Discussion Arising from Session on Prostaglandin E

Dr. Stitt stated he felt that Dr. Mitchell's generalization, that large animals such as sheep did not produce fevers in response to intracerebral injections of PGE, was inaccurate, since there were at least two reports in the literature by Bligh and Milton and by Hales that documented such fevers. Dr. Mitchell acknowledged this fact, but added that these injections of PGE were given intracerebroventricularly, rather than into the hypothalamic tissue. Dr. Bernheim stated that he was puzzled by Dr. Mitchell's suggestion that the mediator of fever was a prostanoid other than PGE. He pointed out Dr. Mitchell's own data, showing that salicylate treatment could suppress PGE rises in the cisternal cerebrospinal fluid, but not fever, in response to pyrogen. He felt that Dr. Mitchell's interpretation of the data, which he did not necessarily agree with, would rule out all prostanoids, not just PGE, since salicylate blocks all cyclooxygenase products of the arachidonic acid pathway. He also pointed out that experiments on the pathogenesis of fever that used the intracerebroventricular route for injecting pyrogen to produce fever were suspect, because of the marked differences between the latency and duration of fevers produced by this method compared to those produced by the intravenous route. Dr. Mitchell conceded that the process that occurs when pyrogen is injected into the cerebral ventricles is different from the process that occurs when it is injected into the systemic circulation; however, he refused to concede that it had been proven that PGE was involved in either process. Dr. Coceani, who said he was really a proponent of the PGE role in the guise of an opponent, felt that he could comment on both sides of the argument. He acknowledged that it was a paradox that fevers produced by intrathecal injections of IL-1 were delayed and slower in progression than those produced by intravenous injections of IL1. However, we must realize that the direct injection of ILI into the brain is a very drastic insult and for the sake of argument, we could postulate that such a procedure could also stimulate the release of hydroperoxides of prostanoic acid which, it is known, can interfere with the activation of, or even deactivate, cyclooxygenase. This process in turn could alter the kinetics of the subsequent febrile response. On the other side of the argument, he was troubled by Dr. Mitchell's experiments using arachidonic acid to produce fever. First, they required microgram quantities of arachidonic acid, compared to nanogram amounts of PGE. Second, arachidonic acid, in common with all fatty acids, acts as a detergent and may itself be an activator of phospholipase. Thus, when we are dealing with arachidonic acid and we assume that there is an effect of anisomycin on the cyclooxygenase because we see a decrease, what we may actually be observing is a depression of the phospholipase A2 that was activated by the arachidonic acid. It is also known that exogenous arachidonic acid can stimulate the formation of prostanoids from endogenous arachidonic acid. He also had reservations about the experiments involving prostaglandin antagonists. He was not convinced that it could be assumed that the prostaglandin antagonists actually inhibit the action of endogenously formed PGE2. Just because exogenously applied PGE2 could be inhibited by the antagonist did not mean that the same was true of endogenously produced PGE2. It is well known that cyclooxygenase is present in both the cell membranes and the endoplasmic reticulum. For the sake of argument, it could be supposed that PGE2 can