SOME EFFECTS OF PROSTAGLANDINS E₁ AND E₂ AND OF ENDOTOXIN INJECTED INTO THE HYPOTHALAMUS OF YOUNG CHICKS: DISSOCIATION BETWEEN ENDOTOXIN FEVER AND THE EFFECTS OF PROSTAGLANDINS

Abstract

I Prostaglandins El and E2 elevated body temperature of young chicks when injected into the hypothalamus at thermoneutrality (31 0C). In contrast, they lowered body temperature when so injected below thermoneutrality (160C): the relation of the fall in body temperature to increased heat loss and decreased heat production was examined. 2 The above effects below thermoneutrality were potentiated by pretreatment with inhibitors of prostaglandin synthetase and possible reasons for this potentiation are given. 3 The '0'-somatic antigen of Shigella dysenteriae consistently evoked hyperthermia when injected into the hypothalamus, irrespective ofwhether the chicks were within or below thermoneutrality. 4 Pretreatment with prostaglandin synthetase inhibitors failed to prevent the onset of endotoxin fever; however, duration of the fever, induced by intrahypothalamic injection of the 0-somatic antigen of Shigella dysenteriae was reduced. 5 The intrahypothalamic injection, below thermoneutrality of prostaglandins E,, E2, noradrenaline, 5-hydroxytryptamine or carbachol reversed endotoxin fever, inducing even substantial falls in body temperature.6 While the results cast some doubts on the role of prostaglandins of the E series as mediators of endotoxin fever in chicks, they cannot be eliminated as mediators until the significance of the reduction in duration of the pyrexic response by indomethacin and 5,8,11,14-eicosatetraynoic acid, and the degree of synthesis inhibition attained, are known.

Role of Prostaglandin E2 and Indomethacin in the Febrile Response of Pigeons

“…All other studies available on avian fever report a monophasic fever regardless of whether LPS was I.V. injected [5,6,11,14] or intraperitoneally injected [15] into the hypothalamus [18] or I.C.V. [1,2].…”

“…Artunkal et al found in chicken that intrahypothalamic or I.V. injections of PGE 1 or PGE 2 induced hyperthermia in warm ambient temperature, but hypothermia in cold ambient temperature [14,18]. On the other hand, a dose-dependent hypothermic effect following I.C.V.…”

Brain IL-6- and PG-dependent actions of IL-1β and lipopolysaccharide in avian fever

“…IL-1␤ is thought to activate IL-6, and circulating IL-6 concentrations are correlated with the upregulated expression of PG-synthesizing enzymes in the periphery and in brain vasculature (5,34,49). Humoral PGE 2 , produced by macrophages of the lungs and liver, was shown to initiate the first febrile phase in mammals (49), while subsequent febrile phases are thought to be mediated by an upregulated expression of PGE 2 in the brain itself as a result of the initiation of cyclooxygenase (COX)-2 and microsomal PGE synthase-1 in endothelial cells (34) and the cerebral microvasculature (39). IL-6 likely initiates the synthesis of PGs in the mammalian brain by 1) acting on cells comprising the organum vasculosum lamina terminalis and the subfornical organ (17,37), 2) crossing the blood-brain barrier (BBB) (3,4), or 3) instigating the de novo synthesis of proinflammatory cytokines in the brain by binding to endothelial cells of the BBB (20), instigating PG synthesis.…”

“…With regard to PGs, intracerebroventricular injection of PGE 1 and PGE 2 induced fever in fowls and broilers (23,30,31) and young chicks (1,2) at thermoneutrality, but intracerebroventricular injection of PGF 2␣ and PGE 2 decreased the body temperature (T b ) of fowls and pigeons, respectively (31,32). The PG synthesis inhibitor indomethacin abolished LPS-induced fever in broilers (10 mg/kg iv) (23) but only reduced the duration of fever in young chicks (50 mg/kg iv) (2). Furthermore, indomethacin had no effect on the rising phase of fever in pigeons (10 mg/kg iv or 100 g/kg icv) (32), whereas another PG synthesis inhibitor, diclofenac (5 and 15 mg/kg ip), reduced LPS-induced fevers in Pekin ducks (14).…”

SOME EFFECTS OF INTRAVENOUS PROSTAGLANDIN E1 AND ENDOTOXIN IN YOUNG CHICKENS

“…These phenomena, dose-dependent inasmuch as larger doses produced correspondingly longer effects, were assumed to be central in origin since similar effects ensued after intrahypothalamic injection (Artunkal, Marley & Stephenson, 1977 PGE1 (2 jig) was recovered in the brain 1 min after injection (Holmes & Horton, 1968 (Artunkal & Marley, 1974;Artunkal el al., 1977 Time (h) lipolysis induced by placing chicks in an ambient temperature of 2-30C for 4 h (Wagner, Peterson & Cenedella, 1971). The relevance of this is difficult to assess since prostaglandin E, did not affect basal lipolysis at thermoneutrality (Wagner et al, 1971) and under the present experimental conditions (2-3 week old chicks at 160C), plasma non-esterified fatty acid concentration was not elevated (Marley & Stephenson, 1975).…”