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

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.

Inhibition of Transglutaminase 2, a Novel Target for Pulmonary Fibrosis, by Two Small Electrophilic Molecules

“…Blockade of the ERK pathway by a small molecule inhibitor reduced inflammation and fibrosis in the mouse bleomycin model (47), and Yoshida and colleagues reported that, compared with control subjects, activated ERK signaling is significantly increased in lung homogenates from patients with IPF (44). It has also been reported that the methyl ester derivative of CDDO can inhibit the ERK pathway in leukemia cells (48) and that 15d-PGJ 2 can inhibit the ERK pathway in human gd T cells (49).…”

Oxymatrine attenuates bleomycin-induced pulmonary fibrosis in mice via the inhibition of inducible nitric oxide synthase expression and the TGF-β/Smad signaling pathway

“…BLM has been shown to be a stimulator of iNOS expression and NO over-production (39)(40)(41). Increased pulmonary expression of iNOS and increased NO production are observed in PF patients; however, no changes in the levels of other NOSs have been detected (22,42).…”

Calcitonin gene-related peptide down-regulates bleomycin-induced pulmonary fibrosis

“…Recent studies demonstrated that inhibition of the ERK1/2 pathway by PD98059 markedly reduced bleomycin induced lung fibrosis and TGF-β 1 induced proliferation of lung fibroblasts [Galuppo et al 2011;Jiang and Guan. 2009].…”