To the Editor: I read with great interest the article by Cao et al[1] reporting a potential therapeutic utility of p38 inhibitors for acute pancreatitis. Using a preclinical mouse model where acute pancreatitis was induced by administration of cerulein (a cholecystokinin analog derived from the tree frog Litoria caerulea), the authors reported that the p38 MAPK inhibitor SB203580, administered intraperitoneally before and after the first administration of cerulein, relieved signs associated with acute pancreatitis, including decreased HSP60 and HSP70 expression, and serum IL-6, amylase and lipase activities. Although the study remains descriptive and pharmacodynamic aspects were not examined in depth, it still has a merit as it undoubtedly provides a basis for further investigation into the potential utility of targeting p38 signaling for acute pancreatitis, a common serious condition that can be life-threatening. In the context of this study, it is worth discussing two main caveats to help future perspectives of using inhibitors of p38 and MAPK in general for acute pancreatitis. The first is regarding the selectivity of the p38 inhibitor used in this study, namely the SB203580. This molecule is a pyridinyl imidazole derivative with a broad selectivity not necessarily limited to p38 kinase.[2] Certainly, testing more selective inhibitors under development, some of which have shown specificity towards specific p38 isoforms (p38 MAPK has 4 isoforms: α, β, γ and δ) and revealed a good safety profile in clinical trials primarily focusing on improving the outcome of patients with acute coronary syndrome.[3-6] The second caveat is the preclinical model used, which is limited to acute cerulein-induced pancreatitis. This model has been widely investigated for pancreatitis-related pulmonary pathogenesis. At present there is no standard animal models for acute pancreatitis but rather a broad range of models ranging from non-invasive to invasive mouse models; each of which has advantages and limitations.[7] Thus, investigating p38 inhibitors in alternative models for acute pancreatitis is suitable to refine the potential utility of targeting the p38 pathway and for optimizing pharmacological properties for future translation into discovery of effective therapeutics for this condition. Several therapeutic discoveries have been guided by incidental observations in defined animal models and further efforts to extend these interesting preliminary observations are timely to establish facts. As well, we cannot dismiss the alternative possibility that a p38 inhibitor can eventually be more effective in combination with existing therapeutics.