Fig. 1 Photographs of a lung specimen in the control (a), sensitized (b), and low (c) and high (d) doses ofN. sativa extract treated sensitized guinea pigs
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Pharmaceutical Research Centre, Department of Physiology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
Department of Physiology, Tabriz University of Medical Sciences, Tabriz, Iran
Tuberculosis and Lung Research Centre, Tabriz University of Medical Sciences, Tabriz, Iran
Drug Applied Research Centre, Tabriz University of Medical Sciences, Tabriz, Iran
1.Pharmaceutical Research Centre, Department of Physiology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
2.Department of Physiology, Tabriz University of Medical Sciences, Tabriz, Iran
3.Tuberculosis and Lung Research Centre, Tabriz University of Medical Sciences, Tabriz, Iran
4.Drug Applied Research Centre, Tabriz University of Medical Sciences, Tabriz, Iran
5.Department of Pathology, Islamic Azad University, Tabriz, Iran
6.Zakaria Research Center, Islamic Azad University, Mashhad, Iran
Published: 2011-03 ,
Received: 01 May 2010 ,
Revised: 18 February 2011 ,
Accepted: 29 September 2010
Cite this article
Mohammad-Hossein Boskabady, Rana Keyhanmanesh, Saeed Khameneh, et al. Potential immunomodulation effect of the extract of
Mohammad-Hossein Boskabady, Rana Keyhanmanesh, Saeed Khameneh, et al. Potential immunomodulation effect of the extract of
Pharmaceutical Research Centre, Department of Physiology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
Several different pharmacological effects have been described for Nigella sativa (Siah-Daneh), including an anti-inflammatory effect. In the present study, the effect of the extract of N. sativa on lung pathology and blood interleukin-4 (IL-4) and interferon-γ (IFN-γ) of sensitized guinea pigs was examined. Three groups (n=8 for each group) of guinea pigs sensitized to ovalbumin (OA) were given drinking water alone, and drinking water containing low and high concentrations of the plant extract, respectively. The animals of the control group (n=8) were treated with saline instead of OA and were given drinking water. The pathological changes of the lung, including infiltration of eosinophils and lymphocytes, local epithelial necrosis, the presence of oedema, thickening of the basement membrane, smooth muscle layer hypertrophy, mucosal secretion, and the presence of mucosal plug, and blood IL-4 and IFN-γ of sensitized guinea pigs were evaluated. The lungs of the sensitized group showed significant pathological changes (P<0.001). Blood IL-4 and IFN-γ were increased in sensitized animals compared to the controls (P<0.01 and P<0.001, respectively). Treatment of sensitized animals with the extract led to a significant decrease in pathological changes of the lung (P<0.01 to P<0.001), except for the oedema in the sensitized group treated with low concentration of the extract, but an increased IFN-γ. These results confirm a preventive effect of N. sativa extract on lung inflammation of sensitized guinea pigs.
Nigella sativa;
Asthma;
Sensitization;
Inflammation;
Cytokine
Asthma is an inflammatory disorder of the airways (Busse et al.,
The pathological changes of the respiratory system include: (1) thickening of the airway wall (subepithelial basement membrane), (2) infiltration of inflammatory cells in the lung parenchyma involving mainly eosinophils, as well as lymphocytes and mast cells, (3) increased smooth muscle mass, (4) mucous gland hypertrophy and vascular congestion (leading to edema or swelling of the airway wall), and (5) collagen deposition in the basement membrane leading to a thickened airway wall and markedly reduced airway caliber, airway epithelial shedding, epithelial desquamation and necrosis, and mucus plugs occluding medium and small bronchi (Barrios et al.,
There are different asthma phenotypes including: (1) symptom-based: age at onset, natural history, and severity; (2) defined by triggers: allergic vs. non-allergic, exercise induced, viral triggered vs. multi-triggered wheeze. The most important asthma phenotypes are intrinsic (non-allergic) and extrinsic (allergic) asthma, classified on the basis of positive skin tests to common allergens or the presence of antibodies in the blood (Handoyo and Rosenwasser,
Any T cell that has the ability to suppress the immune response is known as a regulatory T cell. These cells are classified as natural T regulatory cells and induced or adaptive T regulatory cells. The natural T regulatory (nTreg) cells are self antigen specific CD4+ T cells that express CD25 in high levels and Foxp3. The induced or adaptive T regulatory (aTreg) cells are the type 1 regulatory T (Tr1) cells and T helper 3 (Th3) cells. The Tr1 cells have both Th1 and Th2 phenotypic markers (Nandakumar et al.,
In allergic phenotypes of asthma, two principal immune mechanisms affecting airway obstruction depend on Th1 and Th2 cells. The Th2 cells secrete highly characteristic cytokines including IL-4, IL-5, IL-9, and IL-13, all of which contribute to manifestations of allergic inflammation and disease (Cohn et al.,
The anti-inflammatory activities of both systemic and local administrations of essential oil from Nigella sativa have been demonstrated (Hajhashemi et al.,
The therapeutic effect of the oil of this plant on patients with allergic diseases (allergic rhinitis, bronchial asthma, atopic eczema) has also been documented (Kalus et al.,
N. sativa is widely used in traditional medicine, including in the treatment of respiratory disorders such as tightness and asthma (Ave-Sina,
N. sativa was collected from Torbat Heydarieh (northeast Iran), and its seeds were dried at room temperature in the absence of sunlight. The plant was identified by botanists in the herbarium of the Ferdowsi University of Mashhad; and the specimen number of the plant is 293-0303-1. The hydro-ethanolic extract was prepared as follows: 500 g of chopped N. sativa seeds were mixed with 450 ml 50% ethanol for 72 h at 40 °C and the solution was separated by maceration method. This process was repeated three times. The solution was dried by rotary evaporator at 50 °C.
