Analysis for roles of complement and arachidonate metabolites in occurrence and progression of ARDS.

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To elucidate roles of eicosanoids, complement, and endotoxins in pathogenesis of ARDS, we studied functional changes of AM by using a septic lung model of rats after the operation of cecal ligation and puncture. Septic AM generated significantly less amounts of leukotriene B_4' 12- and 5-HETEs by stimulation with A23187 than the control AM did. Immunoreactive LTC_4 in the bronchoalveolar lavage fluids from the septic rats was more than that from the control rats. Therefore, it was speculated that the AM of endotoxemic rats released lipoxygenase metabolites in alveoli and then these AM obtained showed reduced 5-1ipoxygenase activity. In contrast, these cells released enhanced amounts of O_2^- on stimulation with PMA.Next, we studied influences of the i.v. administration of E. coli LPS on the production of superoxide anion (O_2^-) and 5-lipoxygenase metabolism of arachidonic acid were evaluated in the alveolar (AM) and peritoneal macrophages (PM) on days 1 and 3 after the injection. The … More dose selected was that found to induce a significant leakage of ^<125> I-BSA in the pulmonary vasculature.AM obtained one day after the LPS-injection generated smaller amount of O^-_ on stimulation with C5a but generated same amounts with wheat germ lectin (WGA) or arachidonic acid (AA) compared to control AM. This result suggested a prior complement activation. On day 3, on the contrary, their production of O^-_ significantly exceeded that by the control AM with either of the three stimuli. PM collected on day 1 after the LPS-injection generated a significantly greater amount of O^-_ on stimulation with either WGA or AA than did control PM. The amount of O^-_, however, decreased from day 1 to day 3.AM collected one day after the injection of LPS generated significantly more LTB_4 and 5-HETE on stimulation with A23187 alone and in combination with AA than did the cells from untreated rats. Such activities returned to the control levels in the AM collected on day 3. In contrast, the PM collected on day 1 produced amounts of LTB_4 and 5-HETE similar to those of the control PM but the cells on day 3 produced significantly more LTB_4.Differing responses and time-courses in 5-1ipoxygenase and O^-_ generation system may indicate a difference in mechanisms that regulate the two production systems in macrophages following the injection of LPS. It is also suggested that early increase of endogenous AA availability in AM compared with PM induces more production of LTB_4 following second stimulation and consequently more leukocytes may be attracted to the lung. Less