Peptide-Mediated Inhibition of Mitogen-Activated Protein Kinase–Activated Protein Kinase–2 Ameliorates Bleomycin-Induced Pulmonary Fibrosis
Autor: | Ragini Vittal, Elizabeth A. Mickler, Amanda J. Fisher, George E. Sandusky, Alyssa Panitch, Oscar W. Cummings, Cynthia Lander, David S. Wilkes, Hongmei Gu |
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Rok vydání: | 2013 |
Předmět: |
Pulmonary and Respiratory Medicine
Pathology medicine.medical_specialty Time Factors Pulmonary Fibrosis p38 mitogen-activated protein kinases Interleukin-1beta Molecular Sequence Data Clinical Biochemistry Protein Serine-Threonine Kinases Pharmacology Bleomycin Collagen Type I Mice Idiopathic pulmonary fibrosis chemistry.chemical_compound Transforming Growth Factor beta Fibrosis Pulmonary fibrosis medicine Animals Humans Amino Acid Sequence RNA Messenger Myofibroblasts Protein kinase A Lung Molecular Biology Dose-Response Relationship Drug biology Interleukin-6 Tumor Necrosis Factor-alpha MAPKAPK2 Anti-Inflammatory Agents Non-Steroidal Intracellular Signaling Peptides and Proteins Cell Differentiation Articles Cell Biology Transforming growth factor beta medicine.disease Peptide Fragments Enzyme Activation Mice Inbred C57BL Gene Expression Regulation chemistry Focal Adhesion Kinase 1 biology.protein Peptides |
Zdroj: | American Journal of Respiratory Cell and Molecular Biology. 49:47-57 |
ISSN: | 1535-4989 1044-1549 |
Popis: | 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, we observed 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 μg/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 activated MK2 expression. MK2i also decreased circulating TNF-α and IL-6 concentrations, and modulated the local mRNA expression of profibrotic cytokine il-1β, matrix-related genes col1a2, col3a1, and lox, and transforming growth factor–β family members, including smad3, serpine1 (pai1), and smad6/7. In vitro, MK2i dose-dependently attenuated total MK2, myofibroblast differentiation, the secretion of collagen Type I, fibronectin, and the activation of focal adhesion kinase, whereas activated MK2 was attenuated at optimal doses. The peptide-mediated inhibition of MK2 affects both inflammatory and fibrotic responses, and thus may offer a promising therapeutic target for IPF. |
Databáze: | OpenAIRE |
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