title: Radiation-induced lung injury is mitigated by blockade of gastrin-releasing peptide.
abstract: Gastrin-releasing peptide (GRP), secreted by pulmonary neuroendocrine cells, mediates oxidant-induced lung injury in animal models. Considering that GRP blockade abrogates pulmonary inflammation and fibrosis in hyperoxic baboons, we hypothesized that ionizing radiation triggers GRP secretion, contributing to inflammatory and fibrotic phases of radiation-induced lung injury (RiLI). Using C57BL/6 mouse model of pulmonary fibrosis developing ≥20 weeks after high-dose thoracic radiation (15 Gy), we injected small molecule 77427 i.p. approximately 1 hour after radiation then twice weekly for up to 20 weeks. Sham controls were anesthetized and placed in the irradiator without radiation. Lung paraffin sections were immunostained and quantitative image analyses performed. Mice exposed to radiation plus PBS had increased interstitial CD68(+) macrophages 4 weeks after radiation and pulmonary neuroendocrine cells hyperplasia 6 weeks after radiation. Ten weeks later radiation plus PBS controls had significantly increased pSmad2/3(+) nuclei/cm(2). GRP blockade with 77427 treatment diminished CD68(+), GRP(+), and pSmad2/3(+) cells. Finally, interstitial fibrosis was evident 20 weeks after radiation by immunostaining for α-smooth muscle actin and collagen deposition. Treatment with 77427 abrogated interstitial α-smooth muscle actin and collagen. Sham mice given 77427 did not differ significantly from PBS controls. Our data are the first to show that GRP blockade decreases inflammatory and fibrotic responses to radiation in mice. GRP blockade is a novel radiation fibrosis mitigating agent that could be clinically useful in humans exposed to radiation therapeutically or unintentionally.
authors: Department of Pathology, Duke University Medical Center, Durham, North Carolina 27710, USA. shutang.zhou@duke.edu
authors: Shutang
authors: S
authors: Zhou
authors: Esther
authors: E
authors: Nissao
authors: Isabel L
authors: IL
authors: Jackson
authors: Wei
authors: W
authors: Leong
authors: Lindsay
authors: L
authors: Dancy
authors: Frank
authors: F
authors: Cuttitta
authors: Zeljko
authors: Z
authors: Vujaskovic
authors: Mary E
authors: ME
authors: Sunday
mesh_terms: D000818:Animals; D002452:Cell Count; D003094:Collagen / Q000378:metabolism; D019886:Gastrin-Releasing Peptide / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D008168:Lung / Q000000981:diagnostic imaging / Q000187:drug effects / Q000473:pathology; D055370:Lung Injury / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D055099:Neuroendocrine Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use; D011832:Radiation Injuries / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D011859:Radiography; D051785:Smad Proteins / Q000378:metabolism
chemical_list: D011743:Pyrimidines; D051785:Smad Proteins; C502484:compound 77427; D019886:Gastrin-Releasing Peptide; D003094:Collagen
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