February 2011
Volume 52, Issue 2
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Immunology and Microbiology  |   February 2011
Effect of Artesunate on Endotoxin-Induced Uveitis in Rats
Author Affiliations & Notes
  • Xiao-Qin Wang
    From the Department of Pharmacology, Third Military Medical University, and
  • Hai-Lin Liu
    the Department of Pharmacy, People's Hospital of GaoXinYuan, Newly Developed North District, Chongqing, China.
  • Gui-Bo Wang
    the Institute of Infectious Diseases, Southwest Hospital, Third Military Medical University, Chongqing, China; and
  • Peng-Fei Wu
    From the Department of Pharmacology, Third Military Medical University, and
  • Tian Yan
    From the Department of Pharmacology, Third Military Medical University, and
  • Jia Xie
    From the Department of Pharmacology, Third Military Medical University, and
  • Yong Tang
    From the Department of Pharmacology, Third Military Medical University, and
  • Lu-Kun Sun
    From the Department of Pharmacology, Third Military Medical University, and
  • Chen Li
    From the Department of Pharmacology, Third Military Medical University, and
  • Corresponding author: Xiao-Qin Wang, Department of Pharmacology, Third Military Medical University, Chongqing 400038, China; wxqwsh@163.com
  • Footnotes
    2  These authors contributed equally to this work and should be considered equivalent authors.
Investigative Ophthalmology & Visual Science February 2011, Vol.52, 916-919. doi:10.1167/iovs.10-5892
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      Xiao-Qin Wang, Hai-Lin Liu, Gui-Bo Wang, Peng-Fei Wu, Tian Yan, Jia Xie, Yong Tang, Lu-Kun Sun, Chen Li; Effect of Artesunate on Endotoxin-Induced Uveitis in Rats. Invest. Ophthalmol. Vis. Sci. 2011;52(2):916-919. doi: 10.1167/iovs.10-5892.

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Abstract

Purpose.: The purpose of this study was to explore the effect of artesunate on endotoxin-induced uveitis (EIU) in rats.

Methods.: EIU was induced in male Long-Evans rats by footpad injection of lipopolysaccharide (LPS 200 μg in 0.1 mL PBS; LPS-only group [LG]). PBS (0.1 mL), prednisolone (10 mg/kg in 0.1 mL PBS; prednisolone group [PG]), and artesunate of three concentrations (1, 10, 100 mg/kg; artesunate groups A, B, C [AGA, AGB, AGC]; all in 0.1 mL of PBS) were injected intravenously, respectively, 1 hour after LPS injection. Twenty-four hours after LPS injection, infiltrating cells and protein concentration in the aqueous humor, as well as tumor necrosis factor (TNF)-α, nitric oxide (NO), prostaglandin E2 (PGE2), and monocyte chemoattractant protein (MCP)-1, were measured.

Results.: Rats in AGA did not have significant difference in infiltrating cell number (61.6 × 105 cells/mL; range, 20.0–147.8 cells/mL; P = 0.287), protein concentration (48.0 mg/mL; range, 18.0–101.8 mg/mL; P = 0.349), NO concentration (86.9 μM/L; range, 30.5–192.5 μM/L; P = 0.363), but had significant difference in TNF-α (1144.3 pg/mL; range, 460.0–1840.0 pg/mL; P = 0.038), PGE2 (12.8 ng/mL; range, 4.8–27.2 ng/mL; P = 0.005), and MCP-1 (6136 pg/mL; range, 20.0–147.8 pg/mL; P = 0.009) with those of LG. Artesunate at 10 mg/kg and 100 mg/kg significantly suppressed the infiltrating cells, protein concentration, TNF-α, NO, PGE2, and MCP-1 in the aqueous humor induced by LPS (P = 0.011–0.000).

Conclusions.: Dose-dependent decreases of infiltrating cells, protein concentration, TNF-α, PGE2, NO, and MCP-1 in the aqueous humor by artesunate treatment after LPS injection indicate that artesunate can suppress the inflammation of EIU by inhibiting the production of inflammatory mediators.

