Attenuation of airway inflammation by simvastatin and the implications for asthma treatment: is the jury still out?

Although some studies have explained the immunomodulatory effects of statins, the exact mechanisms and the therapeutic significance of these molecules remain to be elucidated. This study not only evaluated the therapeutic potential and inhibitory mechanism of simvastatin in an ovalbumin (OVA)-specific asthma model in mice but also sought to clarify the future directions indicated by previous studies through a thorough review of the literature. BALB/c mice were sensitized to OVA and then administered three OVA challenges. On each challenge day, 40 mg kg(-1) simvastatin was injected before the challenge. The airway responsiveness, inflammatory cell composition, and cytokine levels in bronchoalveolar lavage (BAL) fluid were assessed after the final challenge, and the T cell composition and adhesion molecule expression in lung homogenates were determined. The administration of simvastatin decreased the airway responsiveness, the number of airway inflammatory cells, and the interleukin (IL)-4, IL-5 and IL-13 concentrations in BAL fluid compared with vehicle-treated mice (P<0.05). Histologically, the number of inflammatory cells and mucus-containing goblet cells in lung tissues also decreased in the simvastatin-treated mice. Flow cytometry showed that simvastatin treatment significantly reduced the percentage of pulmonary CD4(+) cells and the CD4(+)/CD8(+) T-cell ratio (P<0.05). Simvastatin treatment also decreased the expression of the vascular cell adhesion molecule 1 and intercellular adhesion molecule 1 proteins, as measured in homogenized lung tissues (P<0.05) and human epithelial cells. The reduction in the T cell influx as a result of the decreased expression of cell adhesion molecules is one of the mechanisms by which simvastatin attenuates airway responsiveness and allergic inflammation. Rigorous review of the literature together with our findings suggested that simvastatin should be further developed as a potential therapeutic strategy for allergic asthma.

Serum specific IgG response to toluene diisocyanate-tissue transglutaminase conjugate in toluene diisocyanate-induced occupational asthmatics.

BACKGROUND: Tissue transglutaminase (tTG) is a post-translational modifying enzyme located in airway epithelial cells. A potential contribution of serum specific IgG (sIgG) to tTG in airway inflammation of toluene diisocyanate (TDI)-induced occupational asthma (OA) has been suggested. OBJECTIVE: To prepare a TDI-tTG conjugate and detect serum specific antibodies in sera of patients with TDI-OA to understand this mechanism. METHODS: Ninety-nine patients with TDI-OA, 76 asymptomatic exposed controls, 208 patients with non-OA, and 74 unexposed controls were enrolled for this study. The TDI-tTG conjugate was prepared and confirmed by a native gel. Serum sIgG and/or sIgE antibodies to tTG, TDI-tTG, TDI conjugated to human serum albumin, cytokeratin 19, and serum cytokine levels, such as interleukin-8, transforming growth factor-ß1, and tissue inhibitor of metalloproteinase-1, were measured by enzyme-linked immunosorbent assay. The level of interleukin-8 produced from airway epithelial cells (A549) treated with tTG was evaluated to investigate the inflammatory effect of tTG and TDI-tTG. RESULTS: In the TDI-OA group, the prevalence of serum sIgG to TDI-tTG (17.2%) was higher than that of sIgG to tTG (11.1%), which were significantly higher than those of the 3 control groups (P < .05 for all groups). TDI-exposed subjects with high levels of serum sIgG to TDI-tTG had a high prevalence of sIgG to cytokeratin 19 and higher serum levels of transforming growth factor-ß1 and tissue inhibitor of metalloproteinase-1. The tTG and TDI-tTG dose-dependently increased interleukin-8 production from A549 cells. CONCLUSION: These findings suggest that TDI exposure in the workplace binds to tTG to form a conjugate that can induce serum sIgG antibody production, airway inflammation, and airway remodeling in patients with TDI-OA.

Endogenous expression of interleukin-4 regulates macrophage activation and confines cavity formation after traumatic spinal cord injury.

