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Critical Care MedicineNúmero: Volume 26(6), June 1998, pp 1001-1006Copyright: © Williams & Wilkins 1998. All Rights Reserved.Tipo de publicación: [Feature Articles]ISSN: 0090-3493Registro: 00003246-199806000-00015

Mortality is increased by procalcitonin and decreased by an antiserum reactive toprocalcitonin in experimental sepsisNylen, Eric S. MD; Whang, Kevin T. MD; Snider, Richard H. Jr, PhD; Steinwald, Paul M. MD; White, Jon C. MD; Becker, KennethL. MD, PhD

Información sobre el autorFrom the Section of Endocrinology, Department of Medicine (Drs. Nylen, Snider, and Becker), VA Medical Center,

Washington, DC; Section of Endocrinology, Department of Medicine (Drs. Nylen and Becker), George Washington UniversityMedical Center, Washington, DC; Department of Surgery (Dr. White), VA Medical Center, Washington, DC; Department ofSurgery (Drs. Whang and White), Georgetown University, Washington, DC; Department of Surgery (Drs. Steinwald and White),George Washington University Medical Center, Washington, DC.

Supported, in part, by funds from the Department of Veterans Affairs.Address requests for reprints to: Eric S. Nylen, MD, VAMC, 50 Irving Street, NW, Room GE 246, Washington, DC 20422.

Abstract

Objectives: Procalcitonin (ProCT), the precursor to the calcitonin hormone, isabnormally increased in experimental and clinical systemic inflammation, includingsepsis. Initially, we investigated the effects of supraphysiologic amounts of ProCTadministered to animals with septic peritonitis. Subsequently, we evaluated theefficacy of prophylactic and therapeutic immune blockade of ProCT in this lethalmodel of sepsis.

Design: Prospective, experimental, controlled study.

Setting: Animal research laboratory approved by the American Association forthe Accreditation of Laboratory Animal Care at a Veterans Affairs Medical Center.

Subjects: Young male Golden Syrian hamsters, weighing 90 to 120 g.

Interventions: In the first study, serum ProCT concentrations were measured inanimals at 0, 3, 6, 12, and 24 hrs after induction of sepsis by intraperitoneal

implantation of pellets containing Escherichia coli (5 x 108 colony-formingunits/pellet). In the second study, with mortality as the end point, 30 [micro

sign]g/kg of isolated, purified human ProCT in 10% hamster serum (experimental) oran equal volume of 10% hamster serum (control) were administered intravenously atthe time of the E. coli peritoneal implantation. In the third study, experimentalanimals received intraperitoneal injections of a multiregion-specific goat antiserumreactive to hamster ProCT 1 hr before and 24 hrs after E. coli implantation, whilecontrol animals received nonimmune goat serum at the same time points. In thefinal study, the same antiserum was administered in five divided doses during the 24hrs after the insertion of E. coli.

Measurements and Main Results: In the initial study, ProCT concentrations wereincreased shortly after induction of sepsis and peaked at 12 hrs. Administration ofexogenous ProCT to septic animals significantly increased mortality compared withcontrol animals (93% vs. 43%, p = .02). Prophylactic blockade of ProCT almostcompletely protected the animals from the lethal effects of sepsis: the 102-hrmortality rate in the experimental group was 6% compared with 62% in the controlgroup (p < .003). In the therapeutic trial, the 102-hr mortality rate was 54% inexperimental animals compared with 82% in control animals (p < .045).

Conclusions: These results demonstrate that increased ProCT exacerbatesmortality in experimental sepsis, whereas neutralization of ProCT increases survival.Thus, ProCT, in addition to being an important marker of severity of systemicinflammation and mortality, is an integral part of the inflammatory process anddirectly affects the outcome. (Crit Care Med 1998; 26:1001-1006)

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27/01/13 20:45Ovid: Mortality is increased by procalcitonin and decreased by an antiserum reactive to procalcitonin in experimental sepsis.

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Key Words: sepsis; inflammation; calcitonin; procalcitonin; hormone;prohormone; cytokine; antiserum; immunotherapy; peritonitis

Systemic inflammation, including its infectious component, sepsis, is the mostcommon cause of mortality in critical care units, accounting for 100,000 deaths peryear [1]. Systemic inflammation is characterized by a marked and often fatal hostresponse that evokes the secretion of proinflammatory components, resulting fromexposure to a variety of noxious stimuli, such as bacterial products. Several of theseproinflammatory mediators, such as tumor necrosis factor (TNF)-alpha andinterleukin (IL)-1 beta, have been implicated as being proximal signals triggering thishost response [2]. As a consequence, much attention has been devoted to blockingthe action of these putative mediators in an attempt to improve the poor outcome.Increased survival and improvements in physiologic parameters in experimentalsepsis models have been achieved with some agents. However, the results of clinicaltrials [3-6] have been almost uniformly disappointing. This finding suggests thatalternative approaches to detection and therapy of systemic inflammation and sepsisneed to be explored.

