Endotoxin-Induced Abortion in Early Pregnant Gilts and Its Prevention By

Acta vet. scand . 1990,31, 347-358. Endotoxin-induced Abortion inEarlyPregnantGilts andits Prevention by F1unixin Meglumine By Nicholas Cort and Hans Kindahl Department of Obstetrics and Gynaecology, College ofVeterinary Medicine, Swedish University of Agricultural Sciences, Uppsala, Sweden. Cort, N. and H. Kindahl: Endotoxin-induced abortion in early pregnant gills and Its prevention by flunixin megJumine. Acta vet. scand. 1990, 31, 347-358. - The objective ofthe study was to examine the effect ofendotoxin on early pregnancy in gilts and to test the potential of flunixin megJumine (FM), a cyclooxygenase inhi bitor, to counteract abortifacient action of the endotoxin. Ten gilts at 30 days ge station were used in the experiment. Eight were injected with lipopolysaccharide (LPS) of Salmonella typhimurium, while 2 were treated with 500 I1g c1oprostenol (CP). Six of the LPS-injected gilts were treated with a total of 4 mg/kg body weight FM in 2 different dose regimens. Clinical observations were recorded and plasma levels of 15-keto-l3, i4-dihydro-PGF:za, progesterone and estrone sulfate (ES) were determined with radioimmunoassay. LPS induced typical signs of endotoxemia and a monophasic fever in all LPS treated gilts. No antipyretic effect ofFM was observed. The CP-treated gilts abor ted within 34 h as did the gilts treated by LPS only . Of the 6 LPS + FM-treated gilts, I aborted within 34 h, while 5 maintained gestation. These were aborted about a week later by CP and the aborted fetuses anatomically examined. Two of the litters were lost (devoured by the dams), 2 showed no signs ofearlier death and I showed extensive fetal death. The PGF2a metabolite concentrations increased at least 10 fold immediately after the LPS injection. Progesterone plasma concentration decreased rapidly. A 5-10 fold increase in the plasma metabolite levels accompanied all abortions. CP cau sed no immediate change in the PGF:za metabolite levels, but the abortion-related response was similar to that in LPS-injected gilts. In the FM-treated gilts, the LPS induced PGF:za metabolite response was rudimentary and the progesterone decrea se temporary in nonaborting gilts. The elevated concentrations of ES decreased within 48 h in gilts aborting at 30 days gestation, while in nonaborting gilts a slow, graduate decrease of ES occurred within 3-5 days of the LPS injection. These re sults indicate that FM apparently suppressed LPS-induced prostaglandin synthe sis and thus prevented luteolysis and abortion in early pregnant gilts. Introduction (Rieder & Thomas 1960, Dennis 1966, Cul Endotoxins of Gram-negative bacteria ad bertson & Osburn 1980) and the endotoxin ministered to pregnant animals cause abor induced synthesis of endogenous prostag tion and fetal death. Two major mechanisms landins (PG), among which PGF2a may cau are thought to be responsible for the gesta se premature regression ofthe corpus luteum tion failure: Disseminated intravascular coa (c.l.) and abortion (Roberts et al. 1975). gulation and endothelial damage causing Abortion induced by endotoxin in 60-80 malfunction of the placenta and fetal death days pregnant sows (Wratha// et al. 1978, Acta vel. sc:and. vol.31 no. 3 • 1990 348 N. Cart & H. Kindahl Cort et al. 1986) showed similar course and being involved in both luteolytic and fetopa hormonal pattern as abortion induced by thic effect of endotoxin. PGF 2a or CP (Wrathall et 01. 1978, Cort et Luteolysis and expulsion of fetuses in sows 01. 1986,Podany et 01. 1982). These findings occur within 40 h of endotoxin injection , support the theory that the luteolytic effect which does not allow a possible primary fe of endotoxin was the principal abortifacient topathic effect of endotoxin to be distinguis factor (Cort et 01. 1986). In contrast, abor hed from the secondary fetal damage caused tion was not induced by endotoxins in 80 by the process of expulsion (Wrathall et 01. 100days pregnant sows, indicating increased 1978, Cort et 01. 1986). Removing of the PG resistance to abortifacient factors in late ge involvement in the mechanism of initiation station in the pig (Cort & KindahI1986). of abortion may bring some light upon the Early gestation in the pig, as in other animal actual role of PGs in the pathogenic effect species, is generally more sensitive to dama on gestation . ge than mid to late gestation. The embryonic Flunixin meglumine (FM) is a non-steroidal phase is characterized by a dramatic growth antiinflammatory drug, which has been used and development of tissues and organs and for the past 10 years mainly in horses with rapid development of the placenta. Vulnera colic of musculoskeletal disorders (Houdes bility to infectious diseases is high, as the hell & Hennessey 1977, Vernimb & Hennes conceptus is not immunologically competent sey 1977). FM was found to effectively coun until 60-70 days of prenatal age (Wang et 01. teract experimental endotoxemia in horses 1973, WrathaIl1980). Therefore early gesta and dogs (Bottoms et 01. 