MEK inhibition suppresses the development of lung fibrosis in the bleomycin model

Maria Galuppo, Emanuela Esposito, Emanuela Mazzon, Rosanna Di Paola, Irene Paterniti, Daniela Impellizzeri, Salvatore Cuzzocrea

Research output: Contribution to journalArticlepeer-review

Abstract

The extracellular signal-regulated kinase (ERK) cascade has long been known to be central to the activation of cellular processes such as proliferation, differentiation, and oncogenic transformation. The mitogen-activated protein (MAP) serine/threonine family of protein kinases, of which ERK is a member, is activated by a mechanism that includes protein kinase cascades. Mitogen-activated protein kinases (MAPKs) are well-conserved enzymes connecting cell surface receptors to intracellular regulatory targets; they are activated in response to a wide variety of stimuli. The aim of this study was to investigate the effects of PD98059, a highly selective inhibitor of MAP/ERK kinase1 (MEK1) activation, on the development of lung inflammation and fibrosis. Lung injury was induced by intratracheal instillation of bleomycin (1 mg/kg), and PD98059 (10 mg/kg, 10% dimethyl sulfoxide, i.p.) was administrated 1 h after bleomycin instillation and daily for 7 days. PD98059 treatment shows therapeutic effects on pulmonary damage, decreasing many inflammatory and apoptotic parameters, such as (1) cytokine production; (2) IkBα degradation and NF-kB nuclear translocation; (3) iNOS expression; (4) nitrotyrosine and PAR localization; and (5) the degree of apoptosis, as evaluated by Bax and Bcl-2 balance, FAS ligand expression, and terminal deoxynucleotidyl transferase dUTP nick-end labeling staining. In particular, to assess whether PD98059 treatment influences MAPKs pathway, we have also investigated the expression of activated ERK and JNK after bleomycin-induced pulmonary fibrosis, showing that the inhibition of the cascade reduces the inflammatory processes that lead to the appearance of the fibrosis. Taken together, all our results clearly show that PD98059 reduces the lung injury and inflammation due to the intratracheal bleomycin administration in mice.

Original languageEnglish
Pages (from-to)21-37
Number of pages17
JournalNaunyn-Schmiedeberg's Archives of Pharmacology
Volume384
Issue number1
DOIs
Publication statusPublished - Jul 2011

Keywords

  • Apoptosis
  • Inflammation
  • Lung fibrosis
  • MAP kinases pathway
  • PD98059

ASJC Scopus subject areas

  • Pharmacology

Fingerprint Dive into the research topics of 'MEK inhibition suppresses the development of lung fibrosis in the bleomycin model'. Together they form a unique fingerprint.

Cite this