Acute Crit Care.  2019 May;34(2):133-140. 10.4266/acc.2019.00507.

The effects of BMS-470539 on lipopolysaccharide-induced acute lung injury

Affiliations
  • 1Department of Anesthesiology and Pain Medicine, Chonnam National University Medical School and Hospital, Gwangju, Korea. shkwak@jnu.ac.kr
  • 2Brain Korea 21 Project, Center for Creative Biomedical Scientists at Chonnam National University, Gwangju, Korea.

Abstract

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.

Keyword

acute lung injury; cytokines; lipopolysaccharides; melanocortin 1 receptor

MeSH Terms

Acute Lung Injury*
Animals
Bone Marrow
Bronchoalveolar Lavage Fluid
Cytokines
Injections, Subcutaneous
Leukocytes
Lipopolysaccharides
Lung
Macrophages
Mice
Mortality
Multiple Organ Failure
Neutrophil Infiltration
Neutrophils
Pulmonary Edema
Receptor, Melanocortin, Type 1
Sepsis
Survival Rate
Tumor Necrosis Factor-alpha
Cytokines
Lipopolysaccharides
Receptor, Melanocortin, Type 1
Tumor Necrosis Factor-alpha
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