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.
Highlights
Idiopathic pulmonary fibrosis (IPF) is the paradigm of fibrosing interstitial lung diseases
We have found expression of pituitary-type Growth hormone-releasing hormone (GHRH) receptor in normal human and IPF lung tissue by western blotting, suggesting that GHRH or growth hormone (GH) could participate in lung development, growth, and repair [7]
Pathophysiological GH secretion and insulin-like growth factor 1 (IGF-1) activation have growth-promoting effects in the lung resulting in increased alveolar size [28]
Summary
Idiopathic pulmonary fibrosis (IPF) is the paradigm of fibrosing interstitial lung diseases. It occurs more commonly in aging males, and often has a limited survival time of 3–5 years (median 3.8 years) after diagnosis [1]. Fibroblasts proliferate and migrate into the lung. They synthesize extracellular matrix, providing a platform for further cellular growth [3]. Myofibroblasts secrete cytokines, such as TGF-ß, with autocrine and paracrine effects that drive fibrosis in the lung [4]
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