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Infection and Immunity, May 2001, p. 3460-3465, Vol. 69, No. 5
0019-9567/01/$04.00+0   DOI: 10.1128/IAI.69.5.3460-3465.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Assessing Vascular Permeability during Experimental Cerebral Malaria by a Radiolabeled Monoclonal Antibody Technique

Henri C. van der Heyde,1,2,* Philippe Bauer,3 Guang Sun,2 Wun-Ling Chang,4 Lijia Yin,4 John Fuseler,4,5 and D. Neil Granger3

Departments of Microbiology and Immunology,1 Cellular and Molecular Physiology,3 and Medicine,4 Inflammation and Immunology Research Group,2 and Center for Excellence in Arthritis and Rheumatism,5 Louisiana State University Health Sciences Center, Shreveport, Louisiana 71130

Received 3 August 2000/Returned for modification 27 September 2000/Accepted 29 January 2001


    ABSTRACT
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Vascular endothelial integrity, assessed by Evans blue dye extrusion and radiolabeled monoclonal antibody leakage, was markedly compromised in the brain, lung, kidney, and heart during Plasmodium berghei infection, a well-recognized model for human cerebral malaria. The results for vascular permeability from both methods were significantly (P < 0.001) related.


    TEXT
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Changes in vascular permeability are important in the pathogenesis of circulatory shock. Circulatory shock is defined as an inadequacy of blood flow in tissue leading to inadequate delivery of nutrients to tissue and inadequate removal of waste products (reviewed in reference 12). Cardiac abnormalities, such as myocardial infarction, heart arrhythmias, and heart valve dysfunction, lead to circulatory shock. Diminished blood volume, decreased vascular tone, or a blockage of blood flow in the circulation all lead to circulatory shock. Of most interest to infectious disease research is the development of circulatory shock caused by infectious agents, also called septic shock. General features of septic shock include vasodilation with changes in vascular permeability, decreased mean arterial blood pressure, and disseminated intravascular coagulation (12, 38), which are all important factors contributing to decreased tissue perfusion (12). In the late stages of septic shock, this coagulation of blood (sometimes referred to as sludging blood) and other factors leads to impaired consciousness (38). If the patient recovers from septic shock, there is generally no neurological impairment (38).

Malaria, a leading infectious cause of morbidity and mortality, is postulated to cause an inflammatory response (3, 35). Petechial hemorrhaging into the brain is considered a hallmark of cerebral malaria (CM), indicating the brain vasculature in patients with Plasmodium falciparum malaria is often damaged (25, 31). However, the exact contribution of vascular leakage to human CM is still not defined because a recent study by Brown et al. (2) did not detect significant vascular leakage into brains of patients with severe P. falciparum malaria. Patients with P. falciparum infections also develop lung (respiratory distress syndrome), liver, and kidney damage (18). The precise causes of vascular activation and damage in humans are under intense debate, but it is difficult to define pathogenic mechanisms in humans for obvious ethical reasons. Although no model entirely replicates the human condition (reviewed in reference 8), two well-characterized models of CM exist (10, 22, 30, 32). We selected the P. berghei model because P. berghei-infected mice develop impaired consciousness (10, 22, 30). Susceptible mice (C57BL/6 or C3H) infected with P. berghei develop neurological abnormalities 6 days after injection with P. berghei (10, 22). These mice exhibit brain edema, petechial hemorrhages, and monocyte infiltration (30). Several studies using dye extrusion into tissue have documented that vascular permeability is markedly increased in the brain (21, 24, 26). In addition, injection of P. berghei-infected mice with folic acid results in convulsions, indicating that folic acid has crossed the normally impermeable blood-brain barrier and is mediating altered brain signaling (14). Ultrastructural analysis shows perivascular edema in the brain after P. berghei infection in mice (29). There is only a single semiquantitative study of tissue damage outside the brain. Neill and Hunt report extrusion of Monastral Blue, a colloidal dye, into brains, lungs, livers, spleens, and kidneys of P. berghei ANKA-infected mice, i.e., in all organs tested (27).

