Association of prostacyclin production with resistance of C3H/HeJ mice to endotoxin shock.
Persistence of inflammatory cells in the microcirculation due to altered proportions of arachidonate metabolites could contribute to death from endotoxin (ET) shock. We tested this hypothesis by observing ET-induced cellular accumulations in capillaries of genetically resistant C3H/HeJ and sensitive C3HeB/FeJ mice after challenge with 1,000 micrograms of Salmonella typhi ET, a dose lethal only for the sensitive strain. These data were correlated with prostaglandin production by lung tissue. Six hours after challenge with ET, lung capillaries of sensitive animals were occluded with amorphous material and occasional polymorphonuclear leukocytes (PMNL). This inflammation, along with reduction in alveolar volume, was not observed in resistant mice. At this time only 10 PMNL/high-power field were seen with light microscopy in capillaries of resistant mice compared to 60 PMNL/high-power field in sensitive animals. Lung parenchymal tissue was excised from resistant and sensitive (C3H/HeN) mice six hours postchallenge with 800 micrograms of endotoxin and release in vitro of thromboxane A2 (TXA2) or prostacyclin (PGI2) over a 30-minute period was determined by radioimmunoassay. TXA2 and PGI2 released by lung fragments taken six hours after challenge with ET did not differ from normal levels of these substances in C3H/HeN mice. TXA2 release was normal at six hours in C3H/HeJ mice, but PGI2 was significantly increased (from 2.95 ng/mg to 5.73 ng/mg, P less than 0.005). The ratio of PGI2/TXA2 in resistant mice was 24.3 as compared to 10.3 in sensitive mice. Since PGI2 can reduce leukocyte adhesion, an increase in the ratio of this substance to TXA2 may be associated with resolution of PMNL from the pulmonary microcirculation of ET-resistant mice.
D000818:Animals; D004731:Endotoxins / Q000494:pharmacology; D011464:Epoprostenol / Q000032:analysis / Q000096:biosynthesis*; D008168:Lung / Q000503:physiopathology; D051379:Mice; D008809:Mice, Inbred C3H; D008815:Mice, Inbred Strains / Q000235:genetics*; D009504:Neutrophils / Q000187:drug effects; D011453:Prostaglandins / Q000096:biosynthesis*; D012772:Shock, Septic / Q000503:physiopathology*; D013928:Thromboxane A2 / Q000032:analysis
D004731:Endotoxins; D011453:Prostaglandins; D013928:Thromboxane A2; D011464:Epoprostenol