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
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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