Thirty two adult Dunkin-Hartley guinea pigs (400–700 g, 13 females and 17 males) were used throughout the study. They were allowed to get into the habit of the new situation for 10 d. The animals were group-housed in individual cages in climate-controlled animal quarters and given water and food ad libitum, while a 12-h on/12-h off light cycle was maintained. After 10 d, sensitization of animals to ovalbumin (OA) was performed using the method previously described (McCaig,
The study was performed in control animals (C group, treated the same as the sensitized group, but normal saline was used instead of OA and they were given drinking water alone) and three different groups of sensitized animals, which were given various types of drinking water during the sensitization period as follows (n=8 for each group): (1) drinking water alone (S group, sensitized group), (2) drinking water containing 1.25 g/L N. sativa extract (S+LNS group), (3) drinking water containing 2.50 g/L N. sativa extract (S+HNS group).
Guinea pigs were sacrificed by means of cervical dislocation, and the lungs and tracheas were removed and placed into the 10% (v/v) buffered formalin (Merck, Germany). Seven days later, tissues were dried using Autotecnicon apparatus by passage of tissues through 70%–100% ethanol and xylol to clear the tissues, and paraffin blocks of the tissues were prepared. The specimens were cut in 4-µm slices and were stained with hematoxylin-eosin (H&E). The tissues were then evaluated under a light microscope.
The pathologic changes in the lung of sensitized and treated groups with the extract included infiltration of eosinophils and lymphocytes, local epithelial necrosis, the presence of oedema, thickening of basement membrane, smooth muscle layer hypertrophy, mucosal secretion, and the presence of mucosal plug. The pathological changes were scored according previous studies (Boskabady et al.,
A total of 5 ml peripheral blood was obtained immediately after sacrificing the animals and placed at room temperature for 1 h. The samples were then centrifuged at 3 500×g at 4 °C for 10 min. The supernatant was collected and immediately stored at 70 °C until analyzed. Finally blood IL-4 and IFN-γ were measured using the enzyme-linked immunosorbent assay (ELISA) Sandwich method.
The data are expressed as mean±standard error of the mean (SEM). Comparisons between sensitized animals and the control, between two groups treated with different doses of the extract, and between extract treated and sensitized guinea pigs were performed using unpaired t-test. Significance was accepted at P<0.05.
All pathological changes were significantly higher in the S group than in the control group (P<0.001 for all cases; Figs.
Fig. 1 Photographs of a lung specimen in the control (a), sensitized (b), and low (c) and high (d) doses ofN. sativa extract treated sensitized guinea pigs
The photograph of the sensitized group showed local epithelial necrosis (N), mucosal plug (P), severe eosinophil infiltration (EI), and lymphocyte infiltration (LI), but these changes were improved in the treated animals with both doses of the extract. Magnification: (a, b, c) 10×40; (d) 10×60
Fig. 2 Scores of pathological changes in the control (C), sensitized (S), and low and high doses of N. sativa extract treated sensitized (S+LNS and S+HNS, respectively) guinea pigs
The pathological changes include eosinophil infiltration (a), lymphocyte infiltration (b), epithelial necrosis (c), and mucosal plug (d) of the lung. Values are expressed as mean±SEM (n=8 for each group). Statistical differences between the control and other groups: NS Non-significant difference, ++P<0.01, +++P<0.001; Statistical differences between the extract-treated and sensitized groups: *P<0.05, **P<0.01, ***P<0.001
Pretreatment with both concentrations of N. sativa extract caused a significant improvement in all pathological changes of the sensitized animals (P<0.01 to P<0.001), except for oedema in the treated group with a low concentration of N. sativa extract (Fig.