Serum concentrations of procalcitonin (ProCT), the prohormone of the maturehormone calcitonin (CT), as well as other calcitonin gene products, have beenreported to be markedly increased in a variety of clinical and experimentalconditions that lead to systemic inflammation, e.g., burns [7], pneumonitis [8], heatstroke [9], endotoxemia [10], and sepsis [11-13]. In many of these studies, theconcentration of ProCT reflected the severity of the systemic inflammation and waspredictive of mortality. Although ProCT is an important clinical marker, its role inthe inflammatory process is unknown.

Several studies [14] have documented that hypocalcemia correlates with theseverity of systemic inflammation and portends a poor outcome. Moreover,hypocalcemia is frequently associated with abnormally increased ProCT[8,10,15,16]. It is conceivable that ProCT, which binds to the CT receptor [17] andappears to be active in osteoclast bioassays [18], may exert biological activity thatmimics the classical hypocalcemic actions of mature CT. We hypothesized thatProCT bioactivity may be detrimental to host defense and survival in sepsis.Accordingly, we evaluated the effects of the administration and blockade of ProCTin a previously described animal model of lethal sepsis [15].

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MATERIALS AND METHODS

Animals. Male Golden Syrian hamsters (Harlan Animals, Indianapolis, IN),weighing 90 to 120 g, were individually housed in a controlled environment with 12hrs dark/light cycles and were given water and rodent chow ad libitum. Theexperiments were performed with prior Institutional Review Board approval andused techniques similar to techniques previously reported in a rat model [19].

Bacteria. Escherichia coli (E. coli, O18:K1:H7) were obtained from the WalterReed Army Institute of Research, Washington, DC. The bacteria were grown in 100mL of Miller LB (Luria-Bertani) broth (DIFCO laboratories, Detroit, MI) at 98.6[degreesign]F (37[degree sign]C) in a shaker water bath to log phase and stored in 250-[micro sign]L aliquot portions at -94[degree sign]F (-70[degree sign]C) until use.

Pellet Preparation. The 250-[micro sign]L aliquot portions of bacteria werethawed and incubated at 98.6[degree sign]F (37[degree sign]C) in a shaker waterbath for 4 hrs. The optical density of the specimen was measured at 600 nm on aspectrophotometer (Stasar III, Gilford Instruments, Oberlin, OH) and quantified byinterpolation on a previously constructed curve of optical density plotted againstcolony-forming units (cfu). Additional specimens were taken from the stock solution,

diluted, and plated to confirm the counts. Suspensions of 2.0 x 109 cfu/mL of E. coliwere instilled by pipette in 0.5-mL aliquot portions into 8-mm embedding molds(Shandon-Upshaw, Warrington, PA). Each pellet for implantation was made byadding 0.5 mL of sterile molten agar at 122[degree sign]F (50[degree sign]C) to thebacterial suspension; after which, the mixture was allowed to solidify at room

temperature. The final number of viable bacteria was 1.0 x 109 cfu/pellet (5.0 x 108

cfu/pellet was used in the toxicity study).

Induction of Sepsis. The hamsters were fasted the night before the experiment.On the day of the experiment, each animal was anesthetized with pentobarbitalsodium (50 mg/kg ip). Implantation of the pellet was performed after laparotomyand placement of the pellet into the right lower quadrant of the peritoneal cavity.

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Each animal received ceftriaxone (1.0 mg/kg im; Roche, Nutley, NJ) and wasreturned to the cage with unrestricted access to water and chow. Mortality wasdocumented every 12 hrs.