Because defining the sites of organ damage during malaria is key to our understanding of pathogenic mechanisms, we quantified vascular permeability during malaria in a number of tissues, using standard Evans blue dye leakage. Since there are a number of disadvantages associated with the Evans blue dye leakage technique, we also assessed vascular permeability using a radiolabeled monoclonal antibody (MAb) technique and compared the results to those for Evans blue dye extrusion. It is important to quantify precisely vascular leak in order to define the mechanism(s) whereby damage to the endothelium occurs; this ability to measure vascular permeability rapidly is important for malarial research, septic shock, and other forms of circulatory shock. We report here that the radiolabeled MAb technique correlated with Evans blue dye extrusion. Moreover, we observed increased vascular permeability during P. berghei infection in the brain, lung, heart, and kidney, whereas no changes were detected in the small bowel, large bowel, pancreas, liver and spleen.

Parasites and infection of mice. Female (C57BL/6, IL-120/0, GKO0/0, ICAM-10/0, and TNFR10/0) mice all on the CM-susceptible C57BL/6 background were purchased from Jackson Laboratory (Bar Harbor, Maine) at 4 to 5 weeks of age and provided food and water ad libitum. In each experiment, groups of four to eight mice between 6 and 12 weeks of age were used. The animals were housed at the Louisiana Health Sciences Center Animal Care Facility, an Association for Assessment and Accreditation of Laboratory Animal Care-approved facility. IL-120/0, GKO0/0, ICAM-10/0, and TNFR10/0 mice lack intact interleukin-12 (IL-12), gamma interferon (IFN-gamma ), intracellular adhesion molecule 1 (ICAM-1), and tumor necrosis factor receptor 1 (TNFR1) genes, respectively (6, 23, 28, 33), and do not develop clinical signs and symptoms of CM.

P. bergehi ANKA, a gift from William Weidanz, was maintained and used as described previously (15). This strain of Plasmodium kills CM-susceptible C57BL/6 mice on about day 6 of infection. Frozen parasite stabilate was injected intraperitoneally into a CM-resistant BALB/c source mouse. Blood was obtained from the source mouse to generate the inoculum for the experimental animals. Experimental mice were injected intraperitoneally with 106 erythrocytes parasitized with P. berghei, and parasitemia was assessed by enumerating between 200 and 1,000 erythrocytes in Giemsa-stained thin blood films.

Assessment of vascular permeability. Vascular permeability was measured simultaneously by Evans blue dye extraction and by the radiolabeled MAb technique. C57BL/6 mice were anesthetized by a subcutaneous injection of 150 mg of ketamine and 7.5 mg of xylazine per kg of body weight. The right jugular vein and right carotid artery were cannulated with polyethylene tubing (PE-10); 200 µl of Evans blue in saline (2%) was administered via the catheter in the jugular vein, followed by an injection of 200 µl of 0.9% saline. The Evans blue dye circulated for 11 min, and then 500,000 ± 100,000 cpm (0.5 to 5 mg in 200 µl) of nonbinding 131I anti-human P-selection MAb was injected via the jugular vein catheter. No difference (correlation coefficient [R2] = 0.08) in permeability was measured in this range of specific activities. We used a fixed specific activity for the nonbinding MAb because it allows the simultaneous measurement of vascular permeability and cell adhesion molecule expression. Cell adhesion molecule expression is determined as the ratio of tissue accumulation of an 125I-labeled specific MAb to the 131I-labeled nonspecific MAb (1). The nonbinding anti-human P-selectin MAb (designated P-23) was kindly provided by Donald Anderson (Pharmacia-Upjohn) and was labeled by the Iodogen method (1). This antibody is characterized as nonbinding because in comparison to well-established binding MAbs, its accumulation in tissue was minimal and equivalent to that of other nonspecific MAbs. Further, P-23 did not bind to monolayers of cultured murine endothelial cells. Two hundred microliters of 0.9% saline containing 50 U of heparin was injected and allowed to circulate for 5 min. A blood sample (200 µl) was then obtained through the carotid artery to determine 131I levels in serum. An isovolemic blood exchange with bicarbonate-buffered saline (6 ml) was performed through the jugular vein catheter. The thoracic inferior vena cava was cut and flushed with 15 ml of bicarbonate-buffered saline through the carotid artery catheter. Selected organs were dissected from the animal, weighed, and placed in a test tube containing 1 ml of N,N-dimethyl formamide. The levels of radioactivity were immediately assessed by a scintillation counter (Wizard 3; Wallac, Turku, Finland). The level of 131I in tissue was divided by the weight of the tissue and then divided by 131I per milliliter of plasma; the 131I per milliliter of plasma compensates for differences in the concentration of radiolabel achieved in the sera of each animal, which is a factor in the permeability measurement. After determining the radioactivity level in each organ, the amount of Evans blue dye in each organ was assessed by placing the organ in 1 ml of N,N-dimethyl formamide (Sigma, St. Louis, Mo.) for 48 h to extract the Evans blue dye. The absorbance of Evans blue dye solution was measured in a spectrophotometer at 630 nm. If the absorbance was greater than 0.7 optical density units (OD), then the solution was diluted with N,N-dimethyl formamide until the absorbance fell below 0.7 OD. This dilution was necessary to ensure measurements were made in the linear range of the spectrophotometer. The absorbance value was divided by weight of tissue to normalize for the amount of tissue. In other experiments, vascular permeability was assessed only by the radiolabled MAb method, performed as described above except that no Evans blue dye was injected.

