Pentoxifylline lessens the endotoxin-induced increase in albumin clearance across pulmonary artery endothelial monolayers with and without neutrophils.
Pentoxifylline, a methylxanthine with phosphodiesterase inhibitor activity, attenuates endotoxin-induced pulmonary vascular protein leak and decreases lung neutrophil accumulation in vivo. In vitro, pentoxifylline decreases neutrophil activation as measured by superoxide release and phagocytosis of latex beads. To test the hypothesis that the beneficial effect of pentoxifylline may be via a direct effect on the endothelial cells as well as via prevention of neutrophil activation, we incubated bovine pulmonary artery endothelial cell monolayers with endotoxin and pentoxifylline in the presence or absence of human neutrophils. Albumin clearance across the monolayers was used as an index of endothelial permeability. Endotoxin (1.0 micrograms/ml) increased albumin clearance in a dose- and time-dependent fashion (207.5 +/- 25%, P less than 0.05). Co-incubation with neutrophils enhanced this effect. Pentoxifylline significantly attenuated the endotoxin-induced increase in albumin clearance both with and without neutrophils, and lessened endotoxin-induced cell lysis (chromium release) and morphologic changes. Because increased endothelial cyclic adenosine monophosphate (cAMP) levels may decrease protein permeability and pentoxifylline increases cAMP in neutrophils, we measured cAMP levels in endothelial cells. Incubation with pentoxifylline failed to raise cAMP levels in endothelial cells, in contrast to incubation with aminophylline. In conclusion, pentoxifylline attenuates endotoxin-induced increase in albumin clearance across endothelial monolayers both in the presence and absence of neutrophils. These results suggest that part of the protective effect of pentoxifylline may be mediated via effects on endothelium. Furthermore, this pentoxifylline-mediated endothelial barrier effect appears to be independent of an effect on cAMP.
Sato
K
K
Cardiovascular Pulmonary Research Laboratory, University of Colorado Health Sciences Center, Denver.
Stelzner
T J
TJ
O'Brien
R F
RF
Weil
J V
JV
Welsh
C H
CH
D000418:Albumins / Q000378:metabolism; D000818:Animals; D002417:Cattle; D002478:Cells, Cultured; D002860:Chromium Radioisotopes; D000242:Cyclic AMP / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism; D004731:Endotoxins / Q000037:antagonists & inhibitors*; D009504:Neutrophils / Q000502:physiology; D010431:Pentoxifylline / Q000494:pharmacology*; D010539:Permeability / Q000187:drug effects; D011651:Pulmonary Artery / Q000187:drug effects* / Q000378:metabolism
D000418:Albumins; D002860:Chromium Radioisotopes; D004731:Endotoxins; D000242:Cyclic AMP; D010431:Pentoxifylline