Agents Actions 41, Special Conference Issue: C97-C98 (1994) 0065-4299/94/020C97-02 $1.50 + 0.20/0 9 1994 Birkh/iuser Verlag, Basel
5. Histamine and diverse cell types
Inhibition of anaphylactic shock by gadolinium chloride-induced Kupffer cell blockade
G. Lfizfir, Jr. 1, G. Lfizfir 2, J. Kaszaki 3, J. Ol/th 4, I. Kiss 2, and E. Husztik 2
Department of Surgery, 2 Institute of Pathophysiology, 3 Institute of Experimental Surgery, 4 Department of Dermatology, Albert Szent-Gy6rgyi Medical University, P.O. Box 531, 6701 Szeged, Hungary
Abstract. Data in the literature concerning the role of macrophages in anaphylaxis are contradictory. In the present study, the effect of macrophage blockade induced by gadolinium chloride (GdC13) on anaphylactic shock is investigated. Our observations show that GdCI3 prevents lethal anaphylactic shock in mice sensitized to ovalbumin.
Gadolinium chloride given i.v. in a dose of 1 mg/100 g body weight 24 or 48 h before the elicitation of anaphylac- tic shock resulted in 80% survival, compared with the 43% survival in the control group. The same dose of this rare-earth metal salt also greatly reduced the mortality in mice sensitized with ovalbumin containing Bordetella per- tussis vaccine, and similarly abrogated the symptoms of anaphylaxis, including the accumulation of serotonin and histamine in the liver. The results suggest that macro- phages play an important role in mouse anaphylaxis.
In severe injuries, such as shock states, the gradual activa- tion of liver macrophages and the excessive release of macrophage-derived destructive and immunosuppressive products m a y contribute to the development of "multiple organ failure" [t].
Earlier we described that rare-earth metal salts, among them gadolinium chloride (GdC13), reduced reticulo- endothelial activity, and thereby selectively depress the activity of the Kupffer cells [2, 3].
Kupffer cells, the resident macrophages of the liver, have been shown to express class II antigens of the major histocompatibility complex and to have the capacities for antigen uptake and presentation in vitro, but their regula- tory roles in the induction and expression of the immune response have not been well defined. In the present studies we investigated the effects of blockade of Kupffer cell phagocytosis by GdC13 on the course of mouse
Correspondence to: G. Lfizfir
anaphylaxis and the accumulation of anaphylactic medi- ato'rs (histamine and serotonin) in the liver.
Materials and methods
Male CFLP mice (Animal House, G6d6116, Hungary) weighing 27-30 g were injected i.p. with 100 gg ovalbumin (Koch-Licht, Eng- land) precipitated with aluminium hydroxide. In some of the experi- ments BordeteIla pertussis vaccine (10 l~ organisms/animal) (Human Institute for Serological Production and Research, Budapest) was used to augment sensitization. The animals were challenged i.v. 12 days after sensitization with 100 gg of the same antigen in 0.2 ml of physiological saline. The survival rate was recorded over the next 24 h. Serotonin was measured by the spectrofluorimetric method of Shellenberger and Gordon [4] and histamine by means of the radioenzymatic method of Beaven and Horakova [5]. Histamine N- methyltransferase was purified from rat kidney. Kupffer cell phago- cytosis blockade was induced by the method published earlier [2, 3].
Gadolinium chloride (K. and K. Laboratory, Plainview, New York) was dissolved in physiological saline and injected i.v. in a dose of 1 mg/100 g body weight.
Results were evaluated biometrically with the Student t-test, and the chi squared test. Analysis of variance and multiple comparisons were performed by the Scheff6 procedure.
Results
O u r observations show that GdC13 prevents the lethal anaphylactic shock of mice sensitized with ovalbumin.
Gadolinium chloride given i.v. in a dose of 1 mg/100 g body weight 24 or 48 h before the elicitation of anaphylac- tic shock resulted in 90% survival, compared with the 43% survival in the control group injected only with ovalbumin on day 12 of the experiment (Fig. 1). Mice sensitized with ovalbumin containing Bordetella pertussis vaccine exhibited much more severe anaphylaxis (10%
survival), but they too were protected by GdC13 pretreat- ment (80% survival).