Statistical analysis. Analysis of variance with the Statview program (SAS Institute, Cary, N.C.) was performed to statistically compare Evans blue dye and radiolabeled MAb leakage in the different groups of mice. Linear regression analysis of the results was also performed with this program.

Results and discussion. Evans blue dye when injected into blood binds to serum proteins, with the majority binding to albumin. If changes in vascular permeability occur, then dye leaks from vascular lumen into interstitial tissue. The dye in the circulation is then washed out, and the tissues can be visually inspected for dye leakage. For brains and lungs, visualization of dye leakage is easy (data not shown); for more pigmented organs, the dye is difficult to see in tissue. Leakage of dye into the brain coincided with areas of petechial hemorrhaging. Little if any Evans blue dye was retained in the tissue after fixation and paraffin embedding or after snap-freezing in liquid nitrogen and fixation in acetone. We therefore used the technique of Tateishi et al. (34) to extract and quantify dye in tissue.

In organs from uninfected mice, the amount of dye or radiolabel in the tissue is proportional to the amount of vascularization and the permeability of the endothelial barrier. Thus, in the brain, with a tight endothelial barrier and less vascularization than the lung, dye extrusion is about 15-fold lower than in the lung (Table 1). The spleen and liver, which are blood filtration organs with wide pores, have higher dye extrusion levels than the lung (Table 1).

                              
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  		TABLE 1.   Assessment of vascular permeability during the course of P. berghei malariaa

On day 4 of P. berghei infection, parasitemia of mice was 3.1% ± 4.2%, but these mice have no obvious clinical signs of malaria. On day 6 of infection, parasitemia was 13% ± 4%, and virtually all of these mice developed symptoms. The mice were lethargic, were breathing rapidly, and had obvious neurological impairment, such as loss of righting reflex and the ability to grip. Mice on day 4 of P. berghei infection had markedly increased vascular permeability in the brain, lung, heart, and kidney as assessed by the radiolabeled MAb technique or by Evans blue dye leakage (Table 1). Changes in vascular permeability in the kidney may be due to increased glomerular filtration. The vascular permeability increased further on day 6 of P. berghei infection in the brain, lung, heart, and kidney but not in the liver, spleen, and small intestine. In separate experiments, mice on day 2 of P. berghei infection had less than 0.1% parasitemia and similar levels of vascular permeability, assessed by Evans blue dye extrusion, as uninfected controls.

The brain showed the most pronounced change in vascular permeability during P. berghei malaria when assessed by the radiolabeled MAb technique, increasing more than 10-fold compared with uninfected controls (Table 1). The lung, heart, and kidney also showed significant (P < 0.05) increases in vascular permeability, generally about threefold. This increase in vascular leak occurred on day 4 of infection when the mice were asymptomatic, indicating that the observed vascular leakage did not occur merely because the animal was moribund. Additional Evans blue and radiolabeled MAb experiments showed variation from experiment to experiment in the magnitude of permeability changes in the lung and brain. In every experiment changes in the lung and brain reached statistical significance, but in some experiments changes in vascular permeability were greater in the lung than in the brain, whereas other experiments showed more pronounced changes in the brain. The reason for these differences remains to be determined. The permeability in liver and intestine did not increase markedly during the course of P. berghei malaria. The spleen showed a decline in vascular leakage, which was not statistically significant. The decline in permeability may be due to development of shunts in the spleen between the arterioles and venules reducing perfusion through the spleen (36); alternatively, it may be due to the hepatomegaly and splenomegaly that occur during malaria. However, it is difficult to interpret changes in permeability in the liver and spleen because these organs are blood filtration organs and as such have wide pores allowing passage of large macromolecules and cells.

