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INFLAMMATION, IMMUNOPHARMACOLOGY, AND ASTHMA
Department of Pharmacology, School of Basic Medicine, Peking Union Medical College and Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Beijing, China
Received September 19, 2007; accepted January 7, 2008.
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Abstract |
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and interleukin-1β levels at the site of inflammation and in serums, which may contribute to the anti-inflammatory effect. These data suggest that CAI is a promising anti-inflammatory and analgesic agent, and they provide new insight into the biological activity of the drug.
; Jacobs et al., 1997; Lambert et al., 1997; Moody et al., 2003; Enfissi et al., 2004; Perabo et al., 2004).
In addition, the antiangiogenic effect of CAI has also been well established. In vitro studies have shown that CAI reduces proliferation, adhesion, motility, and vascular tube formation of human umbilical vein endothelial cells (Kohn et al., 1995). Local administration of CAI inhibits capillary expansion in the chick chorioallantoic membrane assay. Furthermore, inhibition of angiogenesis by orally administered CAI has been observed in animal models and in tumor xenografts (Luzzi et al., 1998). Herein, CAI is also described as a new nonendothelial cell-specific inhibitor of angiogenesis (or angiopreventive agent). In an earlier study (Felder et al., 1991), CAI was shown to have an immediate inhibitory effect on carbachol-stimulated release of arachidonic acid in muscarinic acetylcholine receptor m2-transfected Chinese hamster ovary cells. Another noticeable finding is that pretreatment of human T cells with CAI inhibits the nuclear accumulation of c-Rel and p65, causing a selective repression of nuclear factor-
B DNA binding and a near complete inhibition of calcium-regulated mitogen-induced transcription from the human immunodeficiency virus long terminal repeat (Yasui et al., 1997).
According to our current knowledge, the above-mentioned events, including angiogenesis, release of arachidonic acid, and nuclear factor-B activation, modulated by CAI are involved in many pathological processes, such as cancer and chronic inflammation (Griffioen and Molema, 2000; Lu et al., 2006). Thus, we put forward the hypothesis that CAI, currently recognized as a tumoristatic and antiangiogenic agent, may have more pharmacological activities in addition to what it already presents.
In the present work, we evaluate the possible beneficial effect of CAI in the treatment of acute and chronic inflammatory processes, such as croton oil-induced ear edema, cotton-induced granuloma, and rat adjuvant-induced arthritis. Local vascular permeability in mouse modulated by CAI has also been determined. In addition, we have assessed the effect of CAI on the levels of proinflammatory cytokines TNF- and IL-1β at the site of inflammation and in sera. Moreover, antinociceptive effect of CAI on inflammatory pain has been assessed using acetic acid-induced writhing model and the formalin test. This study is, to our knowledge, the first showing that CAI possesses anti-inflammatory and analgesic activities.
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Materials and Methods |
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and IL-1β were from R&D Systems (Minneapolis, MN). Animals. Female Wistar rats (180–200 g) or male ICR mice (18–22 g; 6–8 weeks old) were obtained from Beijing Vital River Laboratory Animal Co., Ltd. (Beijing, China). They were housed in an air-conditioned room (22 ± 2°C and 40–70% humidity), with a controlled 12-h light/dark cycle (lights on 8:00 AM). Animals had free access to standard chow and water. All animal studies and procedures were approved by the Institutional Animal Care and Use Committee of Peking Union Medical College.
Croton Oil-Induced Ear Edema. The croton oil ear test was performed as described previously (Olajide et al., 2000). Male ICR mice were randomly divided into five groups, with 15 animals in one group. CAI (10 and 20 mg/kg), dexamethasone (0.8 mg/kg), or vehicle (PEG 400 and 0.9% NaCl) was administered once daily (orally for CAI and PEG 400; i.p. for dexamethasone and saline). One hour after the third administration, 100 µl of croton oil solution (croton oil/ethanol/distilled water/ether, 2:20:5:73) was applied to both sides of the right ear of each mouse. The left ear remained untreated. The animals were sacrificed 4 h later, and a plug (6.5 mm in diameter) was removed from both the treated and untreated ear. The difference in weight between the two plugs was taken as a measure of edema intensity. The anti-inflammatory activity was expressed as percentage of the edema reduction in treated mice compared with control mice.
Induction of Granulomatous Tissue. Subacute inflammation was produced in female Wistar rats (180–200 g) by cotton pellet-induced granuloma (Swingle and Shideman, 1972). Sterile cotton (20 ± 1 mg) soaked in 0.4 ml of 5% ampicillin solution was implanted s.c. bilaterally in groin under anesthesia. The following was administered daily: 0.9% NaCl (NS; i.p.), 0.8 mg/kg dexamethasone (i.p.), PEG 400 (p.o.), and 10 and 20 mg/kg CAI (p.o.). On the 7th day, the animals were sacrificed. The granulomatous tissue with cotton pellet was removed and dried at 60°C to constant weight. Increment in the dry weight of the pellets was taken as measure of granuloma formation.
