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Toxicologic Pathology
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Articles

Effects of p38 MAP Kinase Inhibitors on the Differentiation and Maturation of Erythroid Progenitors

Deidre A. Dalmas, MS, Lauren A. Tierney, DVM, PhD, Cindy Zhang, MS, Padma K. Narayanan, DVM, PhD, Rogely W. Boyce, DVM, PhD, Lester W. Schwartz, DVM, PhD, Kendall S. Frazier, DVM, PhD and Marshall S. Scicchitano, MS

Department of Safety Assessment, GlaxoSmithKline, King of Prussia, Pennsylvania, USA

Correspondence: Address correspondence to: Deidre A. Dalmas, Department of Safety Assessment, 709 Swedeland Road, Mail Stop UE0376, King of Prussia, Pennsylvania 19406, USA; e-mail:deidre.a.dalmas{at}gsk.com.

In rodents, p38 MAP kinase inhibitors (p38is) induce bone marrow hypocellularity and reduce reticulocyte and erythrocyte counts. To identify target cell populations affected, a differentiating primary liquid erythroid culture system using sca-1+cells from mouse bone marrow was developed and challenged with p38is SB-203580, SB-226882, and SB-267030. Drug-related alterations in genes involved at different stages of erythropoiesis, cell-surface antigen expression (CSAE), burst-forming unit erythroid (BFU-E) colony formation, and cellular morphology (CM), growth (CG), and viability were evaluated. CSAE, CM, and decreases in BFU-E formation indicated delayed maturation, while CG and viability were unaffected. Terminal differentiation was delayed until day 14 versus day 7 in controls. CSAE demonstrated higher percentages of sca-1+cells after day 2 and reduced percentages of ter119+ cells after day 7 in all treated cultures. Real-time reverse transcriptase polymerase chain reaction revealed a transient delay in expression of genes involved at early, intermediate, and late stages of erythropoiesis, followed by rebound expression at later time points. Results demonstrate p38is do not irreversibly inhibit erythrogenesis but induce a potency-dependent, transient delay in erythropoietic activity. The delay in activity is suggestive of effects on sca-1+bone marrow cells caused by alterations in expression of genes related to erythroid commitment and differentiation resulting in delayed maturation.

Key Words: p38 MAP kinase inhibitors • mouse bone marrow • erythroid • commitment • differentiation • maturation

Abbreviations: 18S, 18S ribosomal RNA • BFU-E, burst-forming unit erythroid • CG, cellular growth • CM, cellular morphology • CSAE, cell surface antigen expression • DMSO, dimethyl sulfoxide • EKLF, erythroid krüpple-like factor • EPO, erythropoietin • EPO-R, EPO-Receptor • FITC, fluorescein-isothiocyanate • FOG, friend of GATA-1 • FOG2, friend of GATA-2 • GSK, GlaxoSmithKline • p38, p38 mitogen-activated protein kinase • p38iA, SB-203580 • p38iB, SB-226882 • p38iC, SB-267030 • p38i, p38 inhibitor • nRBCs, nucleated red blood cells • PBS, phosphate buffered saline • PE, phycoerythrin • rh, recombinant human • rm, recombinant mouse sca-1 • RT-PCR, reverse transcriptase polymerase chain reaction, stem cell antigen-1 • SCL, stem cell leukemia

Toxicologic Pathology, Vol. 36, No. 7, 958-971 (2008)
DOI: 10.1177/0192623308327121
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