The results for vascular permeability were similar for Evans blue dye leakage and the radiolabeled MAb technique. Indeed, there was a significant (P < 0.001) correlation in the lung, heart, liver, spleen, small bowel, kidneys, pancreas, and brain between the vascular permeability measured by Evans blue dye leakage and that assessed by radiolabel leakage. The R2 values ranged from 0.50 in the liver to 0.91 in the spleen (Table 1); the pancreas and large bowel R2 values were 0.56 and 0.82, respectively. For correlation of the Evans blue dye leakage and radiolabeled MAb techniques, changes in vascular permeability must occur. In those tissues where we observed increased vascular permeability during the course of P. berghei malaria, we also observed excellent linear correlation (high R2) between the two techniques (Table 1). In the liver, we detect little if any change in permeability by the Evans blue dye technique and the lowest R2 (Table 1). The spleen appears to be the exception, with a high R2 but no significant change in vascular permeability. However, changes did occur during malaria that may explain the excellent correlation between the two methods for measuring vascular permeability (Table 1). Collectively, these results indicate that the radiolabel MAb technique is equivalent to the Evans blue dye technique.

Assessing vascular permeability is much more rapid and straightforward by the radiolabeled MAb technique than by the Evans blue dye method. The latter requires a 48-h extraction of the dye from tissue and then measurement of the absorbance in a spectrophotometer. The solution containing the extracted dye is added manually to a cuvette, which is placed in the spectrophotometer. A measurement is made, the cuvette is rinsed, and another sample is added; this is a slow process. In addition, many tissue samples, especially after induction of increased permeability, require dilution to bring the absorbance into the linear range. Collectively, these manual steps make determination of vascular permeability by Evans blue dye leakage into tissue a time-consuming process and explain why few tissues are generally assessed by this technique (Tables 1 and 2). In contrast, with the radiolabeled MAb technique, the tissue dissected from an animal is placed in scintillation fluid, and the amount of radioactivity present is assessed on a scintillation counter. No dilutions or further processing are required, and the scintillation counter automatically measures the radioactivity in each vial. Another advantage of this technique over Evans blue dye leakage is that it takes into account the driving force behind permeability, namely, the concentration of radiolabel achieved in the blood.

                              
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  		TABLE 2.   Vascular permeability assessed by radiolabeled MAb leakage into additional tissues during the course of P. berghei malaria

Several studies have determined that the blood-brain barrier is compromised during P. berghei malaria. A single study using a colloidal Monastral Blue reports that there is increased permeability in the kidneys livers lungs, spleens, and brains of P. berghei-infected mice (27). This approach entails examining tissue sections from Monastral Blue-treated mice and visually scoring the amount of leakage. The advantage of Monastral Blue is that direct visualization of dye extrusion into tissue is obtained; the disadvantages are that the measurements are subjective and time-consuming. In addition, there is no correlation between the location of petechial hemorrhages in the brain and localization of Monastral Blue particles. How the vascular endothelium retained Monastral Blue while allowing an erythrocyte to cross was not addressed. The results of Neill and Hunt (27) raise the possibility that Monastral Blue particles are transported across the endothelium analogously to the transport of latex beads across mucosal epithelium. In our experiments, we found colocalization of Evans blue dye leakage and petechial hemorrhages on the surface of brains from P. berghei-infected mice (data not shown). With both Evans blue dye leakage and the radiolabeled MAb technique, we found markedly increased vascular permeability in the brain, lung, and kidney, which corroborates the results of Neill and Hunt (27). Our study extends their finding to myocardial tissue. We did not observe an increase in vascular permeability for the spleen and liver as reported by Neill and Hunt (27); this difference may be due to the size of Monastral Blue particles and their active transport across the endothelium as described above.

