-Induced Damage than Young Stomach

Abstract

Sorafenib, which is approved for treatment of HCC, has also shown promising antifibrotic activity, and therefore refinement of its dosing requirements and window of efficacy are important goals prior to antifibrotic clinical trials. Aim To determine the minimal effective dose and optimal timing of sorafenib therapy in cultured human stellate cells and in rats with experimental hepatic fibrosis. Methods Effects of sorafenib were assessed in a human stellate cell line (LX-2). In vivo, rats were treated for 8 wks with TAA three times pre week (150 mg/kg IP), and with either PBS, or sorafenib administered daily at doses of 1.25, 5 or 7 mg/kg/day gavage either at the beginning of TAA adminstration for 8 wks, during weeks 4–8, or from weeks 8–12. Results Sorafenib treatment significantly inhibited LX-2 proliferation by > 75% (7.5 or 15 µM). Treatment with 7.5 µM sorafenib for 12 hours markedly inhibited expression of TGFβ1, TIMP-1, collagen I, and MMP2 mRNAs, but not of β-PDGFR or type I TGFβR. In vivo, sorafenib significantly inhibited liver fibrosis when started concurrently with TAA and during weeks 4–8 with TAA. In contrast, there was no significant effect of sorafenib on fibrogenic gene expression or fibrosis when begun after cirrhosis was already established. Conclusion Sorafenib is anti-proliferative and antifibrotic towards human HSCs in culture, and is a potent antifibrotic agent in TAA-induced hepatic fibrosis in rats. The drug is effective at relatively low doses at the early stage of liver fibrosis, but is not effective when cirrhosis is already established.

Pathobiology of liver fibrosis: a translational success story

“…For example, sorafenib, a multiple receptor tyrosine kinase inhibitor approved for therapy in hepatocellular carcinoma, targets the PDGF receptor and Raf/ERK signalling pathways and is antifibrotic in animal models. 107 Downstream mediators of these receptors, in particular Rho/Rac and ROCK2, are appealing targets as well. 108 Similarly, imatinib, a small molecule tyrosine kinase antagonist used in chronic myeloid leukaemia (CML) and GI stromal tumours, is antifibrotic.…”

A comparative study of DA-9601 and misoprostol for prevention of NSAID-associated gastroduodenal injury in patients undergoing chronic NSAID treatment

“…However, compared with healthy volunteers, patients with arthritis are more susceptible to developing NSAID-associated gastropathies (McCafferty et al 1995; Kato and Takeuchi 2002). Furthermore, the risk of development of a serious NSAID-associated peptic ulcer is increased in the elderly (Griffin et al 1988, 1991; Hong et al 2013). …”

Gastric Barrier Function and Toxic Damage

“…The decline of gastric mucosal PG synthesis with age increases the vulnerability to NSAID-associated inflammation. Mechanistically, there are also apparent reductions of gastric mucosal blood flow, bicarbonate secretion, and mucus synthesis in response to NSAID administration in aged persons [35]. Development of ‘coxibs' (selective cyclooxygenase-2, COX-2, inhibitors) offered similar efficacy with reduced toxicity, but coxibs are now dented with associated risks of cardiovascular or intestinal complications.…”