1981, Turek et 01. tion in the pig would have been expected to 1985, Hardie et 0/1987). The antiinflamma be at least as sensitive to endotoxin as mid tory effect is based on potent cyclooxygena gestation . However, what the embryonic se inhibition, preventing metabolism of ara phase has in common with the period from chidonic acid to vasoactive PGs and throm 80 days to term is increased plasma concen boxanes (Moore et 01. 1986). trations of estrone sulfate, synthetised by the The aims of the present study were to i) inve conceptus (Robertson & King 1974).A num stigate the effect of bacterial endotoxin on ber of studies on the early gestation in the pig early pregnancy in gilts by means of clinical indicated that estrogens have an antiluteoly observations and analysis of blood progeste tic/luteotropic function (Bazer & First rone, estrone sulfate and plasma metabolite 1983). of PGF 2a, 15-keto-13, 14-dihydro-PGF2a, ii) Harper & Skarnes (1972) in studies involved to compare these results to the earlier obtai in preventing the abortifacient effect of en ned ones in mid/late gestation and iii) to in dotoxins found that 1) injection of PGF2a vestigate the effect of FM on the synthesis produced the same extent of abortion or in and release of PGF2a and the possibility of trauterine fetal death in mice as endotoxin; preventing endotoxin-induced abortion or 2) progesterone or indomethacin prevented fetal death by treatment with FM. endotoxin-induced abortion, but not fetal death , 3) indomethacin plus cyproheptadine Material and methods (serotonin inhibitor) treatment prevented Ten sexually mature Hampshire x Landrace both abortion and fetal death in endotoxin x Yorkshire gilts were purchased from a injected mice. These results implicate PGs commercial herd , housed individually and Acta vel. scand. vol. 31 no. 3 • 1990 Endotoxin-induced abortion in gilts 349 fed a standard ration. After observation of Student's t-test was used for analysis of dif at least I normal estrous cycle the gilts were ference between the pairs of mean tempera inseminated or mated by a boar. Pregnancy tures of LPS + FM-treated gilts in the pre was confirmed by a Doppler instrument sent study and LPS-treated gilts from a re (Medata System Ltd., Yapton, England) at cent clinical study, which was performed un 25 days after service. Jugular vein catheters der the same conditions (Cort 1986). were inserted surgically under general anes thesia, 5-3 days prior to the experiment (Ro Results driguez-Martinez & Kunavongkrit 1983). At The clinical response to LPS injections at 30 30 days of gestation (±2), 2 gilts were injec days of gestation were arbitrarily characteri ted i.rn. with 500 ug cloprostenol (CP) and 8 zed by a scale from no response (-) to severe gilts were injected i.v. with 2 ug/kg body signs (+ + +) of endotoxemia (Table I). weight (b. w.) lipopolysaccharide (LPS) of These included various degrees of fever, vo Salmonella typhimurium SH (4809) (Svens miting, circulatory shock, dyspnea, ataxia son & Lindberg 1978, Lindberg et al. 1983). and anorexia. LPS injections were followed Six of the LPS-treated gilts were injected i.v. by a severe clinical syndrome, while no clini with 2 mg/kg b.w. flun ixin meglumine (FM) cal response was observed after CP injec (Finadyne, Schering Corp., Kenilworth, tions. All the typical signs of the syndrome N.J ., USA), 12 h prior to the LPS inject ion . were present i LPS + FM-treated gilts al Further treatment by FM was performed in a though none showed as severe clinical endo relat ionsh ip to the LPS injection as follows: toxemia as the LPS-treated ones. The dura 2 gilts, 2 mg/kg b.w. at -2 and + 10h, 4 gilts, tion of the clinical signs was between I and 8 I mg/kg b.w, at -2, +2, +6 and + 10 h. h after injection (a.i.), Anorexia usually per Clinical observations were made and rectal sisted until next day. Yellow discoloration of temperature periodically taken in all ani the plasma was observed between 3 and 12 mals. Blood samples for hormone analysis a.i . in both LPS-treated and LPS + FM-trea were collected at intervals varying between I ted animals. and 12 h. The blood was immediately centri Rectal temperature remained within physio fuged and plasma stored at -20°C. Gilts logical range in CP- injected gilts. The which did not abort due to the LPS injection LPS + FM-treated gilts demonstrated a mo were treated within 5 to 8 days with CP, 500 nophasic fever curve beginning with a sharp ug i.m. The aborted fetuses and fetal mem rise immediately after the LPS injection and branes were anatomically examined. maintaining above 40°C for 2-5 h a.i.: a gra The experimental animals were further ob dual decrease occurred towards the end of served through the first estrus post abortum.

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