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Involvement of CD40-CD40L signaling in postischemic lung injury
Timothy M Moore1, W Bradley Shirah, Pavel L Khimenko
1Department of Physiology, University of Alabama College of Medicine, Mobile, Alabama 36688-0002, USA.
Insights
Ischemia-reperfusion injury in rat lungs involves lymphocytes and CD40-CD40L signaling, increasing microvascular permeability. Blocking this pathway or using IL-10 reduces lung injury.
Area of Science:
- Pulmonary Medicine
- Immunology
- Vascular Biology
Background:
- Ischemia-reperfusion (I/R) injury is a significant cause of lung damage.
- Lymphocyte retention and increased microvascular permeability characterize post-I/R lung injury.
Purpose of the Study:
- To investigate the role of CD40-CD40L interactions and IL-10 in I/R-induced lung injury.
- To determine the impact of these pathways on microvascular permeability and inflammatory responses.
Main Methods:
- Isolated rat lung model subjected to I/R.
- Quantitative measurement of microvascular filtration coefficient (K(f,c)).
- Immunoneutralization of CD40/CD40L and manipulation of IL-10 levels.
Main Results:
- I/R increased K(f,c), indicating enhanced permeability.
- Blocking CD40-CD40L signaling significantly reduced post-ischemic K(f,c) and MIP-2 production.
- Activated lymphocytes exacerbated K(f,c), an effect blocked by anti-CD40.
- IL-10 antagonism worsened I/R injury, while exogenous IL-10 provided protection.
Conclusions:
- Lymphocyte involvement in lung I/R injury is mediated by CD40-CD40L signaling.
- Local IL-10 production influences I/R-induced microvascular damage.
- Targeting CD40-CD40L and modulating IL-10 represent potential therapeutic strategies for lung I/R injury.
Abstract:
Our studies show that ischemia-reperfusion (I/R) in the isolated rat lung causes retention of lymphocytes, which is associated with increased microvascular permeability, as determined by quantitative measurement of the microvascular filtration coefficient (K(f,c)). Immunoneutralization of either CD40 or CD40L, cell surface proteins important in lymphocyte-endothelial cell proinflammatory events, results in significantly lower postischemic K(f,c) values. Antagonism of CD40-CD40L signaling also results in attenuation of I/R-elicited macrophage inflammatory protein-2 production. Rat lymphocytes activated ex vivo with phorbol 12-myristate, 13-acetate increased K(f,c) in isolated lungs independently of I/R, and this increase was prevented by pretreating lungs with anti-CD40. In addition to lymphocyte involvement via CD40-CD40L interactions, our studies also show that I/R injury is potentiated by antagonism of IL-10 produced locally within the postischemic lung, whereas exogenous, rat recombinant IL-10 provided protection against I/R-induced microvascular damage. Thus acute lymphocyte involvement in lung I/R injury involves CD40-CD40L signaling mechanisms, and these events may be influenced by local IL-10 generation.
