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A Method for Generating Pulmonary Neutrophilia Using Aerosolized Lipopolysaccharide
Published on: December 15, 2014
Potentiation by granulocyte macrophage colony-stimulating factor of lipopolysaccharide toxicity in mice
1Department of Biochemical Pharmacology, Faculty of Biology, University of Konstanz, Germany.
Abstract:
GM-CSF is known to prime leukocytes for inflammatory stimuli in vitro. The objective of this study was to investigate the role of GM-CSF in vivo in a systemic inflammatory reaction syndrome. The results demonstrate a potentiation of LPS toxicity by GM-CSF in a mortality model as well as in a septic liver failure model in mice. Pretreatment of animals with 50 micrograms/kg GM-CSF induced lethality within 24 h in mice challenged with a subtoxic dose of LPS while controls survived > 72 h. A monoclonal anti-GM-CSF antibody significantly protected against a lethal LPS dose. Serum GM-CSF was inducible by LPS and peaked at 2 h. GM-CSF pretreatment dramatically potentiated systemic TNF release and hepatotoxicity induced by a subtoxic dose of LPS in galactosamine-sensitized mice. Potentiation of LPS hepatotoxicity was possible until 30 min after LPS challenge. Polyclonal anti-GM-CSF IgG protected against septic liver failure in this model and attenuated serum TNF concentrations. In vitro an ex vivo experiments revealed that after GM-CSF pretreatment LPS-induced IL-1 release from bone marrow or spleen cells was also enhanced. These findings suggest that GM-CSF represents an endogenous enhancer of LPS-induced organ injury, possibly by potentiating the release of proinflammatory cytokines such as TNF and IL-1.
Insights
Granulocyte-macrophage colony-stimulating factor (GM-CSF) enhances lipopolysaccharide (LPS) toxicity in mice, increasing mortality and liver injury. Blocking GM-CSF offers protection, suggesting its role in inflammatory responses.
Area of Science:
- Immunology
- Inflammation Biology
- Toxicology
Background:
- Granulocyte-macrophage colony-stimulating factor (GM-CSF) primes leukocytes for inflammatory stimuli in vitro.
- The in vivo role of GM-CSF in systemic inflammatory response syndrome (SIRS) requires elucidation.
Purpose of the Study:
- To investigate the in vivo role of GM-CSF in a systemic inflammatory reaction syndrome.
- To determine if GM-CSF potentiates lipopolysaccharide (LPS)-induced toxicity and organ injury.
Main Methods:
- Mice were pretreated with GM-CSF or vehicle before challenge with LPS.
- Mortality and septic liver failure models were utilized.
- Anti-GM-CSF antibodies were administered to assess protective effects.
- Serum cytokine levels (TNF, IL-1) and hepatotoxicity were measured.
- In vitro and ex vivo experiments assessed cytokine release from immune cells.
Main Results:
- GM-CSF pretreatment significantly increased mortality in mice challenged with subtoxic LPS doses.
- GM-CSF potentiated LPS-induced hepatotoxicity and systemic TNF release in galactosamine-sensitized mice.
- Anti-GM-CSF antibodies provided significant protection against LPS toxicity and septic liver failure.
- LPS induced serum GM-CSF, peaking at 2 hours.
- GM-CSF pretreatment enhanced LPS-induced IL-1 release from bone marrow and spleen cells.
Conclusions:
- GM-CSF acts as an endogenous enhancer of LPS-induced organ injury.
- GM-CSF potentiates LPS toxicity, likely by amplifying the release of pro-inflammatory cytokines like TNF and IL-1.
- Targeting GM-CSF may be a therapeutic strategy for managing LPS-induced inflammatory conditions.
