Growth hormone-releasing hormone receptor antagonist MIA-602 modulates mouse lung inflammation and fibrosis due to bleomycin

Abstract

Growth hormone-releasing hormone (GHRH), a 40-44 amino acid hypothalamic hormone, regulates growth hormone secretion from the pituitary. GHRH is found in other tissues and has effects on induction of α-smooth muscle actin in fibroblasts. Inhibition of GHRH might limit cellular proliferation and fibrosis. We found expression of GHRH-receptor (GHRH-R) in normal and IPF lung tissue by western blotting. We hypothesized that GHRH-R antagonist, peptide analog MIA-602, would inhibit bleomycin-induced lung inflammation and fibrosis in C57BL/6J mice. Aims were to test whether administration of MIA-602 (5 μg or vehicle on days 1-21) decreased lung inflammation (day 14) and fibrosis (day 28) in mice treated with intraperitoneal bleomycin (0.8 units on days 1, 3, 7, 14 and 21). Lung micro-CT scans, histopathology and hydroxyproline (collagen) content were assessed on days 1, 14 and 28 in mice that received MIA-602 or vehicle. Bleomycin resulted in patchy lung inflammation and fibrosis at day 14. Extent of inflammation and fibrosis (scores were assessed blindly) was less in mice treated with MIA-602 at 14 days. After 28 days, lung hydroxyproline content doubled in mice treated with bleomycin and vehicle, but it did not increase in mice treated with bleomycin and GHRH-R antagonist. GHRH-R antagonists downregulate p21 activated kinase 1 (PAK1) mediated signal transducer and activation of transcription factor 3 (STAT3)/nuclear factor kB (NFkB), implicating this pathway in bleomycin induced lung fibrosis. GHRH-R modulates lung inflammation and fibrosis. Downstream redox signaling pathways may be amenable to therapeutic intervention in fibrosing lung diseases.