Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of nine societies and by invited experts). Eur Heart J 2007;28:2375–414. Alexander Asanau Andrei P. Timoshenko Department of Otolaryngology-Head and Neck Surgery, North Hospital, Saint-Etienne University Hospital Center, 42055 Saint-Etienne Cedex 2, France Tel.: +33 477127568; fax: +33 477127854. E-mail addresses: alexander.asanau@chu-st-etienne.fr (A. Asanau) doi:10.1016/j.mehy.2011.03.026 Phosphoinositide-3-kinase inhibition with theophylline reverses steroid insensitivity in acute alcoholic hepatitis To the Editor, Acute alcoholic hepatitis (AAH) is a condition involving liver inflammation due to excessive intake of alcohol. It is due to the toxic action of alcohol on hepatocytes, in particular in the centri- lobular region and oxidative stress has been implicated in the pathogenesis of AAH. A great number of deaths from alcoholic liver disease occur in patients with rapidly progressive liver failure caused by AAH. Corticosteroid treatment seems to have some advantages in severe AAH, but this is limited by uncertainty in pa- tient selection and variable clinical response [1]. Theophylline, also known as dimethylxanthine, is a methylxanthine drug used in therapy for respiratory diseases has been shown to improve im- paired steroid sensitivity in chronic obstructive pulmonary disease (COPD) by accelerating corticosteroid-induced silencing of proin- flammatory genes. AAH is characterised by a significant inflamma- tory cell infiltrate and elevated proinflammatory cytokine levels that includes IL-6, IL-8 and TNF-a. These inflammatory cell infiltra- tion provides an obvious potential therapeutic approach through anti-inflammatory drugs like corticosteroids [1–3]. Although there is limited data in the literature regarding the use of theophylline in patients with AAH, Kendrick et al. [1] was the first that used theophylline succesfully in patients with AAH. In this study, it has been demonstrated that the lymphocyte ste- roid insensitivity seen in AAH can be ameliorated ex-vivo by the- ophylline. Although it is well established and generally known that corticosteroid-insensitivity in chronic obsctructive pulmonary disease (COPD) can be reversed by theopyhlline, there is no evi- dence in the literature showing its use in hepatic disorders like AAH. The main potential mechanism that is proposed by the authors for explaining the successful effect of theophylline on ste- roid insensitivity is improving histone deacetylase-2 (HDAC2) recruitment, which seems to be reduced due to diminished capac- ity of the glucocorticoid receptor [1]. Although this proposed mechanism is noteworthy, we would like to propose an alternative hypotheses that highlights the importance of phosphoinositide-3- kinase (PI3K) as a possible underlying mechanism. Phosphoinositide-3-kinases are a family of related intracellular signal transducing enzymes that catalyse the production of phos- phatidylinositol-3,4,5-trisphosphate, which is important in cell survival pathways [4]. Oxidative stress activates the PI3K pathway, which results in phosphorylation of serine residues and inactiva- tion of HDAC2, which causes corticosteroid resistance [5]. In a re- cent paper by To et al. [6] the authors have shown that theophylline was a potent selective inhibitor of oxidant-activated PI3K-delta, which was up-regulated in patients with COPD. Fur- thermore, they proposed that cells with a knock-down of PI3K-del- ta failed to develop corticosteroid insensitivity with oxidative stress, and that inhibition of oxidative stress dependent PI3K-delta activation by theophylline could provide a novel treatment modal- ity for reversing corticosteroid-insensitivity in COPD. From this point of view, the molecular mechanism of action of theophylline in restoring HDAC2, may well have been caused by selective inhi- bition of PI3K, which is activated by oxidative stress [7]. As discussed above, in addition to the other mechanisms, we think that in AAH patients, theophylline treatment could also pro- vide its beneficial effects by directly inhibiting oxidant-activated PI3K. Understanding the intricacies of this pathway may also pro- vide new avenues for therapuetic intervention. Further studies are required to assess the exact mechanism as well as the conse- quences of theophylline treatment in patients with AAH. References [1] Kendrick SFW, Henderson E, Palmer J, Jones DEJ, Day CP. Theophylline improves steroid sensitivity in acute alcoholic hepatitis. Hepatology 2010;52:126–31. [2] Sheron N, Bird G, Goka J, Alexander G, Williams R. Elevated plasma interleukin- 6 and increased severity and mortality in alcoholic hepatitis. Clin Exp Immunol 1991;84:449–53. [3] Mathurin P, Mendenhall CL, Carithers RL, Ramond M-J, Maddrey WC, Garstide P, et al. Corticosteroids improve short-term survival in patients with severe alcoholic hepatitis (AH): individual data analysis of the last three randomized placebo controlled double blind trials of corticosteroids in severe AH. J Hepatol 2002;36:480–7. [4] Cantley LC. The phosphoinositide 3-kinase pathway. Science 2002;296:1655–7. [5] Barnes PJ. Histone deacetylase-2 and airway disease. Ther Adv Respir Dis 2009;3:235–43. [6] To Y, Ito K, Kizawa Y, et al. Targeting Phosphoinositide-3-kinase-{delta} with Theophylline Reverses Corticosteroid Insensitivity chronic obstructive pulmonary disease. Am J Respir Crit Care 2010;182:897–904. [7] Barnes PJ. Targeting the epigenome in the treatment of asthma and chronic obstructive pulmonary disease. Proc Am Thorac Soc 2009;6:693–6. Yavuz Beyazit Department of Gastroenterology, Turkiye Yuksek Ihtisas Teaching and Research Hospital, TR-06100 Ankara, Turkey Tel.: +90 5053136779. E-mail addresses: yavuzbeyaz@yahoo.com Abdurrahim Sayilir Murat Kekilli Mevlut Kurt Department of Gastroenterology, Turkiye Yuksek Ihtisas Hospital, Ankara, Turkey Orhan Gorgulu Department of Otolaryngology-Head and Neck Surgery, Adana Numune Research and Education Hospital, Adana, Turkey doi:10.1016/j.mehy.2011.03.031 Correspondence / Medical Hypotheses 77 (2011) 156–157 157