Cargando…
The effects of BMS-470539 on lipopolysaccharide-induced acute lung injury
BACKGROUND: Overactivation of inflammatory cells, including macrophages and neutrophils, is associated with acute lung injury. BMS-470539 is a selective agonist of melanocortin 1 receptor, which triggers the inhibition of proinflammatory responses, suppressing neutrophil infiltration and protecting...
Autores principales: | , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Korean Society of Critical Care Medicine
2019
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6786663/ https://www.ncbi.nlm.nih.gov/pubmed/31723918 http://dx.doi.org/10.4266/acc.2019.00507 |
_version_ | 1783458111944654848 |
---|---|
author | Jang, Eun-A Kim, Jin-Young Tin, Tran Duc Song, Ji-A Lee, Seong-Heon Kwak, Sang-Hyun |
author_facet | Jang, Eun-A Kim, Jin-Young Tin, Tran Duc Song, Ji-A Lee, Seong-Heon Kwak, Sang-Hyun |
author_sort | Jang, Eun-A |
collection | PubMed |
description | BACKGROUND: Overactivation of inflammatory cells, including macrophages and neutrophils, is associated with acute lung injury. BMS-470539 is a selective agonist of melanocortin 1 receptor, which triggers the inhibition of proinflammatory responses, suppressing neutrophil infiltration and protecting tissue. This study evaluated the effects of BMS-470539 on lipopolysaccharide-induced acute lung injury in a mouse model. METHODS: Mice received a subcutaneous injection of saline or BMS-470539 (18.47 mg/kg) 1 hour before an intratracheal injection of saline or lipopolysaccharide (20 μg). Mice were sacrificed to analyze the severity of pulmonary edema (lung wet-to-dry weight [W/D] ratio) and inflammatory responses (level of leukocytes, polymorphonuclear neutrophils [PMNs] and tumor necrosis factor alpha [TNF-α] in bronchoalveolar lavage fluid [BALF]), and neutrophil infiltration (myeloperoxidase activity). TNF-α activation was also measured in neutrophils from bone marrow. Survival was investigated in a second-hit sepsis mouse model. RESULTS: BMS-470539 improved sepsis-induced pulmonary edema, as demonstrated by a decreased W/D ratio (5.76%±0.83% to 3.81%±0.86%, P<0.05). The inflammatory response also improved, as shown by decreased levels of leukocytes (551±116 to 357±86×10²/mm³, P<0.05), PMNs (51.52%±16.23% to 18.41%±7.25%, P<0.01), and TNF-α (550±338 to 128±52 pg/ml, P<0.01) in the BALF. BMS-470539 also improved the inflammatory response, as shown by TNF-α levels (850±158 to 423±59 pg/ml, P<0.01) in neutrophils. BMS-470539 downregulated neutrophil infiltration in the lung (myeloperoxidase: 654±98 to 218±89 U/g, P<0.001). Lastly, BMS improved the survival rate (0% to 70%, P<0.01) in a mice multiple organ failure model. CONCLUSIONS: BMS-470539 improved lipopolysaccharide-induced acute lung injury and mortality in mice by affecting the inflammatory response. |
format | Online Article Text |
id | pubmed-6786663 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Korean Society of Critical Care Medicine |
record_format | MEDLINE/PubMed |
spelling | pubmed-67866632019-11-13 The effects of BMS-470539 on lipopolysaccharide-induced acute lung injury Jang, Eun-A Kim, Jin-Young Tin, Tran Duc Song, Ji-A Lee, Seong-Heon Kwak, Sang-Hyun Acute Crit Care Original Article BACKGROUND: Overactivation of inflammatory cells, including macrophages and neutrophils, is associated with acute lung injury. BMS-470539 is a selective agonist of melanocortin 1 receptor, which triggers the inhibition of proinflammatory responses, suppressing neutrophil infiltration and protecting tissue. This study evaluated the effects of BMS-470539 