Inhibition of Adjuvant-Induced Arthritis. Female Wistar rats (180–200 g) were divided into five groups. On day 0, animals in groups 1 to 4 were induced adjuvant arthritis by a single intradermal injection of 0.1 ml of Freund's complete adjuvant into the plantar region of the right hind paw. NS (i.p.), 0.5 mg/kg dexamethasone (i.p.), PEG 400 (p.o.), and 20 mg/kg CAI (p.o.) were administered once a day from day 0 to day 27. As a nonarthritic control, animals in group 5 were free of Freund's complete adjuvant injection, and they received injections with 0.9% NaCl daily. Right hind paw volume was measured before adjuvant injection and on days 1 to 14 with a water displacement volume meter to assess the primary inflammatory response, and left hind paw volume was measured on days 21, 24, and 27 to assess the secondary inflammatory response. The anti-inflammatory effect was expressed as the difference in paw edema compared with that of saline-treated arthritic rats (Newbould, 1963; Walz et al., 1971).
Histopathology Evaluation. Rat synovial membrane samples were obtained from the knee joint 14 days after adjuvant injection. The specimens were fixed in buffered 10% formalin and embedded in paraffin. They were serially sectioned onto microscope slides at a thickness of 4 µm and then deparaffinized, stained with hematoxylin and eosin, and evaluated for morphological changes and cellular infiltration.
Vascular Permeability Evaluation. Male ICR mice (18–22 g; 6–8 weeks old) were pretreated orally with 0.9% NaCl, PEG 400, or varying doses of CAI for 3 days. Miles assay was then performed (Miles and Miles, 1952; Claffey et al., 1996). In brief, Evans blue solution (dissolved in saline) was injected into mice via the tail vein at a dose of 40 mg/kg. After 10 min, 100 µl of vascular endothelial growth factor (VEGF) (1 µg/ml) or histamine (1 mg/ml) was injected intradermally into the preshaved back skin. After 20 min, the animals were euthanized, and an area of skin that included the entire injection site was removed. Evans blue dye was extracted from the skin by incubation with formamide for 48 h at 37°C, and the absorbance of extracted dye was measured by a Beckman spectrophotometer at 620 nm.
Determination of IL-1β and TNF- in Rat Serum and Paw Tissue. For arthritic rats, serum was collected on the last day of the experiment (day 27). After animals were sacrificed, the s.c. tissue of the right hind paw and that surrounding the ankle joints was removed and placed in 5 ml of saline. The tissues were homogenized at 4°C, and then it was centrifuged at 10,000g for 15 min. The supernatants were stored at –80°C until further analysis. IL-1β and TNF- levels in serum and paw tissue supernatant were measured using specific rat ELISA kits according to the manufacturer's instructions. The sensitivities of the assays for IL-1β and TNF- were 7 and 4 pg/ml, respectively.
Analgesic Activity against Acetic Acid-Induced Writhing. The analgesic activity of CAI was assessed using writhing test (abdominal constriction test) (Collier et al., 1968). Male ICR mice were pretreated with CAI (10 and 20 mg/kg p.o.) for 3 days. Morphine hydrochloride (2 mg/kg i.p.) was used as the reference analgesic drug, and vehicles (PEG 400 and NS) were also administered once daily. One hour after the third administration, 0.1 ml of 0.6% (v/v) acetic acid solution was injected i.p., and the writhing behavior (contraction of abdominal muscles together with stretching of the hind limbs) was cumulatively counted in various groups of animals over a period of 15 min beginning 3 min after acetic acid injection. Analgesic activity was expressed as percentage of inhibition of writhing.
Formalin Test in Mice. The formalin test was carried out as described by Hunskaar and Hole (1987). Mice received injections with 20 µl of 2.5% formalin [formaldehyde solution 37% (w/w) diluted in NS] into the subplantar space of the right hind paw after pretreatment with CAI (20 mg/kg p.o., once daily for 3 days), morphine hydrochloride (2 mg/kg i.p., 10 min before formalin injection), or both. Responses were measured 0 to 5 min (early phase) and 10 to 25 min (late phase) after formalin injection. The animals were placed in a glass cylinder (20 cm in diameter), and the amount of time spent in each one of four behavioral categories was recorded, which were further scored as follows: 0, the injected paw is not favored; 1, the injected paw has little or no weight on it; 2, the injected paw is elevated and is not in contact with any other surface; and 3, the injected paw is licked, bitten, or shaken. An average pain intensity score was calculated, according to the weighed-scores technique (Dubuisson and Dennis, 1977), by multiplying the amount of time spent in each category by its assigned category score, adding these products and dividing by the total time of observation (i.e., 300 and 900 s).
