Mechanisms of increased pulmonary microvascular permeability induced by FMLP in isolated rabbit lungs.
We observed that the chemotactic peptide N-formyl-L-methionyl-L-leucyl-L- phenylalanine (FMLP) induced pulmonary edema when polymorphonuclear leukocytes (PMNs) were added to isolated constant-flow buffer-perfused rabbit lungs. This study was designed to test the hypothesis that PMNs activated by FMLP induced lung injury by the modulation of reactive oxygen species (ROS), cyclooxygenase products, or cysteinyl leukotrienes (LTs). Addition of FMLP alone did not increase microvascular permeability (Kf). When PMNs were added to the isolated lung, FMLP caused an 80% increase in Kf. Wet-to-dry weight ratio was also significantly increased with PMNs + FMLP compared with FMLP only. There was a significant positive correlation between total myeloperoxidase activity in lung tissue and Kf values after FMLP (30 min). Pretreatment with two dissimilar cyclooxygenase inhibitors, meclofenamate or ibuprofen, had no effect on the PMN + FMLP-induced increase in Kf. However, the ROS inhibitor catalase and the nonantioxidant LT synthesis blocker MK 886 inhibited the PMN + FMLP increase in Kf. Perfusate levels of LTs (LTC4, -D4, and -E4) were significantly increased from baseline values 30 min after FMLP. Both MK 886 and catalase suppressed the elevation of LTs after PMN + FMLP. These results indicate that FMLP increased a pulmonary microvascular permeability in isolated buffer-perfused rabbit lungs that is PMN dependent and mediated by LT produced possibly by a result of ROS production.
Tanaka
H
H
Department of Anesthesiology, St. Louis University School of Medicine, Missouri 63110.
Bradley
J D
JD
Baudendistel
L J
LJ
Dahms
T E
TE
D000818:Animals; D002199:Capillary Permeability / Q000187:drug effects*; D002374:Catalase / Q000494:pharmacology; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D007052:Ibuprofen / Q000494:pharmacology; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D007958:Leukocyte Count; D020024:Leukotriene Antagonists; D015289:Leukotrienes / Q000378:metabolism; D008168:Lung / Q000187:drug effects; D008469:Meclofenamic Acid / Q000494:pharmacology; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology*; D009504:Neutrophils / Q000187:drug effects; D009195:Peroxidase / Q000378:metabolism; D011652:Pulmonary Circulation / Q000187:drug effects*; D011654:Pulmonary Edema / Q000503:physiopathology; D011669:Pulmonary Wedge Pressure / Q000187:drug effects; D011817:Rabbits; D002722:Chlorobenzenes
D002374:Catalase; D016861:Cyclooxygenase Inhibitors; D007052:Ibuprofen; D007211:Indoles; D020024:Leukotriene Antagonists; D015289:Leukotrienes; D008469:Meclofenamic Acid; D009240:N-Formylmethionine Leucyl-Phenylalanine; D009195:Peroxidase; C060893:MK-886; D002722:Chlorobenzenes