Abstract
Growth hormone-releasing hormone (GHRH) is secreted primarily from the hypothalamus, but other tissues, including the lungs, produce it locally. GHRH stimulates the release and secretion of growth hormone (GH) by the pituitary and regulates the production of GH and hepatic insulin-like growth factor-1 (IGF-1). Pituitary-type GHRH-receptors (GHRH-R) are expressed in human lungs, indicating that GHRH or GH could participate in lung development, growth, and repair. GHRH-R antagonists (i.e., synthetic peptides), which we have tested in various models, exert growth-inhibitory effects in lung cancer cells in vitro and in vivo in addition to having anti-inflammatory, anti-oxidative, and pro-apoptotic effects. One antagonist of the GHRH-R used in recent studies reviewed here, MIA-602, lessens both inflammation and fibrosis in a mouse model of bleomycin lung injury. GHRH and its peptide agonists regulate the proliferation of fibroblasts through the modulation of extracellular signal-regulated kinase (ERK) and Akt pathways. In addition to downregulating GH and IGF-1, GHRH-R antagonist MIA-602 inhibits signaling pathways relevant to inflammation, including p21-activated kinase 1-signal transducer and activator of transcription 3/nuclear factor-kappa B (PAK1-STAT3/NF-κB and ERK). MIA-602 induces fibroblast apoptosis in a dose-dependent manner, which is an effect that is likely important in antifibrotic actions. Taken together, the novel data reviewed here show that GHRH is an important peptide that participates in lung homeostasis, inflammation, wound healing, and cancer; and GHRH-R antagonists may have therapeutic potential in lung diseases.
Highlights
The goal of this review is to present and critically evaluate new findings regarding growth hormone-releasing hormone (GHRH) and its actions in the settings of lung inflammation, fibrosis, and cancer
The essential, unanswered question we address is whether Growth hormone-releasing hormone (GHRH), as revealed by synthetic peptide probes that activate or inhibit its receptor, plays key roles in lung pathophysiology that are distinct from its effects on growth and metabolism
Data reviewed here illustrate the physiologic role of GHRH per se in the lung, which is independent of effects of GHRH-R agonists or antagonists that we describe later
Summary
The goal of this review is to present and critically evaluate new findings regarding growth hormone-releasing hormone (GHRH) and its actions in the settings of lung inflammation, fibrosis, and cancer. The essential, unanswered question we address is whether GHRH, as revealed by synthetic peptide probes that activate or inhibit its receptor, plays key roles in lung pathophysiology that are distinct from its effects on growth and metabolism. It provides background on the physiology of GHRH in the lung, which was elucidated using recently developed GHRH receptor peptide agonists and antagonists as mechanistic probes. His–Orn–Val–Leu–Abu–Gln–Leu–Ser–Ala–His–Orn–Leu–Leu–Gln–Asp–Ile–Nle–D–Arg–Ha–NH2 has been synthesized by solid phase methods and purified by HPLC This antagonist and related GHRH agonists (e.g., MR-409) that bind to GHRH-R have been useful in revealing the physiologic and systemic activities of GHRH distinct from its hormonal effects on the pituitary and the GH/insulin-like growth factor-1 (IGF-1) pathway. The suppression of cellular growth likely could be induced by the downregulation of GHRH receptors levels [3]
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