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

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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.

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Acknowledgments

This work was supported by a grant from IRCCS Centro Neurolesi “Bonino-Pulejo.” We thank Tiziana Genovese and Carmelo La Spada for their excellent technical assistance during this study, Mrs. Caterina Cutrona for secretarial assistance, and Miss Valentina Malvagni for editorial assistance with the manuscript.

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Authors and Affiliations

  1. Department of Clinical and Experimental Medicine and Pharmacology, School of Medicine, University of Messina, Torre Biologica, Policlinico Universitario Via C. Valeria, Gazzi, 98100, Messina, Italy

    Maria Galuppo, Emanuela Esposito, Irene Paterniti, Daniela Impellizzeri & Salvatore Cuzzocrea

  2. IRCCS Centro Neurolesi Bonino-Pulejo, Messina, Italy

    Emanuela Esposito, Emanuela Mazzon, Rosanna Di Paola & Salvatore Cuzzocrea

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  1. Maria Galuppo
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  2. Emanuela Esposito
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  5. Irene Paterniti
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  6. Daniela Impellizzeri
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  7. Salvatore Cuzzocrea
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Correspondence to Salvatore Cuzzocrea.

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Maria Galuppo and Emanuela Esposito contributed equally to the present results and share the first authorship.

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Galuppo, M., Esposito, E., Mazzon, E. et al. MEK inhibition suppresses the development of lung fibrosis in the bleomycin model. Naunyn-Schmiedeberg's Arch Pharmacol 384, 21–37 (2011). https://doi.org/10.1007/s00210-011-0637-7

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  • DOI: https://doi.org/10.1007/s00210-011-0637-7

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