Pentoxifylline inhibits FMLP-induced macromolecular leakage.
The acute inflammatory responses to the chemotactic peptide N-formyl-methionyl-leucyl-phenylalanine (FMLP) and the effects of pentoxifylline (PTXF) on the responses in vivo were studied. We used intravital microscopy with rat cremaster muscle preparation to determine inflammatory responses of microcirculation. Macromolecular leakage from postcapillary venules was evaluated by quantifying the extravasation of fluorescein isothiocyanate conjugated to bovine serum albumin. FMLP induced a rapid increase in macromolecular leakage, an increase in leukocyte-endothelium adhesion, and a decrease in blood flow in the microcirculation. PTXF inhibited FMLP-induced responses in a dose-dependent manner but failed to block the histamine-dependent leakage induced by compound 48/80. In addition, diphenhydramine, a histamine-receptor blocker, did not affect the macromolecular leakage induced by FMLP. The cell-permeable adenosine 3',5'-cyclic monophosphate (cAMP) analogue N6,2'-O-dibutyryladenosine 3',5'-cyclic monophosphate mimicked PTXF's effects on the microcirculation and also inhibited FMLP-induced macromolecular leakage. PTXF is known to inhibit phosphodiesterase and increase intracellular cAMP, which modulates functions of endothelial cells, smooth muscle cells, and neutrophils in vitro. Our findings suggest that FMLP induces acute inflammatory responses through activation of neutrophils, independent of endogenous histamine release, and that PTXF inhibits these responses through elevated intracellular cAMP.
Nakagawa
K
K
Department of Surgery, University of Louisville, Kentucky 40292, USA.
Miller
F N
FN
Knott
A W
AW
Edwards
M J
MJ
D000818:Animals; D003994:Bucladesine / Q000494:pharmacology; D002199:Capillary Permeability / Q000187:drug effects*; D002448:Cell Adhesion / Q000187:drug effects; D007962:Leukocytes / Q000187:drug effects / Q000502:physiology; D046911:Macromolecular Substances; D008297:Male; D008833:Microcirculation / Q000187:drug effects; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D010431:Pentoxifylline / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012710:Serum Albumin, Bovine / Q000493:pharmacokinetics
D046911:Macromolecular Substances; D012710:Serum Albumin, Bovine; D009240:N-Formylmethionine Leucyl-Phenylalanine; D003994:Bucladesine; D010431:Pentoxifylline