Thalidomide Attenuates Airway Hyperresponsiveness and Eosinophilic Inflammation in a Murine Model of Allergic Asthma

Abstract

Bronchial asthma has clinical manifestations, which include variable degrees of airflow obstruction, airway hyperresponsiveness, and airway inflammation.1) The inflammatory process in asthma is dominated by T helper-2 (Th2) cells which produce interleukin-4 (IL-4), IL-5, and IL-13. 2)Thalidomide was synthesized in 1954 by CIBA Pharmaceutical Company, and prescribed as a sedative, tranquiliser, and antiemetic for morning sickness. Because the highest risk for teratogenicity arose when the drug was taken between weeks 3 and 8 after conception, it was withdrawn from many countries including Japan. However, the drug was revived as an effective treatment for erythema nodosum leprosum lesions in 1965. The U.S.A. Food and Drug Administration approved it for this indication in 1998. 3)Thalidomide, which is metabolized by cytochrome P450, 3,4) has a wide range of pharmaceutical and biological activities. Currently, clinical investigations of thalidomide have been conducted in patients with diverse diseases, including multiple myeloma, rheumatoid arthritis, and human immunodeficiency virus infection. 5,6) The beneficial pharmacological effects elicited by thalidomide include anti-angiogenic, anti-viral, anti-inflammatory, and immunomodulatory activities, 5,7) although the precise mechanisms are unknown.8)It has been reported that thalidomide administered with albendazole suppressed eosinophilic infiltration in cerebrospinal fluid in a murine vermination model. 9) However, little is known about the effect of thalidomide on the airway hyperresponsiveness and eosinophilic inflammation in allergic asthma.The purpose of this study was to investigate the effects of thalidomide on airway inflammation and hyperresponsiveness in a murine model of allergic asthma. We hypothesized that thalidomide would have anti-inflammatory effects in allergic asthma. MATERIALS AND METHODS Sensitisation and Challenge with OvalbuminSevenweek-old female BALB/c mice (SLC, Shizuoka) were purchased and maintained in our specific pathogen-free animal facility. The mice were maintained at room temperature (23Ϯ2°C) and humidity (55Ϯ10%) in an air-conditioned room. They were fed a standard laboratory diet and given water ad libitum. They were sensitised by an intraperitoneal injection with 100 mg ovalbumin (OVA) and 1 mg alum in 200 ml of phosphate-buffered saline (PBS) on day 0, and then by a hypodermic injection with 10 mg OVA in 20 ml of PBS on day 14. They were then placed in an acrylic chamber and challenged with 1% OVA for 10 min daily by a nebulizer (IS-2; Paris, Starnberg, Germany) between days 21 and 25. 10)Saline was used in place of OVA during the sensitisation and challenge stages of the protocol as a negative control. All protocols described in this study were approved by the Animal Ethics Committee of Nagoya University Graduate School of Medicine, Nagoya, Japan.Treatment Protocols For in vivo animal experiments, thalidomide (30, 100, or 300 mg/kg) was suspended in 0.5% carboxymethylcellulose, vortexed for 5 min, and administered orally via a ...

Inhibition of Airway Contraction and Inflammation by Pomalidomide in a Male Wistar Rat Model of Ovalbumin-induced Asthma

“…Airway hyperresponsiveness was significantly decreased in pomalidomide (0.8 mg/mL) treatment as compared with pomalidomide (0.4 mg/mL).In addition, according to the previous studies, there is a positive relationship between the thickness of the ASM layer with airway responsiveness also between the regulator of inflammatory cells and the level of airway hyperresponsiveness. 4,38 In addition, histological H&E staining and Masson's trichrome analysis of the airways tissues displayed that there was additional deposition of collagen in the asthmatic rat administered with the pomalidomide treatment. Several lines of evidence demonstrated too much production of mucus and collagen and thus augmentation the thickness of airway wall as one of the important symptoms that occur in asthma.…”

Anti-inflammatory aminoacetylenic isoindoline-1,3-dione derivatives modulate cytokines production from different spleen cell populations

“…The suppression activity of all ZM compounds against LPS-induced TNF-α production is mainly attributed to the isoindoline1,3-dione moiety in the ZM compounds. It has been shown that phthalimide (isoindoline1,3-dione) and thalidomide analogues do inhibit synthesis of TNF-α from LPS-activated macrophages through impairing the intracellular LPS signaling such as NF-kB activation, MyD88 expression and p38 phosphorylation [28][29][30][31]. Furthermore, since oral administration 20 mg/kg of ZM compounds showed antiinflammatory in carrageenan-induced rat paw edema within hours post administration [9] and modulated LPS-induced cytokine in mice spleen, these ZM compounds are readily bioavailable in blood and suggest proper pharmacokinetic properties for anti-inflammatory drugs.…”

Effect of Hyssopus officinalis L. on inhibiting airway inflammation and immune regulation in a chronic asthmatic mouse model

“…A minimum of ten airways were observed in each section. The PAS positively-stained cells were counted and scored using previously described methods ( 16 , 17 , 18 ). The scoring method used was as follows: 0, <5%; l, 5–25%; 2, 25–50%; 3, 50–5%; and 4, >75% PAS positively-stained cells.…”