| Autor: |
Morris DL; Pfizer Inc., Drug Safety R&D, Research, Pharmacokinetics, Dynamics & Metabolism, and Pharmaceutical Sciences, St. Louis, Missouri, USA. dale.1.morris@pfizer.com, O'Neil SP, Devraj RV, Portanova JP, Gilles RW, Gross CJ, Curtiss SW, Komocsar WJ, Garner DS, Happa FA, Kraus LJ, Nikula KJ, Monahan JB, Selness SR, Galluppi GR, Shevlin KM, Kramer JA, Walker JK, Messing DM, Anderson DR, Mourey RJ, Whiteley LO, Daniels JS, Yang JZ, Rowlands PC, Alden CL, Davis JW 2nd, Sagartz JE |
| Jazyk: |
angličtina |
| Zdroj: |
Toxicologic pathology [Toxicol Pathol] 2010 Jun; Vol. 38 (4), pp. 606-18. Date of Electronic Publication: 2010 May 06. |
| DOI: |
10.1177/0192623310367807 |
| Abstrakt: |
Exposure to moderately selective p38alpha mitogen-activated protein kinase (MAPK) inhibitors in the Beagle dog results in an acute toxicity consisting of mild clinical signs (decreased activity, diarrhea, and fever), lymphoid necrosis and depletion in the gut-associated lymphoid tissue (GALT), mesenteric lymph nodes and spleen, and linear colonic and cecal mucosal hemorrhages. Lymphocyte apoptosis and necrosis in the GALT is the earliest and most prominent histopathologic change observed, followed temporally by neutrophilic infiltration and acute inflammation of the lymph nodes and spleen and multifocal mucosal epithelial necrosis and linear hemorrhages in the colon and cecum. These effects are not observed in the mouse, rat, or cynomolgus monkey. To further characterize the acute toxicity in the dog, a series of in vivo, in vitro, and immunohistochemical studies were conducted to determine the relationship between the lymphoid and gastrointestinal (GI) toxicity and p38 MAPK inhibition. Results of these studies demonstrate a direct correlation between p38alpha MAPK inhibition and the acute lymphoid and gastrointestinal toxicity in the dog. Similar effects were observed following exposure to inhibitors of MAPK-activated protein kinase-2 (MK2), further implicating the role of p38alpha MAPK signaling pathway inhibition in these effects. Based on these findings, the authors conclude that p38alpha MAPK inhibition results in acute lymphoid and GI toxicity in the dog and is unique among the species evaluated in these studies. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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