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Critical role of pulmonary endothelial production of prostacyclin in the endotoxin-resistant mechanism in mice

Tumor necrosis factor-α (TNF-α) plays an important role in the induction of the pulmonary endothelial cell injury by activating neutrophils in sepsis. The resultant pulmonary endothelial cell injury leads to a decrease in the production of PGI2, which might be an important etiology for the development of acute respiratory distress syndrome, a critical complication of sepsis. Endotoxin (ET)-resistant mechanisms in C3H/HeJ mice involve the mutation of Toll-like receptor-4 (TLR-4) by which ET signals to increase TNF-α production in monocytes. Thus, it is possible that the pulmonary endothelial cell injury leading to the impairment of the production of PGI2 could be attenuated in C3H/HeJ mice, contributing to the ET-resistant mechanism. The present study was conducted to examine this possibility.

Plasma levels of 6-keto-PGF1a were significantly higher in C3H/HeJ mice than those in C3H/HeN mice, the ET-sensitive strain, 90 min after intravenous injection (IV) of ET. Survival rates on the 6th day of IV of ET were 100.0% and 0% in C3H/HeJ mice and C3H/HeN mice, respectively, while it was 50.0% in C3H/HeJ mice when they were pretreated with indomethacin (IM), which inhibits PGI2 production. Plasma levels of 6-keto-PGF1a in C3H/HeJ mice 90 min after intra-arterial injection (IA) were significantly lower than those in C3H/HeJ mice 90 min after IV of ET. Although the survival rate of C3H/HeJ mice on the 6th day of IV of ET was 81.2%, it was only 27.7% in these mice on the 6th day of IA of ET. These observations suggested that the major part of 6-keto-PGF1a in the plasma of C3H/HeJ mice after IV of ET could be derived from PGI2 released from the lung vasculature, and the PGI2 release might be critical for the ET-resistance in C3H/HeJ mice. Plasma levels of 6-keto-PGF1a 90 min after IV of ET were significantly higher in C3H/HeN mice pretreated with ONO-5046, an inhibitor of neutrophil elastase, than those in these mice without ONO-5046 pre-treatment. The survival rate of C3H/HeN mice pretreated with ONO-5046 on the 6th day of IV of ET was 80.0%, while that of these mice without ONO-5046 pretreatment was 10.0%.

Taken together, these observations raise a possibility that the activated neutrophil-induced pulmonary endothelial cell injury could be attenuated in C3H/HeJ mice, leading to maintaining higher production of PGI2 than that in C3H/HeN mice, which could at least partly explain the ET-resistant mechanism in C3H/HeJ mice.

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Okajima, K., Enkhbaatar, P., Isobe, H. et al. Critical role of pulmonary endothelial production of prostacyclin in the endotoxin-resistant mechanism in mice. Crit Care 7, P030 (2003). https://doi.org/10.1186/cc1919

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  • DOI: https://doi.org/10.1186/cc1919

Keywords

  • Plasma Level
  • Indomethacin
  • Respiratory Distress Syndrome
  • Distress Syndrome
  • Acute Respiratory Distress Syndrome