Isolation and Purification of Endogenous Human Procalcitonin. Human ProCT wasisolated and purified from the supernatant of the medullary thyroid cancer cell lineTT (courtesy Dr. Michael Kelly, National Institutes of Health, Bethesda, MD). Thesupernatant media (1.7 L) were lyophilized and reconstituted in 300 mL of 0.1 Mammonium bicarbonate (NH4 HCO3). After separation from insoluble matter,

proteins were precipitated from the clear supernatant with 600 mL of 95% ethanol.After separation from the protein precipitate, the clear supernatant wasconcentrated to dryness using both flash evaporation and a Speed Vac Plus (SC110A,Savant Instruments, Farmingdale, NY). This product was reconstituted to 45 mL,which was applied in nine 5-mL aliquot portions to a 2.7 x 95-cm column containingG-75 Sephadex superfine (Pharmacia Biotech, Piscataway, NJ), suspended in 0.1 MNH4 HCO3. Out of 110 fractions, four pools were collected and assayed for ProCT.

Pool 2, enriched with ProCT, was combined and lyophilized. This product wasreconstituted in 4 mL of 0.1 M NH4 HCO3, containing 0.1% Triton-X100. Eight 0.4-mL

aliquot portions were separated by C18 reverse-phase HPLC on a 2.5 x 100-mm

endcapped column containing 3-[micro sign]m particles, using a previously describednonlinear step gradient [20]. The fractions having the retention time of ProCT (48min observable by UV at 210 nm) were combined and concentrated on the SavantSpeed Vac Plus. After reconstitution in 2 mL of 0.1 M NH4 HCO3, the clear

supernatant product, containing [similar]1 mg of ProCT, was further cleaned up on aC18 SepPak cartridge (Waters, Milford, MA). The final product was free of other CT-

containing products, as assessed by HPLC with monitoring at 210 nm.

Procalcitonin-Reactive Antiserum. The binding characteristics of AbV (developedin our laboratory), a multiregion-specific, polyclonal goat antiserum developedagainst synthetic human CT, have been reported previously [20,21]. This antiserum(estimated radioimmunoassay titer of 1:1,000,000) detects the CT sequence in allforms of human and hamster CT in standard radioimmunoassays, including hamsterProCT. We have previously demonstrated that this antiserum also cross-reacts withthe 11-28 (27%), the 11-32 (38%), the 17-28 (14%), and the 17-32 (23%) fragments ofhuman CT, as well as with 1-32 human CT (100%). (There is no cross-reactivity withother neuroendocrine peptides, including human CT gene-related peptide,bombesin/gastrin-releasing peptide, and neurotensin.) The in vivo binding capacityof intraperitoneal injections was determined by injection of 0.5 mL of antiseruminto hamsters, which were killed by exsanguination under pentobarbital sodium (50mg/kg) anesthesia at 4, 24, and 72 hrs. Serial dilutions of the hamster sera werecompared with serial dilutions of control AbV antiserum. The hamster serum

capacity for binding CT was established by comparing the binding of125 I human CTto 0.05 mL of a 1:10 dilution of hamster serum, both with and without the additionof 1 ng of synthetic human CT. Intramuscular and subcutaneous injections ofantiserum were evaluated in a similar fashion.

Procalcitonin Distribution Kinetics. Ten hamsters were injected intravenouslywith 400 to 1000 ng of synthetic human ProCT (BRAHMS Diagnostica, Berlin,Germany). Serum samples collected at 30 mins and at 2 hrs were assayed for ProCTusing an immunochemiluminescent, two-monoclonal antiserum sandwich assay(BRAHMS Diagnostica).

Calcitonin Radioimmunoassay. The change in concentration of serum total CTafter implantation of the bacterial pellet was evaluated using an antiserum (R1B4)raised to the 11-28 fragment of human CT. This antiserum cross-reacts 100% withhuman ProCT, CT:calcitonin carboxyterminal peptide-1, immature CT, and mature

CT. Furthermore, it has five-fold the cross-reactivity with hamster ProCT of ourantiserum previously reported to be useful in hamster studies, i.e., AbIV [22]. Itcross-reacts with hamster mature CT [similar]64% as well as does AbIV. Thesensitivity is 1.5 pg and 50% bound counts/initial bound counts (B/B0) is 30 pg. In the

time-course experiments, hamsters were killed at 0, 3, 6, 12, and 24 hrs (n = 16 pertime point) after induction of E. coli sepsis. Intracardiac blood specimens wereobtained after exsanguination under pentobarbital sodium anesthesia (50 mg/kg ip).