Having established that the radiolabeled MAb technique measures vascular permeability, we applied it to induced mutant mice that are protected from CM to determine whether these mice are protected from increased vascular permeability. ICAM-1-, IL-12-, TNFR1-, and IFN-gamma -deficient mice do not develop and succumb to CM after infection with P. berghei (7, 9, 11, 20). All strains of mice had significant parasitemia (Table 3). Thus, changes in vascular permeability cannot be attributed to inadequate infection. The parasitemia after injection of 106 P. berghei-parasitized erythrocytes was markedly enhanced in IL-12- and IFN-gamma -deficient mice compared with C57BL/6 controls, with the caveat that the groups of mice were not injected with the same inoculum of parasites. Each type of mouse developed significantly (P < 0.05) increased vascular permeability in the brain and lung during P. berghei malaria compared with uninfected matched controls (Table 4). Significantly (P < 0.05) increased permeability during P. berghei malaria in the heart was detected in TNFR1-deficient mice and C57BL/6 controls. Decreased or similar permeability was observed in spleens and livers of P. berghei-infected mice compared with uninfected controls for each type of mouse. These results collectively indicate that vascular permeability changes during P. berghei malaria occur in a number of tissues, but these changes by themselves are not life threatening or are markedly ameliorated by damping the inflammatory response. A change in vascular permeability is probably one factor of many that ultimately leads to death from malaria.

                              
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  		TABLE 3.   Parasitemia in selected induced mutant mice (five to eight mice per group) on days 4 and 6 of P. berghei infection


                              
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  		TABLE 4.   Vascular permeability assessed by radiolabeled MAb leakage in tissues of selected induced mutant mice on day 6 of P. berghei malaria

Vascular permeability is a major factor in the pathogenesis of circulatory shock, and our results show that the radiolabeled MAb technique is a useful assay to measure vascular permeability changes. Our finding of significant vascular leakage in several tissues (including pancreas and thymus) during the course of P. berghei malaria raises the question of whether circulatory shock may explain the pathogenesis of malaria. Individuals in septic shock and those with CM both develop impaired consciousness, and only very few individuals in septic shock or with CM develop neurological sequelae if they recover, suggesting similar pathogenic mechanisms in the brain. In addition, individuals with septic shock often have sludging blood wherein minithrombi are formed. This may be analogous to the rosetting described in CM with parasitized and nonparasitized erythrocytes binding together, although the precise role of rosetting in CM is under debate (25). Jennings et al. (16, 17) have proposed that CM is an encephalitis or inflammation of the brain. Indeed, immune cells (macrophages; CD4+ and CD8+ T cells) and inflammatory cytokines are essential for the pathogenesis of experimental CM (4, 5, 13, 19, 37). When extrapolated to other tissues showing vascular damage, these results suggest that CM is a systemic inflammatory response.

Our results showing damage during experimental malaria in the brain, lung, heart, and kidney may be important because vascular damage is also reported in these tissues in humans infected with P. falciparum. Humans with P. falciparum malaria succumb to CM, respiratory distress, anemia, and occasionally acute kidney failure. These life-threatening complications often occur in the same patient with P. falciparum malaria. The results of others and our studies show compromised vascular permeability in the brain; this compromise may contribute to the pathogenesis of experimental CM. Whether this compromise in brain vascular integrity occurs during human CM is controversial (2). Our observation of increased vascular leak in kidneys suggests that kidneys may also be damaged during experimental malaria. The finding of an early compromise of the blood-lung barrier during P. berghei malaria prior to the onset of symptoms suggests that these animals develop lung injury at an early stage. Damage to the heart during P. berghei malaria may lead to cardiac insufficiency and might further exacerbate the respiratory distress syndrome. The fact that all of these pathologic changes occur in the same animal suggests that the mechanisms mediating damage may be similar. Collectively, these observations suggest that experimental malaria may yield important information regarding human malarial pathogenesis.


    ACKNOWLEDGMENTS

This research was supported by NIH grants KO8 AI01438, PO1 DK43785, and RO1 AI40667. Support was also received from the Center for Excellence in Arthritis and Rheumatism.

We acknowledge the assistance of Clay Watson, Deborah Yanez, Dean Manning, and William Weidanz in initiating these studies.


    FOOTNOTES

* Corresponding author. Mailing address: LSU Health Sciences Center---Shreveport, Department of Microbiology and Immunology, P.O. Box 33932, Shreveport, LA 71130. Phone: (318) 675-4457. Fax: (318) 675-5764. E-mail: hvande{at}lsuhsc.edu.

Editor:   J. M. Mansfield


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Infection and Immunity, May 2001, p. 3460-3465, Vol. 69, No. 5
0019-9567/01/$04.00+0   DOI: 10.1128/IAI.69.5.3460-3465.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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