Beneficial Effects of a Novel Platelet-Activating Factor Receptor Antagonist, St 899, on Endotoxin-Induced Shock in Mice

Platelet Activating Factor (PAF): A Mediator of Inflammation

“…These results suggest that both PAF and cyclooxygenase product(s), including thromboxane A2, mediate the decrease in CO, and hypotension in rat experimental endotoxic shock. Using a mouse model of experimental endotoxin shock, the effect of ST 899, a PAF‐RA, on serum tumor necrosis factor (TNF), interleukin‐6 (IL‐6), and interferon‐γ (IFN‐γ) production as well as on lethality in an experimental endotoxin shock model was investigated in C57BL/6 mice 58 . Animals received 40 mg/kg LPS ( E .…”

Pathological Aspects of Platelet-Activating Factor (PAF)

“…The involvement of P AF in endotoxic shock was evaluated by the following observations: (1) Administration (infusion) of PAF mimics effects of endotoxin or rather the state of shock (McMANUS et al 1980), even if its action is more venoconstrictive than arterioconstrictive (BAR-NATAN et al 1995); (2) endotoxin induces rise of PAF in blood (CHANG et al 1987;DOBROWSKY et al 1991), or rather PAF is generated during the state of shock (PINCKARD et al 1979) produced by lung and liver (ANDERSON et al 1991;RABINOVICI et al 1991), which is paralleled by a decrease in acethydrolase (NARAHARA and JOHNSTON 1993); endotoxin may also activate PAF receptors (NAKAMURA et al 1992;WAGA et al 1993); (3) PAF rises in blood before TNF rises (DOEBBER et al 1985), with PAF antagonists impeding TNF rise and action (FLOCH et al 1989;FERGUSON-CHANOWITZ et al 1990;RUGGIERO et al 1994); (4) synergistic effects of P AF and LPS at the cellular level have been reported (PIRES et al 1994;FOUDA et al 1995), and (5) specific PAF antagonists improve survival and provide significant protection against the state of shock (DOEBBER et al 1985;TERASHITA et al 1985;INNAREA et al 1985;ETIENNE et al 1986;ADNOT et al 1986;HANDLEY et al 1986;CASALS-STENZEL 1987c;YUE et al 1990a;TANG et al 1993) or against lung injury by endotoxin (CHANG et al 1987(CHANG et al , 1990OLSON et al 1990a,b).…”

“…Concerning the cooperation of P AF with TNF in endotoxin shock, the question arises whether TNF acts only by induction of PAF biosynthesis from hematologic and endothelial cells (CAMUSSI et al 1987(CAMUSSI et al ,1989SUN and HSUEH 1988;BUSSOLINO et al 1988b) or inversely by its PAF-stimulated release (FLOCH et al 1989;HAYASHI et al 1989) from monocytes (BONAVIDA et al 1989(BONAVIDA et al , 1990 or from macrophages (ROLA-PLESZCZYNSKI et al 1988a;DUBOIS et al 1989). It should be mentioned that other mediators in endotoxic shock such as interleukin-6 and interferon-gamma (RUGGIERO et al 1994) are important for lethality marker function (KELLY and CROSS 1992) or as mediators of lethality (DOHERTY et al 1992). Furthermore, leukotriene B4 is released by PAF (DUBOIS et al 1989;CHANG et al 1990;OLSON et al 1990b) Interleukin-1 is also released by endotoxin (OKUSAWA et al 1988;OHLSSON et al 1990) which is involved in the development of tachycardia, hypotension, and tissue damage (EVERAERDT et al 1989;OHLSSON et al 1990).…”

Signaling via Platelet-Activating Factor Receptors Accounts for the Impairment of Neutrophil Migration in Polymicrobial Sepsis

“…In fact, it is reported that PAF itself is capable of eliciting many symptoms associated with endotoxic shock (7). Moreover, the overexpression of the PAFR increases lethality in response to LPS administration in mice (14), and the administration of PAFR antagonists to animals and humans protect them from the deleterious effects of LPS (15)(16)(17)(18)(19)(20). However, clinical trials using recombinant human PAF acetylhydrolase or PAFR antagonists failed to reduce the mortality of severe septic patients, although a substantial reduction in organ dysfunction was achieved (21)(22)(23).…”