Pathological finding | Score | |||
---|---|---|---|---|
C | S | S+LNS | S+HNS | |
Eosinophil infiltration | 0.28±0.14 | 2.62±0.15 | 0.96±0.11 | 0.81±0.09 |
Lymphocyte infiltration | 0.62±0.11 | 2.06±0.24 | 0.84±0.13 | 0.71±0.11 |
Local epithelial necrosis | 0.12±0.09 | 2.43±0.22 | 1.62±0.15 | 1.47±0.18 |
Mucosal plug | 0.15±0.10 | 2.37±0.15 | 1.34±0.17 | 1.22±0.17 |
Oedema | 0.65±0.11 | 1.90±0.06 | 1.62±0.12 | 1.47±0.12 |
Basement membrane thickening | 0.03±0.03 | 1.68±0.20 | 0.93±0.10 | 0.87±0.15 |
Muscular hypertrophy | 0.03±0.03 | 2.90±0.06 | 2.31±0.18 | 1.90±0.12 |
Mucosal secretion | 0.62±0.11 | 1.75±0.13 | 0.90±0.04 | 0.84±0.04 |
Values are presented as mean±SEM (n=8 for each group). There was not statistical difference between effects of two concentrations of the extract
The lung pathological changes in the animals treated with the low concentration of N. sativa extract were also not significantly greater than those of the animals treated with high concentration (Table
The mean value of blood IL-4 of the S group [(4.90±0.15) pg/ml] was significantly higher than that of the C group [(3.52±0.37) pg/ml] (P<0.01; Fig.
Fig. 3 Blood levels of IL-4 (a) and IFN-γ (b) in the control (C), sensitized (S), and low and high doses ofN. sativa extract treated sensitized (S+LNS and S+HNS, respectively) guinea pigs
Values are presented as mean±SEM (n=8 for each group). Statistical differences between the control and other groups: NS Non-significant difference, ++P<0.01, +++P<0.001; Statistical differences between the extract-treated and sensitized groups: *P<0.05, **P<0.01, ***P<0.001. There was no statistical difference between the effects of two concentrations of the extract
The mean value of blood IFN-γ of the S group [(3.86±0.21) pg/ml] was significantly higher than that of the C group [(1.21±0.13) pg/ml] (P<0.001; Fig.
Blood IL-4 level in the animals treated with the low concentration of the extract was not significantly greater than that in the high concentration group. However, blood IFN-γ level in the treated group with low concentration of the extract was lower than that in the high concentration group (Fig.
In the present study, the preventive effects of long-term administration of hydro-ethanolic extract of N. sativa (during sensitization period, i.e., (32±1) d) on pathological changes of the lung and the level of cytokines (IL-4 and IFN-γ) were examined. The results showed increased IL-4 and IFN-γ in sensitized guinea pigs. Histological evaluations of the lung tissues also showed the infiltration of eosinophils and lymphocytes in the lung parenchyma, epithelial damage, mucosal plug, oedema, basement membrane thickening, and muscular hypertrophy in sensitized guinea pigs, similar to the results of previous studies (Boskabady and Kiani,
Pretreatment of sensitized animals with N. sativa extract prevented increased IL-4 and almost all lung histological changes of sensitized guinea pigs. In addition, pretreatment of sensitized animals with N. sativa increased IFN-γ. There were no significant differences between the preventive effects of different doses of N. sativa extract on lung pathologic changes.
The preventive effects of long-term administration of the extract of N. sativa on pathological changes of the lungs in the sensitized animals are perhaps due to its suppressing effects on inflammation. In fact, the inhibitory effects of the essential oil of N. sativa have been shown in both cyclooxygenase and 5-lipoxygenase pathways of arachidonic acid metabolism and also in membrane lipid peroxidation (Houghton et al.,
One proposed mechanism of action for the extract of N. sativa on cytokines and pathological changes of the sensitized guinea pigs is its regulation of Th1 and Th2 balance. It has been shown that the inflammatory condition, such as airway inflammation, seen in asthma is regulated by the balance of two T helpers, Th1, and Th2 cells. Th2 cells promote the activities of macrophages and regulate the pro-inflammatory response, whereas Th1 cells inhibit the activity of Th2 (Romagnani,
Another possible mechanism of action for N. sativa may be due to its antioxidant effect. In fact, the antioxidant effects of N. sativa (Burits and Bucar,
Although Büyüköztürk et al. (
The study of Talatt Abbas et al. (
The effect of N. sativa oil on murine cytomegalovirus infection showed the most striking inhibition of virus titers in the spleen and liver and an increase in the serum level of IFN-γ (Salem and Hossain,
The bronchodilatory (Boskabady et al.,
The goal of the treatment of asthma is reducing airway inflammation with anti-inflammatory drugs. However, the available anti-inflammatory drugs for asthma do not lead to complete cure of airway inflammation. In fact, GINA guideline (National Institutes of Health,
A non-significant difference between the preventive effects of two concentrations of the extract on cytokines and pathological changes may indicate that the maximum preventive effect of the plant extract was obtained at lower concentration used.
In conclusion, the results of the present study indicated that N. sativa extract prevents pathological changes of the lung.
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