Toxicity Studies of Procalcitonin. The endogenous ProCT was reconstituted in anormal saline vehicle containing 10% hamster serum. Animals injected with ProCTalone did not die. For this reason, we used a model of E. coli sepsis that resulted inminimal mortality and administered ProCT or the 10% hamster serum vehicle todetermine whether mortality would be augmented. At the time of E. coliimplantation, each experimental animal (n = 16) received 3 [micro sign]g([approximately =]30 [micro sign]g/kg) of ProCT (to achieve a concentration of

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([approximately =]30 [micro sign]g/kg) of ProCT (to achieve a concentration ofProCT equivalent to that observed in severe human sepsis [unpublished information])in 0.1 mL of vehicle by an intravenous injection. The control animals (n = 16) weregiven the same dose of E. coli and 10% hamster serum vehicle (n = 16). Mortality wasrecorded during the next 72 hrs.

Neutralization of Procalcitonin. In the prophylactic phase of the study, 0.5 mLof AbV antiserum was injected intraperitoneally 1 hr before the insertion of thebacterial pellet, and a booster dose of 0.2 mL was injected intraperitoneally at 24hrs. The control animals received injections of the same volumes of nonimmune goatserum at the same time points. Each group consisted of 16 animals.

In the therapeutic phase of the study, 0.1 mL of AbV antiserum was injectedintraperitoneally at 1 and 3 hrs after bacterial pellet implantation, and 0.2 mL wasinjected intraperitoneally at 6, 12, and 24 hrs. The control animals receivedinjections of the same volumes of nonimmune goat serum at the same time points.Each group consisted of 28 animals.

Statistical Analysis. Data are expressed as mean +/- SEM. The SigmaStat[trademark sign] statistical and SigmaPlot[trade mark sign] plotting packages (JandelScientific, San Rafael, CA) were used to analyze and plot the experimental data.Among the statistical tests applied were the Student's t-test, paired t-test, Mann-Whitney rank-sum test (when the normality test was violated), Fisher's exact test,chi-square test, log-rank, and Cox-Mantel survival analysis.

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RESULTS

Time Course of Total CT. In the initial experiment, we established the timecourse of serum total CT during experimental sepsis. As shown in Figure 1, theincrease in total CT was significant at 6 hrs (1800 +/- 300 pg/mL [0.53 +/- 0.088nmol/L]) and peaked at 12 hrs (6900 +/- 1100 pg/mL [2.0 +/- 0.32 nmol/L]),followed by a decrease at 24 hrs (5000 +/- 1100 pg/mL [1.46 +/- 0.32 nmol/L]). Inour previous studies [15], we showed that ProCT is the major circulating CT speciesduring hamster sepsis.

Figure 1

Procalcitonin Toxicity. The exogenous administration of the purified endogenousProCT at the time of E. coli implantation resulted in a cumulative mortality rate of43% at 24 hrs and 93% at 72 hrs in the ProCT-treated animals compared with 25% and56% at the same time points for the control animals (p = .02 at 72 hrs, log-rank; p =.029, Cox-Mantel; p = .025) (Figure 2, top).

Figure

2

Procalcitonin-Reactive Antiserum. Intravenous injection of ProCT resulted inserum concentrations of ProCT at 30 mins and 2 hrs that were 1/160 of the injectedamount. The amount of immunoreactive CT to be neutralized by antiserum wasestimated to be 11.5 ng/mL (3.36 nmol/L) (i.e., the highest individual peakconcentration of total CT) x 160 (i.e., the whole body dilution factor) = 1840 ng(i.e., the total dose per animal).

Intraperitoneal injection of AbV resulted in a 1:24 dilution of the antiserum at 4and 24 hrs, and a 1:50 dilution at 72 hrs. The binding capacity of the antiserumdeclined from 170 ng/mL (49.71 nmol/L) at 4 and 24 hrs to 26 ng/mL (7.60 nmol/L)at 72 hrs. Based on these results, it is estimated that an intraperitoneal injection ofthis antiserum is capable of binding 2 [micro sign]g/0.5 mL (1170 nmol/L) of matureCT or 8 [micro sign]g/0.5 mL (1170 nmol/L) of ProCT. In comparison with themaximum amount of ProCT anticipated to be present during the septic exposure, thebinding capacity after a single intraperitoneal injection was adequate at 4 and 24hrs, but less than the potential maximum concentration at 72 hrs. Intraperitonealinjections achieved maximum titers of antiserum that were 2.5-fold greater thanintramuscular injections and five-fold greater than subcutaneous injections.

