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.

 

 

Moulay Alaoui-Jamali

 

 

1 Cao MH, Xu J, Cai HD, Lv ZW, Feng YJ, Li K, et al. p38 MAPK inhibition alleviates experimental acute pancreatitis in mice. Hepatobiliary Pancreat Dis Int 2015;14:101-106. PMID: 25655298

2 Lali FV, Hunt AE, Turner SJ, Foxwell BM. The pyridinyl imidazole inhibitor SB203580 blocks phosphoinositide-dependent protein kinase activity, protein kinase B phosphorylation, and retinoblastoma hyperphosphorylation in interleukin-2-stimulated T cells independently of p38 mitogen-activated protein kinase. J Biol Chem 2000;275:7395-7402. PMID: 10702313

3 Norman P. Investigational p38 inhibitors for the treatment of chronic obstructive pulmonary disease. Expert Opin Investig Drugs 2015;24:383-392. PMID: 25599809

4 Watz H, Barnacle H, Hartley BF, Chan R. Efficacy and safety of the p38 MAPK inhibitor losmapimod for patients with chronic obstructive pulmonary disease: a randomised, double-blind, placebo-controlled trial. Lancet Respir Med 2014;2:63-72. PMID: 24461903

5 Newby LK, Marber MS, Melloni C, Sarov-Blat L, Aberle LH, Aylward PE, et al. Losmapimod, a novel p38 mitogen-activated protein kinase inhibitor, in non-ST-segment elevation myocardial infarction: a randomised phase 2 trial. Lancet 2014;384: 1187-1195. PMID: 24930728

6 Martin ED, Bassi R, Marber MS. p38 MAPK in cardioprotection - are we there yet? Br J Pharmacol 2015;172:2101-2113. PMID: 25204838

7 Zhao JB, Liao DH, Nissen TD. Animal models of pancreatitis: can it be translated to human pain study? World J Gastroenterol 2013;19:7222-7230. PMID: 24259952

 

(doi: 10.1016/S1499-3872(15)60366-6)

Published online May 6, 2015