Endotoxin-induced uveitis (EIU) is an acute uveal inflammation that is induced by intraocular injection of lipopolysaccharide (LPS). 1 It has been reported that EIU could be regarded as an experimental model for some types of human uveitis, which may be connected with Reiter's syndrome, where Gram-negative bacteria such as Shigella, Salmonella, and Yersinia may play an important role. 2 The inflammation of EIU is characterized by the infiltration of iris and ciliary body by a large number of inflammatory cells, accompanied with cellular exudation into the anterior chamber. Exposure to LPS stimulates cellular inflammatory responses, and releases inflammatory mediators such as cytokines and chemokines, including tumor necrosis factor alpha (TNF-α), 3 interleukin-6 (IL-6), 4 and monocyte chemoattractant protein 1 (MCP-1). 5  
The metabolites of arachidonic acid such as prostaglandin-E2 (PGE2) are now well appreciated. These metabolites could be found at inflammatory sites and lead to local blood flow increases, edema formation, and pain sensitization in the aqueous humor. Furthermore, the generation of reactive oxygen species (ROS) and excessive amounts of nitric oxide (NO) are other responses. 6 In the present study, we investigated eye inflammation by measurement of infiltrating cells, protein concentration, PGE2, TNF-α, NO, and MCP-1 levels in aqueous humor. 
Artesunate, a water-soluble hemisuccinate derivative of artemisinin extracted from the Chinese herb artemisia annua, is a safe and effective antimalarial drug. 7 Artesunate has been reported to possess antitumor 8,9 and anti-angiogenic effects, 10 to decrease serum endotoxin release in sepsis mice, 11 and to have a protective effect on LPS-induced human umbilical vein endothelia-1 cell (HUVEC) activation, which might be associated with the inhibition of TNF-α mRNA expression and a decrease in the secretion of interleukin (IL)-1 beta, IL-6, and IL-8 from TNF-α stimulated rheumatoid arthritis (RA) or fibroblast-like synoviocytes (FLS). 12  
However, whether artesunate is capable of reducing inflammatory cytokine release of EIU in vivo is unknown. In this report, we investigated the effects of artesunate on endotoxin-induced uveitis in rats in vivo and examined the possible molecular mechanisms involved in the inhibition of inflammatory responses released by artesunate. 
Methods
Animals and EIU Induction
Eight-week-old male Long-Evans rats (210–250 g) were used in this study. EIU of rats was induced by footpad injections of 200 μg LPS (100 μg each footpad) from Salmonella typhimurium (Sigma-Aldrich, St. Louis, MO) that had been diluted in 0.1 mL phosphate buffered saline (PBS; pH 7.4). Artesunate was dissolved in 1 mL 5% sodium bicarbonate (to form sodium artesunate) and then diluted in PBS (pH 7.4). In the artesunate group. Twelve rats each were injected intravenously with 1 mg/kg (artesunate group A [AGA]), 10 mg/kg (artesunate group B [AGB]), or 100 mg/kg artesunate (artesunate group C [AGC]) in 0.1 mL PBS (pH 7.4) 1 hour after LPS injection, respectively. PBS (0.1 mL; LPS-only group [LG]) and prednisolone (10 mg/kg in 0.1 mL PBS; prednisolone group [PG]) were injected intravenously in 12 rat,s respectively, 1 hour after LPS injection. In the normal control group (NG), neither LPS nor artesunate or prednisolone was used in the 12 rats. Animals were handled and cared for in accordance with the ARVO Statement for the Use of Animals in Ophthalmic and Vision Research. 
