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Mepacrine decreases lung leak in rats given interleukin-1 intratracheally
Y M Lee1, B M Hybertson, L S Terada
1Webb-Waring Institute for Biomedical Research and the Department of Medicine at the University of Colorado Health Sciences Center, Denver, USA.
Abstract:
We hypothesized that phospholipase A2 (PLA2) metabolites contribute to the acute, neutrophil-dependent, edematous lung leak that develops after administration of interleukin-1 (IL-1) intratracheally to rats and tested this premise by using mepacrine to inhibit PLA2 activity in vivo. We found that lung PLA2 activity, lung lavage phospholipid content, lung leak index, lung weight gain, and lung lavage protein concentrations were increased in rats given IL-1 intratracheally compared with sham-treated control rats. By comparison, lungs of mecaprine and IL-1-treated rats had decreased PLA2 activity, lavage phospholipid content, leak, weight gain, and lavage protein increases compared with rats given IL-1 intratracheally. Mepacrine treatment also decreased lung neutrophil accumulation, but not lung lavage cytokine-induced neutrophil chemoattractant (CINC) levels, in rats given IL-1 intratracheally. In parallel experiments, mepacrine treatment reduced the adhesion of human neutrophils to IL-1-treated human umbilical vein endothelial cells in vitro. Our results indicate that PLA2 activity participates in the lung neutrophil retention and pulmonary vascular leak that develops in rats given IL-1 intratracheally.
Insights
Phospholipase A2 (PLA2) metabolites contribute to acute lung injury. Inhibiting PLA2 with mepacrine reduced lung leak and neutrophil accumulation in rats, suggesting PLA2 plays a key role in pulmonary vascular injury.
Area of Science:
- Pulmonary Medicine
- Inflammation Research
- Biochemistry
Background:
- Acute lung injury involves neutrophil infiltration and vascular leakage.
- Interleukin-1 (IL-1) is implicated in initiating inflammatory responses in the lungs.
- Phospholipase A2 (PLA2) enzymes generate lipid mediators that can influence inflammation.
Purpose of the Study:
- To investigate the role of phospholipase A2 (PLA2) metabolites in acute lung leak induced by IL-1.
- To determine if inhibiting PLA2 activity can mitigate IL-1-induced pulmonary inflammation and vascular permeability in rats.
Main Methods:
- Administered IL-1 intratracheally to rats to induce lung injury.
- Used mepacrine, a PLA2 inhibitor, to assess its effects on lung inflammation.
- Measured lung PLA2 activity, phospholipid content, vascular permeability (leak index), lung weight gain, and protein concentration in bronchoalveolar lavage fluid.
- Assessed neutrophil accumulation and cytokine-induced neutrophil chemoattractant (CINC) levels.
- Evaluated neutrophil adhesion to endothelial cells in vitro.
Main Results:
- IL-1 administration significantly increased lung PLA2 activity, phospholipid content, lung leak, weight gain, and protein leakage.
- Mepacrine treatment significantly reduced these IL-1-induced effects, including decreased PLA2 activity, leak, and weight gain.
- Mepacrine also reduced neutrophil accumulation in the lungs but did not affect CINC levels.
- In vitro, mepacrine inhibited the adhesion of neutrophils to IL-1-stimulated endothelial cells.
Conclusions:
- PLA2 activity is a significant contributor to the acute neutrophil-dependent lung leak and vascular permeability induced by IL-1.
- Inhibition of PLA2 by mepacrine effectively mitigates IL-1-induced pulmonary vascular injury and neutrophil retention.
- These findings highlight PLA2 as a potential therapeutic target for managing acute lung inflammation and injury.