on lipopolysaccharide-induced acute lung injury in a mouse model. METHODS: Mice received a subcutaneous injection of saline or BMS-470539 (18.47 mg/kg) 1 hour before an intratracheal injection of saline or lipopolysaccharide (20 μg). Mice were sacrificed to analyze the severity of pulmonary edema (lung wet-to-dry weight [W/D] ratio) and inflammatory responses (level of leukocytes, polymorphonuclear neutrophils [PMNs] and tumor necrosis factor alpha [TNF-α] in bronchoalveolar lavage fluid [BALF]), and neutrophil infiltration (myeloperoxidase activity). TNF-α activation was also measured in neutrophils from bone marrow. Survival was investigated in a second-hit sepsis mouse model. RESULTS: BMS-470539 improved sepsis-induced pulmonary edema, as demonstrated by a decreased W/D ratio (5.76%±0.83% to 3.81%±0.86%, P<0.05). The inflammatory response also improved, as shown by decreased levels of leukocytes (551±116 to 357±86×10²/mm³, P<0.05), PMNs (51.52%±16.23% to 18.41%±7.25%, P<0.01), and TNF-α (550±338 to 128±52 pg/ml, P<0.01) in the BALF. BMS-470539 also improved the inflammatory response, as shown by TNF-α levels (850±158 to 423±59 pg/ml, P<0.01) in neutrophils. BMS-470539 downregulated neutrophil infiltration in the lung (myeloperoxidase: 654±98 to 218±89 U/g, P<0.001). Lastly, BMS improved the survival rate (0% to 70%, P<0.01) in a mice multiple organ failure model. CONCLUSIONS: BMS-470539 improved lipopolysaccharide-induced acute lung injury and mortality in mice by affecting the inflammatory response. Korean Society of Critical Care Medicine 2019-05 2019-05-31 /pmc/articles/PMC6786663/ /pubmed/31723918 http://dx.doi.org/10.4266/acc.2019.00507 Text en Copyright © 2019 The Korean Society of Critical Care Medicine This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Original Article Jang, Eun-A Kim, Jin-Young Tin, Tran Duc Song, Ji-A Lee, Seong-Heon Kwak, Sang-Hyun The effects of BMS-470539 on lipopolysaccharide-induced acute lung injury |
title | The effects of BMS-470539 on lipopolysaccharide-induced acute lung injury |
title_full | The effects of BMS-470539 on lipopolysaccharide-induced acute lung injury |
title_fullStr | The effects of BMS-470539 on lipopolysaccharide-induced acute lung injury |
title_full_unstemmed | The effects of BMS-470539 on lipopolysaccharide-induced acute lung injury |
title_short | The effects of BMS-470539 on lipopolysaccharide-induced acute lung injury |
title_sort | effects of bms-470539 on lipopolysaccharide-induced acute lung injury |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6786663/ https://www.ncbi.nlm.nih.gov/pubmed/31723918 http://dx.doi.org/10.4266/acc.2019.00507 |
work_keys_str_mv | AT jangeuna theeffectsofbms470539onlipopolysaccharideinducedacutelunginjury AT kimjinyoung theeffectsofbms470539onlipopolysaccharideinducedacutelunginjury AT tintranduc theeffectsofbms470539onlipopolysaccharideinducedacutelunginjury AT songjia theeffectsofbms470539onlipopolysaccharideinducedacutelunginjury AT leeseongheon theeffectsofbms470539onlipopolysaccharideinducedacutelunginjury AT kwaksanghyun theeffectsofbms470539onlipopolysaccharideinducedacutelunginjury AT jangeuna effectsofbms470539onlipopolysaccharideinducedacutelunginjury AT kimjinyoung effectsofbms470539onlipopolysaccharideinducedacutelunginjury AT tintranduc effectsofbms470539onlipopolysaccharideinducedacutelunginjury AT songjia effectsofbms470539onlipopolysaccharideinducedacutelunginjury AT leeseongheon effectsofbms470539onlipopolysaccharideinducedacutelunginjury AT kwaksanghyun effectsofbms470539onlipopolysaccharideinducedacutelunginjury |