Traumatic spinal cord injury (SCI) triggers inflammatory reactions in which various types of cells and cytokines are involved. Several proinflammatory cytokines are up-regulated after SCI and play crucial roles in determining the extent of secondary tissue damage. However, relatively little is known about antiinflammatory cytokines and their roles in spinal cord trauma. Recent studies have shown that an antiinflammatory cytokine, interleukin-4 (IL-4), is expressed and exerts various modulatory effects in CNS inflammation. We found in the present study that IL-4 was highly expressed at 24 hr after contusive SCI in rats and declined thereafter, with concurrent up-regulation of IL-4 receptor subunit IL-4alpha. The majority of IL-4-producing cells were myeloperoxidase-positive neutrophils. Injection of neutralizing antibody against IL-4 into the contused spinal cord did not significantly affect the expression levels of proinflammatory cytokines such as IL-1beta, IL-6, and tumor necrosis factor-alpha or other antiinflammatory cytokines such as IL-10 and transforming growth factor-beta. Instead, attenuation of IL-4 activity led to a marked increase in the extent of ED1-positive macrophage activation along the rostrocaudal extent at 7 days after injury. The enhanced macrophage activation was preceded by an increase in the level of monocyte chemoattractant protein-1 (MCP-1/CCL2). Finally, IL-4 neutralization resulted in more extensive cavitation at 4 weeks after injury. These results suggest that endogenous expression of antiinflammatory cytokine IL-4 regulates the extent of acute macrophage activation and confines the ensuing secondary cavity formation after spinal cord trauma.

Using pCIN-mIL-4 DNA vector to express mRNA and protein and to improve herpes simplex virus-induced Behcet's disease symptoms in mice.

Behcet's disease (BD) is a chronic, recurrent, inflammatory, multisystemic disorder characterized primarily by vasculitis. The etiopathogenesis of BD involves immunogenetics, infectious organisms (streptococcus, herpes simplex virus), immunoregulation and vascular dysfunctions. We previously found that immunoregulation associated with viral infection was important to the development of BD-like symptoms. Recently, we demonstrated that Th2 cytokines up-regulated by Th2 adjuvant were efficient in attenuating or improving these BD-like symptoms. In order to directly augment IL-4 expression, a DNA vector (pCIN-mIL-4) was administered to BD-like mice using the Helios gene gun system. Two injections of the pCIN-mIL-4 vector, spread over 2 weeks, attenuated or improved the mucocutaneous symptoms of 10 out of 12 BD-like mice in our study. The improved mucocutaneous symptoms were crust in face, ulcer in mouth, scruff, back, genital and erythema. This improvement also correlated with induction of IL-4 mRNA in lymph nodes, protein in serum and intracellular IL-4 staining in splenocytes. Normal control mice (n = 10) injected with the pCIN-mIL-4 vector expressed IL-4 mRNA and showed more splenocytes stained with anti-IL-4 antibody (5.77 +/- 0.92%) than did mice injected with the pCIN control vector (3.34 +/- 0.25%; p = 0.02). These findings indicate that an IL-4 DNA vector could be used to express mRNA and protein in vivo and further suggest that such an IL-4 DNA vector could be used as a therapeutic treatment in recurrent inflammation shifted to T helper type 1 cytokine production.

Combined treatment with colchicine and Herba Taraxaci (Tarazacum mongolicum Hand.-Mazz.) attenuates Behcet's disease-like symptoms in mice and influences the expressions of cytokines.

Herbal medicine, Herba Taraxaci (Tarazacum mongolicum Hand.-Mazz.), was administered to mice with Behcet's disease (BD)-like symptoms induced by herpes simplex virus (HSV). BD is a chronic recurrent inflammatory disease. Herba Taraxaci (6 mg) was administered alone or in combination with 2 microg of colchicine to BD-like mice. Colchicine is a drug that is widely used as a medication for BD patients. The water extracts of Herba Taraxaci were administered orally once per day for 20 days. Eighty percent (8 of 10) of mice treated with Herba Taraxaci combined with colchicine showed improvement in mucocutaneous symptoms compared to 0% (0 of 10) of the nontreated group and 30% (3 of 10) treated with colchicine alone. Cytokine expression in spleen tissue collected from treated mice was analyzed by RT-PCR and FACS. Treatment with Herba Taraxaci induced IL-4 mRNA, and spleen from mice receiving the combined treatment (Herba Taraxaci and colchicines) showed an increased number of splenocytes staining with anti-IL-10 (46.8+/-6.80) compared to Herba Taraxaci (35.4+/-2.17) (p<0.05) or colchicine alone (26.2+/-4.47) (p<0.001). These results suggest that the Herba Taraxaci may be an effective complementary agent in the treatment of BD.