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Updated: Aug 15, 2026
Inducing Acute Lung Injury in Mice by Direct Intratracheal Lipopolysaccharide Instillation
Published on: July 6, 2019
Blockade of p38 map kinase inhibits complement-induced acute lung injury in a murine model
Steven P Nash1, Rita M Heuertz
1School of Medicine, Saint Louis University, St. Louis, MO 63104, USA.
Abstract:
Features of acute lung injury include neutrophil influx and increased vascular permeability with resultant pulmonary edema. Inhibition of p38 mitogen-activated protein kinase (MAPK) in in vivo models of endotoxin-induced inflammation results in reduction of organ injury as well as symptomatic relief. In this study, mice received an oral dose (100 mg/kg) of the p38 MAPK inhibitor, SB203580, followed by intratracheal instillation of an agent of complement origin, C5a des arg, at a concentration (10 microg) that induced acute lung injury. Neutrophil and protein content of bronchoalveolar lavage fluid as indicators of leukocyte influx and vascular permeability respectively were assessed. Animals that received C5a-instillation had a significant influx of neutrophils into the lungs (49+/-8%) while mice receiving C5a-instillation and prior treatment with SB203580 exhibited diminished influx (16+/-5%). Similarly, pretreatment with oral SB203580 resulted in decreased vascular permeability (241+/-34 microg/ml) than the positive control animals (407+/-135 microg/ml). Activity analysis of total lung p38 MAPK revealed that p38 activity was increased at 4 h after C5a-instillation and that SB203580-treated C5a-instilled mouse lungs had lower p38 activity than did the C5a-instilled control. These data indicate that oral administration of an agent inhibitory for p38 MAPK offers a protective effect in the lungs from both neutrophil influx and protein leak associated with acute lung injury.
Insights
Inhibiting p38 mitogen-activated protein kinase (MAPK) with SB203580 reduced acute lung injury in mice. This treatment decreased neutrophil influx and vascular permeability, offering lung protection.
Area of Science:
- Pulmonary Medicine
- Inflammation Research
- Pharmacology
Background:
- Acute lung injury (ALI) is characterized by neutrophil infiltration and increased vascular permeability, leading to pulmonary edema.
- p38 mitogen-activated protein kinase (MAPK) plays a role in inflammatory responses and organ injury.
- Inhibition of p38 MAPK has shown promise in reducing inflammation in preclinical models.
Purpose of the Study:
- To investigate the protective effects of the p38 MAPK inhibitor SB203580 against C5a-induced acute lung injury in a mouse model.
- To assess the impact of SB203580 on neutrophil influx and vascular permeability in the lungs.
- To evaluate the effect of SB203580 on p38 MAPK activity in lung tissue.
Main Methods:
- Mice were administered an oral dose of SB203580 (100 mg/kg) followed by intratracheal instillation of C5a des arg (10 microg) to induce ALI.
- Neutrophil and protein content in bronchoalveolar lavage fluid were measured as indicators of leukocyte influx and vascular permeability.
- p38 MAPK activity in lung tissue was analyzed at 4 hours post-C5a instillation.
Main Results:
- C5a instillation significantly increased neutrophil influx (49+/-8%) and vascular permeability (407+/-135 microg/ml).
- Prior treatment with SB203580 markedly reduced neutrophil influx (16+/-5%) and vascular permeability (241+/-34 microg/ml).
- p38 MAPK activity was elevated after C5a instillation, and SB203580 treatment lowered this activity.
Conclusions:
- Oral administration of the p38 MAPK inhibitor SB203580 confers significant protection against acute lung injury.
- SB203580 effectively mitigates C5a-induced neutrophil influx and protein leakage in the lungs.
- Targeting p38 MAPK represents a potential therapeutic strategy for managing acute lung injury.