Statistical Analysis. The results are expressed as the mean ± S.E.M.; n represents the number of experiments or animals. Statistical analysis was determined by analysis of variance followed by Dunnett's test for multiple comparisons. p values less than 0.05 were considered statistically significant.
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Results |
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CAI Reduced the Severity of Synovial Histopathological Changes in Arthritic Rats. The synovial lining was discerned at 40x magnification (Fig. 4, A–D). In naive animals (Fig. 4A), the synovial cells formed a thin layer, and they were flat and quiescent. No leukocyte infiltration was observed. In animals treated with vehicle PEG 400, the synovial membrane cells became hyperplastic, and it formed a thick, multicelled layer, suggesting active proliferation. In addition, the synovial membrane showed infiltration by leukocytes and hyperanemia with dilated blood microvessels (Fig. 4B). In the synovial tissues of CAI- or dexamethasone-treated rats (Fig. 4, C and D), cell hyperplasia and hypertrophy were significantly inhibited, few or no leukocytes were present, and fewer blood microvessels were seen.
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). CAI treatment at 20 mg/kg for 3 days strikingly inhibited VEGF- or histamine-induced extravasation of Evans blue dye in mice by 35 and 44%, respectively (Fig. 5A). Furthermore, the antipermeabilizing effect of CAI was dose-dependent. As shown in Fig. 5B, oral administration of CAI at doses of 5, 10, and 20 mg/kg reduced histamine-induced Evans blue dye accumulation by 7.2, 27.5, and 46.4%, respectively.
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Effect of CAI on TNF- and IL-1β Levels in Paw Homogenates and Sera of Arthritic Rats. Because proinflammatory cytokines play critical role in the pathogenesis of autoimmune and inflammatory diseases such as arthritis, the effect of CAI (20 mg/kg p.o.) and dexamethasone (0.5 mg/kg i.p.) on TNF- and IL-1β levels in paw homogenates and sera of arthritic rats was determined. CAI reduced tissue TNF- and IL-1β levels by 54.1 and 26.3%, respectively, which was comparable with the inhibitive effect of dexamethasone (Fig. 6, A and B). In serum, TNF- and IL-1β levels were also significantly reduced by CAI and dexamethasone (Fig. 6, C and D).
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Formalin Test. The effect of CAI treatment on both early and late phases of the formalin test was investigated. During the initial 5 min after formalin injection, CAI did not affect the nociceptive response of mice (data not shown). In the late phase (i.e., 10–25 min after formalin) of the protocol, CAI significantly attenuated nocifensive response as indicated by lower pain scores compared with the vehicle group. Moreover, the coadministration of CAI and morphine produced more pronounced antinociceptive effect than either of drug alone (Table 2).
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Discussion |
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, 2002; Kohn et al., 1997, 2001; Bauer et al., 1999). Here, we reported for the first time that CAI has potential anti-inflammatory and analgesic effects in addition to its antitumor activity.
In this study, the effects of CAI on acute and chronic phases of inflammation were investigated using models of croton oil-induced ear edema, cotton pellet granuloma, and adjuvant-induced rat arthritis. In addition, the effect of CAI on capillary permeability was investigated by Evans blue leakage assay. Oral administration of CAI was found protective against croton oil-induced ear edema; however, the power of anti-inflammatory activity of CAI was less than that of dexamethasone at both doses (10 and 20 mg/kg) used. In cotton pellet granuloma test, CAI significantly decreased the final dry weight of the cotton pellets that correlates very well with the amount of granulomatous tissue (Swingle and Shideman, 1972), suggesting that CAI has the capability in reducing the synthesis of mucopolysaccharide and collagen and the number of fibroblasts, which are natural proliferative events of granulation in tissue formation.
CAI was shown to reduce the vascular permeability by reduction of VEGF- or histamine-induced Evans blue dye leakage. Previous studies demonstrated that VEGF induces venular hyperpermeability through a kinase insert domain-containing receptor-mediated activation of phospholipase C (PLC), subsequent protein kinase C activation and cytosolic Ca2+ elevation, as well as endothelial constitutive nitric-oxide synthase activation (Wu et al., 1999). Regarding histamine-mediated vascular hyperpermeability, the production of inositol triphosphate via PLC and an internal release and further influx of calcium serve important functions (Rotrosen and Gallin, 1986). It has been well established that CAI preferentially blocks calcium influx and inhibits downstream phosphorylation events involving PLC
and inositol triphosphate (Kohn and Liotta, 1990; Hupe et al., 1991). The modulation of Ca2+-mediated signal transduction by CAI might disturb the above-mentioned pathways involved in VEGF- or histamine-induced vascular hyperpermeability, resulting in decreased capillary leakage.
