Growth Hormone-Releasing Hormone Receptor Antagonist Modulates Lung Inflammation and Fibrosis due to Bleomycin

Autor: Gaëtan J.-R. Delcroix, Renzhi Cai, Mehdi Mirsaeidi, Andrew V. Schally, Aaron Lazerson, Anthony J. Griswold, Robert M. Jackson, Chongxu Zhang, Medhi Wangpaichitr
Rok vydání: 2019
Předmět:
Pulmonary and Respiratory Medicine
Male
medicine.medical_specialty
Growth-hormone-releasing hormone receptor
medicine.medical_treatment
Pulmonary Fibrosis
Inflammation
Idiopathic pulmonary fibrosis
Lung injury
Bleomycin
Growth Hormone-Releasing Hormone
Interstitial Lung Disease
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
Hormone Antagonists
Fibrosis
Internal medicine
Medicine
Animals
030212 general & internal medicine
Extracellular Signal-Regulated MAP Kinases
Lung
Sermorelin
Cells
Cultured
business.industry
Pneumonia
respiratory system
Fibroblasts
MIA-602
Growth hormone–releasing hormone
medicine.disease
respiratory tract diseases
Mice
Inbred C57BL
Disease Models
Animal
Hydroxyproline
Endocrinology
Cytokine
030228 respiratory system
chemistry
Gene Expression Regulation
Cytoprotection
medicine.symptom
Inflammation Mediators
business
Signal Transduction
Zdroj: Lung
ISSN: 1432-1750
Popis: Purpose Growth hormone-releasing hormone (GHRH) is a 44-amino acid peptide that regulates growth hormone (GH) secretion. We hypothesized that a GHRH receptor (GHRH-R) antagonist, MIA-602, would inhibit bleomycin-induced lung inflammation and/or fibrosis in C57Bl/6J mice. Methods We tested whether MIA-602 (5 μg or vehicle given subcutaneously [SC] on days 1–21) would decrease lung inflammation (at day 14) and/or fibrosis (at day 28) in mice treated with intraperitoneal (IP) bleomycin (0.8 units on days 1, 3, 7, 10, 14, and 21). Bleomycin resulted in inflammation and fibrosis around airways and vessels evident histologically at days 14 and 28. Results Inflammation (histopathologic scores assessed blindly) was visibly less evident in mice treated with MIA-602 for 14 days. After 28 days, lung hydroxyproline (HP) content increased significantly in mice treated with vehicle; in contrast, lung HP did not increase significantly compared to naïve controls in mice treated with GHRH-R antagonist. GHRH-R antagonist increased basal and maximal oxygen consumption of cultured lung fibroblasts. Multiple genes related to chemotaxis, IL-1, chemokines, regulation of inflammation, and extracellular signal–regulated kinases (ERK) were upregulated in lungs of mice treated with bleomycin and MIA-602. MIA-602 also prominently suppressed multiple genes related to the cellular immune response including those for T-cell differentiation, receptor signaling, activation, and cytokine production. Conclusions MIA-602 reduced lung inflammation and fibrosis due to bleomycin. Multiple genes related to immune response and T-cell functions were downregulated, supporting the view that MIA-602 can modulate the cellular immune response to bleomycin lung injury.
Databáze: OpenAIRE
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