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

Abstract

PurposeGrowth 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.MethodsWe 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.ResultsInflammation (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.ConclusionsMIA-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.

Activity of the GHRH Antagonist MIA602 and its Underlying Mechanisms of Action in sarcoidosis

“…The anti-inflammatory effects of MIA602 in granuloma is a novel finding consistent with previous reports on anti-inflammatory properties of GHRH-R antagonists in pulmonary fibrosis (11), ocular inflammation (20), and chronic prostatitis (21). Our study has several limitations.…”

“…These peptides include the MIA and AVR classes of antagonists (10). MIA602 has been shown to modulate lung inflammation and fibrosis (11). GHRH-R antagonists function in a cAMP-dependent pathway and GHRH-R antagonists downregulate p21 activated kinase 1 (PAK1)-mediated signal transducer and activation of transcription factor 3 (STAT3)/nuclear factor kB (NFkB) (12).…”

Growth Hormone-Releasing Hormone in Lung Physiology and Pulmonary Disease

“…As reviewed above, MIA-602 and MIA-690 induce changes in mitochondrial function, resulting in elevated reactive oxygen species (ROS), which is consistent with the data reviewed above regarding the effects of MIA-602 on fibroblast respiration [ 17 ]. An increase in intracellular ROS due to chemotherapy would render cancer cells beyond their baseline ability to tolerate oxidant stress, leading to cell death.…”

“…GHRH-R antagonist peptides influence fibroblast respiration and apoptosis in ways that impact fibrogenesis. MIA-602 increased basal oxygen consumption and maximal, uncoupled respiration of normal mouse lung fibroblasts; it also increased both basal respiration and spare respiratory capacity [ 17 ]. The maintenance of cellular respiration is evidently supported by MIA-602, and enhanced mitochondrial function would maintain fibroblast apoptotic capacity, which is consistent with the observed and potentially beneficial inhibition of fibrosis.…”

“…GHRH-R antagonist MIA-602 limits inflammation and fibrosis in a model of intraperitoneal, bleomycin-induced lung fibrosis. MIA-602 effectively decreased inflammation (reported as histopathological scores) due to bleomycin, compared to mice receiving vehicle [ 17 ].…”