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Iloprost inhibits neutrophil-induced lung injury and neutrophil adherence to endothelial monolayers
C M Riva1, M L Morganroth, A G Ljungman
1Department of Pediatrics, University of Michigan, Ann Arbor.
Abstract:
We hypothesized that Iloprost, a long-acting prostacyclin analog, would inhibit neutrophil (PMN)-induced lung injury and decrease PMN adherence to vascular endothelium. Human PMNs infused into isolated buffer-perfused rat lungs subsequently stimulated with phorbol myristate acetate (PMA) resulted in lung injury as assessed by the accumulation of [125I]bovine serum albumin (125I-BSA) in lung parenchyma and alveolar lavage fluid. Addition of Iloprost to the lung perfusate, prior to activation of the PMNs, reduced lung injury as assessed by a decrease in the accumulation of 125I-BSA in the lung. This protective effect was not due to the vasodilatory effect of Iloprost. Protection by Iloprost was not linked to a reduction in PMA-induced PMN superoxide production since Iloprost did not reduce the amount of superoxide released into lung perfusate. In vitro, Iloprost caused a dose-dependent inhibition of PMA-stimulated PMN adherence to endothelial cells. Iloprost did not affect the number of Mo1 adhesion molecules constitutively expressed or the number of receptors expressed on the PMNs following PMA. Addition of cAMP or dibutyryl cAMP to the endothelial cells mimicked the effects of Iloprost, diminishing PMA-stimulated PMN adhesion. In separate experiments, addition of the phosphodiesterase inhibitor IBMX to Iloprost resulted in a greater inhibition of PMA-stimulated PMN adherence, while addition of an adenylate cyclase inhibitor, SQ 22,536, or cAMP antibodies with the Iloprost abolished Iloprost's inhibitory effect on PMN adhesion. Thus, Iloprost inhibits PMA-activated PMN-induced lung injury despite continued superoxide production. Iloprost inhibition of PMN adhesion is dependent on cAMP.
Insights
Iloprost, a prostacyclin analog, reduces neutrophil-induced lung injury by inhibiting neutrophil adherence to blood vessels. This effect is mediated by cyclic AMP (cAMP) and does not depend on superoxide production.
Area of Science:
- Pulmonary Medicine
- Pharmacology
- Cell Biology
Background:
- Neutrophil (PMN) adherence to vascular endothelium contributes to lung injury.
- Prostacyclin analogs, like Iloprost, may offer therapeutic benefits by modulating inflammatory responses.
Purpose of the Study:
- To investigate the effect of Iloprost on neutrophil-induced lung injury and adherence to endothelial cells.
- To elucidate the mechanism underlying Iloprost's protective effects, particularly its relationship with cyclic AMP (cAMP) signaling.
Main Methods:
- Isolated buffer-perfused rat lungs were used to model lung injury induced by phorbol myristate acetate (PMA) stimulated human PMNs.
- Lung injury was assessed by measuring [125I]bovine serum albumin (125I-BSA) accumulation.
- In vitro experiments assessed PMN adherence to endothelial cells, with and without Iloprost, and measured superoxide production.
- The role of cAMP was investigated using cAMP, dibutyryl cAMP, IBMX, SQ 22,536, and cAMP antibodies.
Main Results:
- Iloprost significantly reduced lung injury and PMN adherence to endothelial cells in a dose-dependent manner.
- Iloprost's protective effect was independent of its vasodilatory action and did not involve reduced PMN superoxide production.
- Iloprost's inhibition of PMN adherence was mimicked by cAMP and dibutyryl cAMP, and potentiated by IBMX.
- Inhibiting adenylate cyclase or blocking cAMP abolished Iloprost's effect on PMN adherence, confirming a cAMP-dependent mechanism.
Conclusions:
- Iloprost effectively inhibits neutrophil-induced lung injury by reducing PMN adherence to vascular endothelium.
- The mechanism of action involves a cAMP-dependent pathway, independent of superoxide production or vasodilation.
- Iloprost represents a potential therapeutic agent for inflammatory lung conditions driven by neutrophil activation.