Prophylactic Treatment. The cumulative mortality in animals given AbVantiserum at 1 hr before, and 24 hrs after, the bacterial exposure are shown inFigure 2 (middle). The control animals showed a progressive mortality, reaching 38%at 24 hrs, 46% at 72 hrs, and a plateau of 62% at 90 and 102 hrs. In comparison, theexperimental group experienced no deaths at 24 hrs (p < .011) or 72 hrs (p < .0034)(Fisher's exact test) and only a 6% mortality at 96 and 102 hrs (p < .003 at both timepoints) (log-rank p = .0001; Cox-Mantel p = .00005).

Therapeutic Treatment. The cumulative mortality in the animals injected withAbV, commencing at 1 hr after bacterial exposure, is shown in Figure 2 (bottom). Inthis study, the control animals exhibited a progressive increase in mortality,attaining 75% at 72 hrs and 82% at 102 hrs. However, the animals that received

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attaining 75% at 72 hrs and 82% at 102 hrs. However, the animals that receivedneutralizing antiserum attained a mortality of 43% at 72 hrs (p < .03, chi-squaretest) and 54% at 102 hrs (p < .045, chi-square test) (log-rank p = .022; Cox-Mantel p= .021).

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DISCUSSION

The results of these experiments are notable for uncovering an important, andhitherto unsuspected, role of ProCT in experimental sepsis. Several studies [7-9,11-13] have shown that increased ProCT and some of its components occur in manyconditions associated with systemic inflammation and its infectious variant, sepsis.Furthermore, these findings have indicated that high concentrations of ProCT haveominous prognostic implications. In human volunteers, a sustained increase in serum

ProCT occurred after the experimental injection of lipopolysaccharide [10]. Thisincrease in ProCT was preceded by activation of the proinflammatory cytokines,TNF-alpha and IL-1 beta . The current study demonstrates a progressive andsustained increase in ProCT in response to bacterial peritonitis.

Acute exposure to supraphysiologic concentrations of exogenously administeredProCT resulted in decreased survival in septic animals. However, no mortality wasobserved when ProCT was administered to healthy animals. There are severalpossible explanations for this finding. It is conceivable that the healthy animalsgiven ProCT became mildly ill, but showed no easily detectable signs of illness.Alternatively, ProCT may not act as a trigger for the inflammatory cascade as doTNF-alpha and IL-1 beta, but may act as a mediator that sustains and augments theinflammatory response, such as IL-6 and IL-8. It has been observed that infusions ofIL-6 do not induce the inflammatory cascade, although the concentration of IL-6 isan accurate cytokine predictor of mortality in a number of inflammatory states [6].

A prior exposure to a ProCT-reactive antiserum, followed by a booster dose at24 hrs, almost eliminated the mortality of sepsis. Such a finding is similar to whathas been reported in other animal studies using various types of immuneneutralization against endotoxin, TNF-alpha, and IL-1 beta [3,6,23,24]. Thisprofound decrease in mortality induced by the prophylactic administration of anantiserum reactive to ProCT strongly suggests that ProCT is integral both to the hostresponse and to the ultimate outcome.

In addition to preventing the mortality of lethal sepsis when the initial dose wasgiven prophylactically, the ProCT-reactive antiserum also diminished the mortalitywhen it was administered after the induction of sepsis. In this case, the reduction ofmortality was less pronounced than in the prophylactic study, suggesting that someof the effects of ProCT occur as proximal events in the course of sepsis (althoughprobably not as proximal as TNF-alpha, IL-1 beta, or endotoxin, which cannot be assuccessfully blocked after initiation of inflammation [5,6]). The fact that ProCTconcentrations remain increased longer than some of the proinflammatory cytokinesmay also be important [10]. ProCT neutralization for 24 hrs after the induction ofsepsis, at a time when ProCT concentrations remain substantially increased,provides a significant survival advantage. Refinements in the timing, dosing, androute of administration of ProCT antiserum may further reduce mortality.

The implications of these findings are that ProCT not only is a marker, but alsois a mediator and motive force, in systemic inflammation and its sequelae. Unlikemany cytokines, whose appearance in the systemic circulation is evanescent [25,26],the ProCT concentration remains increased for the duration of the inflammatorystimulus. This feature of ProCT makes it a more useful indicator for outcomeprediction, as well as a potential target for therapeutic blockade. The findings thatProCT is noxious and that antiserum neutralization of ProCT markedly improves thesurvival of animals may have important implications for humans with sepsis.

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Figure 1

27/01/13 20:45Ovid: Mortality is increased by procalcitonin and decreased by an antiserum reactive to procalcitonin in experimental sepsis.

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