Collection and Preservation of Aqueous Humor
Twenty-four hours after LPS injection, the rats in each group were killed, and the aqueous humor was collected immediately. Briefly, the aqueous humor (15–20 μL/rat) was collected from both eyes of a rat through an anterior chamber puncture using a 50 μL microplus sampler (Shanghai Guangzheng Medical Equipment Co., Ltd., Shanghai, China) under a surgical microscope. Aqueous humor was preserved at −80°C. In this study, each aqueous humor sample was diluted 50-fold with PBS before detection. All final detection results of this experiment represent the original liquid levels before dilution. 
Number of Infiltrating Cells and Protein Concentration in Aqueous Humor
The number of cells infiltrating into the aqueous humor and the protein concentration in the aqueous humor were used as two indicators of the degree of anterior inflammation. For infiltrating cells counting, an aqueous humor sample was suspended in an equal amount of Türk stain solution (Merck, Germany), and the cells were counted by hemocytometer under a light microscope. The number of cells per field (equivalent to 0.1 μL) was manually counted, and the results of four fields from each sample were averaged to calculate the number of cells per microliter. The total protein concentration in an aqueous humor sample was measured using a BCA protein assay reagent kit (Pierce, Rockford, IL). 
Determination of NO, PGE2, TNF-α, MCP-1 Levels in Aqueous Humor
The levels of TNF-α, PGE2, and MCP-1 concentration in aqueous humor were detected by ELISA (R&D Systems, Minneapolis, MN) according to the manufacturer's instructions. All ELISA assays were performed in duplicate. The level of NO in the aqueous humor was measured with a total nitrite colorimetric assay kit (Sigma) according to the manufacturer's instructions. One hundred μL diluted aqueous humor sample was mixed with 100 μL Griess reagent for 10 minutes, then the absorbance of the mixture was measured in a microplate reader at 550 nm. Finally, the concentration of nitrite in the aqueous humor was detected with reference to a sodium nitrite standard curve. 
Statistical Analysis
All statistical analyses were performed using computer software (SPSS 14.0; SPSS Inc., Chicago, IL). The results were expressed as median and range, and compared using the Mann–Whitney test. P < 0.05 was considered statistically significant. 
Results
Number of Inflammatory Cells in Aqueous Humor
In the normal control group (NG), infiltrating cells were not detected in the aqueous humor. In the LPS group (LG), the number of inflammatory cells that had infiltrated into the aqueous humor 24 hours after LPS injection was 72.3 × 105 cells/mL (range,17.9–230.1 × 105 cells/mL). Rats treated with artesunate of 1 mg/kg (AGA) did not have significant difference in the number of infiltrating inflammatory cells (AGA; 61.6 × 105 cells/mL; range, 20.0–147.8 cells/mL; P = 0.287) with that of LG. Rats treated with artesunate of 10 mg/kg (AGB) or 100 mg/kg (AGC) showed significantly reduced number of infiltrating inflammatory cells (AGB: 25.4 × 105 cells/mL; range 8.3–60.0 cells/mL; P = 0.003; AGC: 17.0 × 105 cells/mL; range, 5.3–46.5 cells/mL; P = 0.001). Rats treated with prednisolone (PG) showed a significantly reduced number of infiltrating inflammatory cells (19.1 × 105 cells/mL; range, 6.0–52.3 cells/mL; P = 0.002) compared with LG (Fig. 1A). 
Figure 1.
 