Gadolinium chloride pretreatment also greatly re- duced the symptoms of anaphylaxis, including the accu- mulation of histamine and serotonin in the liver. Our
C98 Agents Actions, Special Conference lssue (1994) 100-
80-
"-" 60 40
r
20
o
m
301 20
GdCI3 A CJdCI 3
** p<O.O01; *** p<O.O1 [] Sensitized with ovalbumin [] Sensitized with ovalbumha + BordeteUa pertussis vaccine
Fig. 1. Effect of gadolinium chloride on the survival rate in anaphylactic shock. Mice were sensitized with ovalbumin or oval- bumin containing Bordetella pertussis vaccine. Gadolinium chloride was injected in a dose of 1 mg/100 g body weight, i.v., before anaphylactic challenge on the day indicated in the figure. The numbers in the columns are the number of animals per group.
p<0.001
80 ]
40 20
C GdCI3
Serotonin
200 .~ 150 100 50 o
p<0.001
11
GdCI 3 Histamine
o Before challenge 1 h after challenge
Fig. 2. Effect of gadolinium chloride on the accumulation of serotonin and histamine in the liver in anaphylactic shock. Both serotonin and histamine were determined before and 1 h after anaphylactic challenge. Mice were sensitized with ovalbumin plus Bordetella pertussis vaccine and gadolinium chloride was injected at a dose of 1 rag/t00 g body weight, i.v., 1 day before the challenge.
o b s e r v a t i o n s show t h a t the elicitation of a n a p h y l a c t i c shock leads to the a c c u m u l a t i o n of h i s t a m i n e a n d s e r o t o n i n in the liver, b u t this was p r e v e n t e d b y GdC13 p r e t r e a t m e n t (Fig. 2).
D i s c u s s i o n
R a r e - e a r t h metals have diverse biological a n d p h a r m a c o - logical effects. M a n y of these can be explained b y the r e p l a c e m e n t of calcium ion, or the inhibition of its m o v e - m e n t across the cell m e m b r a n e by these elements [3, 6].
Since the crystal radii of the r a r e - e a r t h m e t a l ions are very similar to t h a t of the calcium ion, a n d because of their higher valency, they can displace a n d replace calcium ions
in biological systems, as well as p r e v e n t the u p t a k e of calcium ions at various cellular sites. T h e r a r e - e a r t h m e t a l ions m a r k e d l y affect the functions of cells involved in i n f l a m m a t i o n a n d i m m u n o l o g i c a l p h e n o m e n a [6]. T h e lanthanides inhibit the reticuloendothelial stimulation in- duced b y z y m o s a n , triolein a n d Bacillus Callmette Gubrin (BCG) [2], c h e m o t a x i s of p o l y m o r p h o n u c l e a r leukocytes, the antigen-induced h i s t a m i n e release f r o m m a s t cells, a n d the proliferative response of h u m a n l y m p h o c y t e s to vari- ous m i t o g e n s a n d to "purified p r o t e i n derivative" ( P P D ) of tuberculin antigen [6]. A c c o r d i n g to o u r recent studies, GdC13 also inhibits the h y p o t e n s i o n induced by i m m u n e globulin aggregates [7]. H a r d o n k et al. [-8] in recent studies with the aid of K u p f f e r cell specific m o n o c l o n a l antibodies d e m o n s t r a t e d t h a t GdC13 n o t only blocks p h a g o c y t o s i s of K u p f f e r cells, b u t also selectively elimin- ates the large m a c r o p h a g e s situated in the p e r i p o r t a l zone of the liver acinus. T h e o b s e r v a t i o n s t h a t the K u p f f e r cell p h a g o c y t o s i s b l o c k a d e with GdC13 greatly reduced the m o r t a l i t y rates a n d the s y m p t o m s of m o u s e anaphylaxis, including the a c c u m u l a t i o n of s e r o t o n i n a n d h i s t a m i n e in the liver, suggest t h a t the a c t i v a t i o n of K u p f f e r cells m a y c o n t r i b u t e to the d e v e l o p m e n t of "multiple o r g a n failure".
Acknowledgement. This work was supported by the Hungarian National Science Foundation (OTKA, grant No. 2684).
R e f e r e n c e s
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