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

Chongxu Zhang, Renzhi Cai, Aaron Lazerson, Gaetan Delcroix, Medhi Wangpaichitr, Mehdi Mirsaeidi, Anthony Griswold, Andrew V Schally, Robert Jackson

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
JournalLung
DOIs
StateAccepted/In press - Jan 1 2019

Fingerprint

Hormone Antagonists
Bleomycin
Pneumonia
Fibrosis
Growth Hormone-Releasing Hormone
Lung
Hydroxyproline
Inflammation
Cellular Immunity
Genes
Lung Injury
Chemotaxis
T-Cell Antigen Receptor
GHRH(1-29)NH2, (PhAc-Ada)(0)-Tyr(1), Arg(2), Fpa(5,6), Ala(8), Har(9), Tyr(Me)(10), His(11), Orn(12,) Abu(15), His(20), Orn(21), Nle(27), Arg(28), Har(29)-
somatotropin releasing hormone receptor
Interleukin-1
Chemokines
Oxygen Consumption
Growth Hormone
Cell Differentiation

Keywords

  • Bleomycin
  • Growth hormone-releasing hormone
  • Idiopathic pulmonary fibrosis
  • MIA-602

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine

Cite this

@article{2ca1396be3b54587bfce584caffbdf50,
title = "Growth Hormone-Releasing Hormone Receptor Antagonist Modulates Lung Inflammation and Fibrosis due to Bleomycin",
abstract = "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 na{\"i}ve 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.",
keywords = "Bleomycin, Growth hormone-releasing hormone, Idiopathic pulmonary fibrosis, MIA-602",
author = "Chongxu Zhang and Renzhi Cai and Aaron Lazerson and Gaetan Delcroix and Medhi Wangpaichitr and Mehdi Mirsaeidi and Anthony Griswold and Schally, {Andrew V} and Robert Jackson",
year = "2019",
month = "1",
day = "1",
doi = "10.1007/s00408-019-00257-w",
language = "English (US)",
journal = "Lung",
issn = "0341-2040",
publisher = "Springer New York",

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TY - JOUR

T1 - Growth Hormone-Releasing Hormone Receptor Antagonist Modulates Lung Inflammation and Fibrosis due to Bleomycin

AU - Zhang, Chongxu

AU - Cai, Renzhi

AU - Lazerson, Aaron

AU - Delcroix, Gaetan

AU - Wangpaichitr, Medhi

AU - Mirsaeidi, Mehdi

AU - Griswold, Anthony

AU - Schally, Andrew V

AU - Jackson, Robert

PY - 2019/1/1

Y1 - 2019/1/1

N2 - 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.

AB - 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.

KW - Bleomycin

KW - Growth hormone-releasing hormone

KW - Idiopathic pulmonary fibrosis

KW - MIA-602

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U2 - 10.1007/s00408-019-00257-w

DO - 10.1007/s00408-019-00257-w

M3 - Article

JO - Lung

JF - Lung

SN - 0341-2040

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