The infiltrating cells number, protein concentration, TNF-α, PGE2, NO, and MCP-1 concentrations in the aqueous humor in various groups. (A) Infiltrating cells number; (B) protein concentration; (C) level of TNF-α; (D) content of NO; (E) PGE2 concentration; (F) MCP-1 concentration.
Figure 1.
 
The infiltrating cells number, protein concentration, TNF-α, PGE2, NO, and MCP-1 concentrations in the aqueous humor in various groups. (A) Infiltrating cells number; (B) protein concentration; (C) level of TNF-α; (D) content of NO; (E) PGE2 concentration; (F) MCP-1 concentration.
Protein Concentration in Aqueous Humor
In NG and LG, protein concentrations in the aqueous humor were 3.3 mg/mL (range, 1.2–6.9 mg/mL) and 55.8 mg/mL (range, 17.1–143.5 mg/mL), respectively. In AGB and AGC, protein concentrations were significantly lower than that of LG (AGB: 28.7 mg/mL; range, 10.4–62.6 mg/mL; P = 0.011; AGC: 21.2 mg/mL; range, 7.8–49.8 mg/mL; P = 0.002). Artesunate of 1 mg/kg only slightly reduced protein concentration (AGA: 48.0 mg/mL; range, 18.0–101.8 mg/mL; P = 0.349) without significant difference compared to LG. Rats in PG showed a significantly reduced protein concentration (23.3 mg/mL; range, 8.5–54.8 cells/mL; P = 0.005) compared with rats in LG; Fig. 1B). 
Levels of TNF-α in Aqueous Humor
In NG, TNF-α was not detected in the aqueous humor. In LG, TNF-α level in the aqueous humor was 1592.0 pg/mL (range, 688.0–2851.2 pg/mL). In AGA, AGB, and AGC, TNF-αs were significantly lower than that of LG (AGA: 1144.3 pg/mL; range, 460.0–1840.0 pg/mL; P = 0.038; AGB: 552.5 pg/mL; range, 179.7–1303.5 pg/mL; P = 0.000; AGC: 318.0 pg/mL; range, 116.4–746.7 pg/mL; P = 0.000). Compared with rats in LG, rats in PG showed a significantly reduced TNF-α (371.0 pg/mL; range, 158.3–871.2 pg/mL; P = 0.000); Fig. 1C). 
Content of NO in Aqueous Humor
In NG and LG, NO concentrations in the aqueous humor were 6.6 μM/L (range, 2.3–14.6 μM/L) and 97.5 μM/L (range, 27.0–277.2 μM/L), respectively. In AGB and AGC, NO concentrations were significantly lower than that of LG (AGB: 35.1 μM/L; range, 12.2–79.4 μM/L; P = 0.002; AGC: 15.9 μM/L; range, 5.8–37.3 μM/L; P = 0.000). Artesunate of 1 mg/kg only slightly reduced NO concentration without significance (AGA: 86.9 μM/L; range, 30.5–192.5 μM/L; P = 0.363 compared with LG). Compared with rats in LG, rats in PG showed a significantly reduced NO concentration (17.0 μM/L; range, 5.8–42.9 μM/L; P = 0.000; Fig. 1D). 
PGE2 Concentration in Aqueous Humor
In NG and LG, PGE2 in the aqueous humor were 1.6 ng/mL (range, 0.7–2.5 ng/mL) and 27.4 ng/mL (range, 8.4–70.3 ng/mL), respectively. In rats treated with artesunate, PGE2 were significantly lower than that of LG (AGA: 12.8 ng/mL; range, 4.8–27.2 ng/mL; P = 0.005; AGB: 6.1 ng/mL; range, 2.2–13.4 ng/mL; P = 0.000; AGC: 4.5 ng/mL; range, 1.6–10.5 ng/mL; P = 0.000). Compared with rats in LG, rats in PG showed a significantly reduced PGE2 (4.2 ng/mL; range, 1.6–10.0 ng/mL; P = 0.000; Fig. 1E). 
MCP-1 Concentration in Aqueous Humor
In NG and LG, MCP-1 in the aqueous humor were 8.8 pg/mL (range, 2.8–21.4 pg/mL) and 134.7 pg/mL (range, 33.3–428.8 pg/mL), respectively. In rats treated with artesunate, MCP-1 were significantly lower than that of LG (AGA: 6136 pg/mL; range, 20.0–147.8 pg/mL; P = 0.009; AGB: 24.3 pg/mL; range, 7.9–57.4 pg/mL; P = 0.000; AGC: 11.7 pg/mL; range, 3.7–31.9 pg/mL; P = 0.000). Compared with rats in LG, rats in PG showed a significantly reduced MCP-1 (10.6 pg/mL; range, 3.3–29.0 pg/mL; P = 0.000; Fig. 1F). 
Discussion
In the present study, we investigated the effect of artesunate on EIU in rats. Decreases of infiltrating cells, protein concentration, TNF-α, PGE2, NO, and MCP-1 contents in the aqueous humor by artesunate treatment after LPS injection indicate that artesunate can suppress the inflammation of EIU by inhibiting the production of inflammatory mediators dose-dependently. Its anti-inflammatory effect on EIU was comparable to the effect of prednisolone used in similar dose. 
