The tyrosine kinase inhibitor Tyrphostin AG 126 reduces the development of colitis in the rat

Salvatore Cuzzocrea, Michelle C. McDonald, Emanuela Mazzon, Helder Mota-Filipe, Valeria Lepore, Antonio Ciccolo, Maria Luisa Terranova, Domenico Britti, Achille P. Caputi, Christoph Thiemermann

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

Inflammatory bowel disease is characterized by oxidative and nitrosative stress, leukocyte infiltration, up-regulation of the expression of intercellular adhesion molecule-1 (ICAM-1), and up-regulation of P-selectin in the colon. Here we investigate the effects of the tyrosine kinase inhibitor, Tyrphostin AG 126, in rats subjected to experimental colitis. Colitis was induced in rats by intracolonic instillation of dinitrobenzene sulfonic acid (DNBS). Rats experienced hemorrhagic diarrhea and weight loss. Four days after administration of DNBS, the mucosa of the colon exhibited large areas of necrosis. Neutrophil infiltration (determined by histology as well as an increase in myeloperoxidase activity in the mucosa) was associated with up-regulation of ICAM-1 and P-selectin, as well as high tissue levels of malondialdehyde. Immunohistochemistry for nitrotyrosine and poly(ADP-ribose) polymerase showed an intense staining in the inflamed colon. Staining with an anti-COX-2 antibody of sections of colon obtained from DNBS-treated rats showed a diffuse staining of the inflamed tissue. Furthermore, expression of inducible nitric oxide synthase was found mainly in macrophages located within the inflamed colon of DNBS-treated rats. Tyrphostin AG 126 (5 mg/kg daily ip) significantly reduced the degree of hemorrhagic diarrhea and weight toss caused by administration of DNBS. Tyrphostin AG 126 also caused a substantial reduction of (1) the phosphorylation of tyrosine residues of proteins (immunoblots of inflamed colon), (2) the degree of colonic injury, (3) the rise in myeloperoxidase activity (mucosa), (4) the increase in the tissue levels of malondialdehyde, (5) the increase in staining (immunohistochemistry) for nitrotyrosine and poly(ADP-ribose) polymerase, as well as (6) the up-regulation of ICAM-1 and P-selectin caused by DNBS in the colon. Thus, we provide the first evidence that the tyrosine kinase inhibitor Tyrphostin AG126 reduces the degree of colitis caused by DNBS.

Original languageEnglish
Pages (from-to)1439-1453
Number of pages15
JournalLaboratory Investigation
Volume80
Issue number9
Publication statusPublished - 2000

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Dinitrobenzenes
Sulfonic Acids
Colitis
Protein-Tyrosine Kinases
Colon
P-Selectin
Up-Regulation
Intercellular Adhesion Molecule-1
Staining and Labeling
Mucous Membrane
Poly(ADP-ribose) Polymerases
Malondialdehyde
Peroxidase
Diarrhea
Immunohistochemistry
Tyrphostins
Neutrophil Infiltration
Nitric Oxide Synthase Type II
tyrphostin AG 126
Inflammatory Bowel Diseases

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Cuzzocrea, S., McDonald, M. C., Mazzon, E., Mota-Filipe, H., Lepore, V., Ciccolo, A., ... Thiemermann, C. (2000). The tyrosine kinase inhibitor Tyrphostin AG 126 reduces the development of colitis in the rat. Laboratory Investigation, 80(9), 1439-1453.

The tyrosine kinase inhibitor Tyrphostin AG 126 reduces the development of colitis in the rat. / Cuzzocrea, Salvatore; McDonald, Michelle C.; Mazzon, Emanuela; Mota-Filipe, Helder; Lepore, Valeria; Ciccolo, Antonio; Terranova, Maria Luisa; Britti, Domenico; Caputi, Achille P.; Thiemermann, Christoph.

In: Laboratory Investigation, Vol. 80, No. 9, 2000, p. 1439-1453.

Research output: Contribution to journalArticle

Cuzzocrea, S, McDonald, MC, Mazzon, E, Mota-Filipe, H, Lepore, V, Ciccolo, A, Terranova, ML, Britti, D, Caputi, AP & Thiemermann, C 2000, 'The tyrosine kinase inhibitor Tyrphostin AG 126 reduces the development of colitis in the rat', Laboratory Investigation, vol. 80, no. 9, pp. 1439-1453.
Cuzzocrea S, McDonald MC, Mazzon E, Mota-Filipe H, Lepore V, Ciccolo A et al. The tyrosine kinase inhibitor Tyrphostin AG 126 reduces the development of colitis in the rat. Laboratory Investigation. 2000;80(9):1439-1453.
Cuzzocrea, Salvatore ; McDonald, Michelle C. ; Mazzon, Emanuela ; Mota-Filipe, Helder ; Lepore, Valeria ; Ciccolo, Antonio ; Terranova, Maria Luisa ; Britti, Domenico ; Caputi, Achille P. ; Thiemermann, Christoph. / The tyrosine kinase inhibitor Tyrphostin AG 126 reduces the development of colitis in the rat. In: Laboratory Investigation. 2000 ; Vol. 80, No. 9. pp. 1439-1453.
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