Iloprost inhibits neutrophil-induced lung injury and neutrophil adherence to endothelial monolayers.
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.
Riva
C M
CM
Department of Pediatrics, University of Michigan, Ann Arbor.
Morganroth
M L
ML
Ljungman
A G
AG
Schoeneich
S O
SO
Marks
R M
RM
Todd
R F
RF
Ward
P A
PA
Boxer
L A
LA
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000067956:Adenylyl Cyclase Inhibitors; D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects; D000242:Cyclic AMP / Q000502:physiology; D016285:Iloprost / Q000494:pharmacology*; D066298:In Vitro Techniques; D016177:Macrophage-1 Antigen / Q000378:metabolism; D008297:Male; D009504:Neutrophils / Q000166:cytology / Q000502:physiology*; D009543:Nifedipine / Q000494:pharmacology; D010539:Permeability; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D051381:Rats; D012128:Respiratory Distress Syndrome / Q000503:physiopathology*; D013481:Superoxides / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D000067956:Adenylyl Cyclase Inhibitors; D016177:Macrophage-1 Antigen; D010726:Phosphodiesterase Inhibitors; D013481:Superoxides; C017759:9-(tetrahydro-2-furyl)-adenine; D000242:Cyclic AMP; D009543:Nifedipine; D000225:Adenine; D016285:Iloprost; D013755:Tetradecanoylphorbol Acetate; D015056:1-Methyl-3-isobutylxanthine