We chose the infiltrating cells number and protein concentration in the aqueous humor as the indicators of the degree of anterior inflammation. We found artesunate at 10 mg/kg and 100 mg/kg significantly suppressed the infiltrating cells and protein concentration. The exact mechanism by which artesunate inhibits EIU is yet to be studied; however, our results support the findings that artesunate suppresses EIU by blocking the local TNF-α production. TNF-α is a cytokine involved in systemic inflammation, cell apoptosis, cell death, and immune cell regulation. It is a member of a group of cytokines that stimulate the acute phase reaction of inflammation. 13 In this study, TNF-α concentrations in the aqueous humor of artesunate treated groups were significantly decreased. In the report of Gumede, 14 artesunate produced dose-dependent inhibition of ConA-induced TNF-α release of splenocytes from healthy C57BL/6 mice in an in vitro system, which is in accordance with our results. 
Nitric oxide is generated by phagocytes (monocytes, macrophages, and neutrophils). It is well known that oxidative stress is the major factor in the course of local inflammation and tissue damage during inflammatory process. In the human immune response, phagocytes are armed with inducible nitric oxide synthase (iNOS), which is activated by tumor necrosis factor. NO plays an important role in endotoxemia and inflammatory conditions. 15 As a member of oxidative stress factors, nitric oxide secreted is toxic to cells for DNA damage and degradation of iron sulfur centers into iron ions and iron-nitrosyl compounds were found. 16 In this study, elevated levels of nitrite would be related to increased NO generation in the inflamed eye because NO is rapidly oxidized to nitrite and then to nitrate and the Griess reagent can only assay for nitrite. Also, some of the NO can combine with reactive oxygen to become peroxynitrite, which is also rapidly lost. Our results indicated that artesunate at 10 mg/kg and 100 mg/kg suppressed the NO level (actually, level of nitrite) in the aqueous humor induced by LPS significantly. The results of this study showed that artesunate suppresses the expression of NO in EIU rats. 
PGE-2 is one of the prostaglandins, a group of hormone-like substances involved in various functions such as contraction and relaxation of smooth muscle, dilation and constriction of blood vessels, blood pressure control, and inflammation modulation. 17 When tissues are exposed to different physiological and pathologic stimuli, arachidonic acid is liberated from membrane phospholipids by phospholipase A2 and is transformed to PGH2 by prostaglandin H synthase (PGHS; also known as cyclooxygenase [COX]). PGH2 is the common substrate for PGD2, PGE2, prostacyclin (PGI2), and tromboxane (TXA2). PGE2 plays important roles in various biological activities such as neuronal function, female reproduction, vascular hypertension, tumor angiogenesis, renal function, and inflammation. In our study, artesunate suppressed PGE2 levels markedly. Artesunate at 1 mg/kg, 10 mg/kg, and 100 mg/kg significantly suppressed PGE2 in the aqueous humor induced by LPS. 
MCP-1 recruits monocytes, memory T cells, and dendritic cells to sites of tissue injury and infection. 18,19 It is a monomeric polypeptide located on chromosome 17 in humans, with a molecular weight of approximately 13 kDa. MCP-1 has monocyte activation, demonstrated in human eyes during acute anterior uveitis and described in the rat EIU model. 20 Data of this experiment showed that artesunate can decrease MCP-1 concentration in the aqueous humor, suggesting that artesunate expresses its anti-inflammatory action by affecting monocytes, or memory T cells, or dendritic cells recruitment. 
Since endotoxin-induced uveitis is the result of a systemic response to an endotoxin injection distant to the eye and that the artesunate itself was systemically injected. The results of this study showed that artesunate has a significant effect on endotoxin-induced inflammation, which then suppresses EIU. 
Footnotes
 Disclosure: X.-Q. Wang, None; H.-L. Liu, None; G.-B. Wang, None; P.-F. Wu, None; T. Yan, None; J. Xie, None; Y. Tang, None; L.-K. Sun, None; C. Li, None
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Figure 1.
 
The infiltrating cells number, protein concentration, TNF-α, PGE2, NO, and MCP-1 concentrations in the aqueous humor in various groups. (A) Infiltrating cells number; (B) protein concentration; (C) level of TNF-α; (D) content of NO; (E) PGE2 concentration; (F) MCP-1 concentration.
Figure 1.
 
The infiltrating cells number, protein concentration, TNF-α, PGE2, NO, and MCP-1 concentrations in the aqueous humor in various groups. (A) Infiltrating cells number; (B) protein concentration; (C) level of TNF-α; (D) content of NO; (E) PGE2 concentration; (F) MCP-1 concentration.
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