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Mechanisms of increased pulmonary microvascular permeability induced by FMLP in isolated rabbit lungs
H Tanaka1, J D Bradley, L J Baudendistel
1Department of Anesthesiology, St. Louis University School of Medicine, Missouri 63110.
Abstract:
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.
Insights
The chemotactic peptide FMLP, with neutrophils, causes lung injury by increasing vascular permeability. This lung injury is mediated by leukotrienes, possibly from reactive oxygen species, not cyclooxygenase products.
Area of Science:
- Pulmonary medicine
- Immunology
- Cellular biology
Background:
- The chemotactic peptide N-formyl-L-methionyl-L-leucyl-L-phenylalanine (FMLP) is known to activate polymorphonuclear leukocytes (PMNs).
- PMN activation can lead to inflammatory responses and tissue injury, particularly in the lungs.
Purpose of the Study:
- To investigate the role of reactive oxygen species (ROS), cyclooxygenase (COX) products, and cysteinyl leukotrienes (LTs) in FMLP-induced lung injury.
- To test the hypothesis that PMNs activated by FMLP induce lung injury through modulation of these mediators.
Main Methods:
- Isolated constant-flow buffer-perfused rabbit lungs were used.
- FMLP was added to lungs with or without PMNs.
- Microvascular permeability (Kf) and wet-to-dry weight ratio were measured.
- Myeloperoxidase activity was assessed as an indicator of PMN infiltration.
- Inhibitors of COX (meclofenamate, ibuprofen), ROS (catalase), and LT synthesis (MK 886) were used for pretreatment.
Main Results:
- FMLP alone did not increase microvascular permeability, but with PMNs, it caused an 80% increase in Kf and elevated lung wet-to-dry weight ratio.
- A positive correlation was found between myeloperoxidase activity and Kf.
- COX inhibitors had no effect, but catalase and MK 886 inhibited the FMLP-induced increase in Kf.
- Perfusate levels of LTs increased significantly after FMLP and PMN addition, and both MK 886 and catalase suppressed this increase.
Conclusions:
- FMLP-induced pulmonary microvascular injury in rabbit lungs is dependent on PMNs.
- The injury is mediated by leukotrienes, with a possible role for ROS production in their generation.
- Cyclooxygenase products do not appear to play a significant role in this specific model of lung injury.