Peptide-mediated inhibition of mitogen-activated protein kinase-activated protein kinase-2 ameliorates bleomycin-induced pulmonary fibrosis

Ragini Vittal, Amanda Fisher, Hongmei Gu, Elizabeth A. Mickler, Alyssa Panitch, Cynthia Lander, Oscar W. Cummings, George E. Sandusky, David S. Wilkes

Research output: Contribution to journalArticle

33 Scopus citations

Abstract

Mitogen-activated protein kinase-activated protein kinase-2 (MAPKAPK2, or MK2), a serine/threonine kinase downstream of p38 mitogen-activated protein kinase, has been implicated in inflammation and fibrosis. Compared with pathologically normal lung tissue, significantly higher concentrations of activated MK2 are evident in lung biopsies of patients with idiopathic pulmonary fibrosis (IPF). Expression is localized to fibroblasts and epithelial cells. In the murine bleomycin model of pulmonary fibrosis,weobserved robust, activated MK2 expression on Day 7 (prefibrotic stage) and Day 14 (postfibrotic stage). To determine the effects of MK2 inhibition during the postinflammatory/prefibrotic and postfibrotic stages, C57BL/6 mice received intratracheal bleomycin instillation (0.025 U; Day 0), followed by PBS or the MK2 inhibitor (MK2i; 37.5 mg/kg), administered via either local (nebulized) or systemic (intraperitoneal) routes. MK2i or PBS was dosed daily for 14 days subsequent to bleomycin injury, beginning on either Day 7 or Day 14. Regardless of mode of administration or stage of intervention, MK2i significantly abrogated collagen deposition,myofibroblast differentiation and activatedMK2 expression.MK2i also decreased circulating TNF-α and IL-6 concentrations, and modulated the local mRNA expression of profibrotic cytokine il-1b, matrix-related genes col1a2, col3α1, and lox, and transforming growth factor-b family members, including smad3, serpine1 (pai1), and smad6/7. In vitro, MK2i dosedependently attenuated total MK2, myofibroblast differentiation, the secretionofcollagenTypeI,fibronectin,andthe activationof focal adhesion kinase, whereas activated MK2 was attenuated at optimal doses. The peptide-mediated inhibition of MK2 affects both inflammatory and fibrotic responses, and thusmay offer a promising therapeutic target for IPF.

Original languageEnglish (US)
Pages (from-to)47-57
Number of pages11
JournalAmerican journal of respiratory cell and molecular biology
Volume49
Issue number1
DOIs
StatePublished - Jul 1 2013

Keywords

  • Established fibrosis
  • IPF
  • MK2
  • SMAD
  • Transforming growth factor-b

ASJC Scopus subject areas

  • Cell Biology
  • Pulmonary and Respiratory Medicine
  • Molecular Biology
  • Clinical Biochemistry

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