CAI exposure has been shown to inhibit vascular tube formation in Matrigel and aortic ring assays and to inhibit capillary expansion in the chick chorioallantoic membrane assay (Kohn et al., 1995; Bauer et al., 1999). Furthermore, inhibition of angiogenesis by orally administered CAI has been observed in animal models and in tumor xenografts (Luzzi et al., 1998). The relation between angiogenesis and chronic inflammation has attracted a lot of attention in recent years. In the first acute phase of inflammation, functional changes in the vasculature such as dilatation, increase in permeability, and endothelial activation occur. In the second subacute phase, capillaries and venules remodel with extensive endothelial mitotic activity (Majno, 1998). Upon chronic stimulation, both increases in capillary density and vascular dilatation can be observed (Thurston et al., 1998). In rheumatoid arthritis, neovascularization, which is one of the earliest histopathological findings, is thought to be required for pannus development. Rheumatoid synovial endothelium is constantly subjected to remodeling. Besides nurturing the pannus, the blood vessels also play an active role in the inflammation by being a source of cytokines, chemokines, and proteases (Storgard et al., 1999). So, it can be expected that CAI, a known antiangiogenic agent, may have the potential for treatment of arthritis and other chronic inflammatory diseases accompanied by overt neovascularization.
To confirm the hypothesis mentioned above, the model of adjuvant-induced rat arthritis was used. In this model, rats develop a chronic swelling in multiple joints, with influx of inflammatory cells, erosion of joint cartilage, and bone destruction of joint integrity and loss of function. This model of chronic inflammation is a complex response involving different mediators; therefore, there is a possibility of multiple interactions (Stefanovic-Racic et al., 1993; Kollias et al., 1999). Our data indicate that CAI is effective, by oral route, in the treatment of experimental chronic inflammation and that the inhibition of joint inflammation was accompanied by reduction of TNF- and IL-1β levels both in arthritic paws and in sera. It has been well established that proinflammatory cytokines such as TNF- and IL-1β promote cartilage and bone resorption by inhibiting proteoglycan and collagen synthesis and induce the expression of collagen degrading enzymes, leading to bone and cartilage destruction in the rheumatoid synovium (Feldmann et al., 2002). They also induce the expression of other proinflammatory mediators, such as IL-8, granulocyte-macrophage colony-stimulating factor, and IL-6, and facilitate inflammatory cell infiltration by enhancing neutrophil and T cell adhesion to endothelium (Arend and Dayer, 1995). In addition, it should be noted that proinflammatory cytokines, including TNF- and IL-1β, are also involved in the progression of tumors and increasingly recognized to be key molecular players in linking inflammation to cancer (Coussens and Werb, 2002; Lu et al., 2006). Therefore, it may be reasonable to declare the correlation between anti-inflammatory and anticancer properties of CAI, and new research strategies for unraveling the mechanism of CAI based on the correlation might be promising.
Our study also revealed that CAI has potent antinociceptive action in the acetic acid and formalin tests, two highly sensitive and useful tests for analgesic screening. The abdominal constrictions produced after administration of acetic acid are thought to involve the release of endogenous substances such as bradykinin and prostanoids, among others. Therefore, it is possible that CAI exerts analgesic effect probably by inhibiting the synthesis of these substances or by directly affecting peripheral nerves. The formalin test is thought to be a more valid analgesic model, and it is better correlated with clinical pain (Tjølsen et al., 1992). The early (acute) phase is due to direct stimulation of nociceptors, and the second phase is mainly inflammatory in origin (Hunskaar et al., 1987). CAI had no effect on the early phase response, but it attenuated nociceptive response in the late phase, which together with the findings that CAI showed no analgesic effect in hot-plate and the light tail-flick tests (data not shown), supports the absence of central component in mechanism of CAI analgesia. The anti-inflammatory potential may account for its peripheral analgesic activity.
In summary, the present study strongly suggests that CAI has good anti-inflammatory and peripheral analgesic activities. The marked inhibition of TNF- and IL-1β levels by CAI together with its previously well established antiangiogenetic property may play an important role in the anti-inflammatory process. Based on the findings, it is reasonable to develop CAI as a new anti-inflammatory and analgesic agent.
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Footnotes |
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L.G. and C.Y. contributed equally to this work.
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
ABBREVIATIONS: CAI, carboxyamidotriazole; TNF, tumor necrosis factor; IL, interleukin; PEG, polyethylene glycol; ELISA, enzyme-linked immunosorbent assay; NS, 0.9% NaCl; VEGF, vascular endothelial growth factor; PLC, phospholipase C.
Address correspondence to: Dr. Dechang Zhang, Department of Pharmacology, School of Basic Medicine, Peking Union Medical College, No. 5 Santiao, Dongdan, Beijing 100005, China. E-mail: pumc01{at}126.com
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