Archives of Medical Research
Volume 43, Issue 1 , Pages 36-41, January 2012

Serum Chemokines RANTES and Monocyte Chemoattractant Protein-1 in Egyptian Patients with Atopic Asthma: Relationship to Disease Severity

  • Sahar Saad-El-Din Bessa

      Affiliations

    • Department of Internal Medicine, Faculty of Medicine, Tanta University, Tanta, Egypt
    • Corresponding Author InformationAddress reprint requests to: Sahar Saad-El-Din Bessa, Department of Internal Medicine, Faculty of Medicine, Tanta University, Al-Geish Street, Tanta, Al-Gharbia 31527, Egypt; Phone: +202 040-3419831; FAX: +202 040-3419831
    • ,
  • Gehan Hassan Abo El-Magd

      Affiliations

    • Department of Respiratory Medicine, Faculty of Medicine, Tanta University, Tanta, Egypt
    • ,
  • Maaly Mohamed Mabrouk

      Affiliations

    • Department of Clinical Pathology, Faculty of Medicine, Tanta University, Tanta, Egypt

Received 12 November 2011; accepted 18 January 2012. published online 01 February 2012.

(ARCMED-D-11-00569)

Article Outline

Background and Aims

Asthma is a highly prevalent, complex inflammatory disease of the airways often associated with bronchial hyperreactivity and atopy. The chemokine RANTES (regulated upon activation, normal T -cell expressed and secreted) is an important element for the chemotaxis at the site of allergic inflammation. This study aimed to assess the serum levels of the chemokines RANTES and monocyte chemoattractant protein-1 (MCP-1) in Egyptian patients with atopic asthma and to evaluate their possible relation t the severity of airway obstruction.

Methods

The study included 60 Egyptian patients with atopic asthma and 20 healthy volunteers. Serum levels of the chemokines RANTES and MCP-1 were measured. Total serum IgE level and absolute eosinophil counts were determined. The severity of airway obstruction was assessed using spirometric measurement (FEV1).

Results

The serum levels of RANTES were significantly higher in all asthmatic patients than the controls (p <0.001). Moreover, RANTES levels were significantly increased in patients with moderate and severe asthma as compared to those with mild asthma (p <0.001). Serum RANTES correlated positively with absolute eosinophil counts and total serum IgE and negatively with FEV1, whereas there was no significant correlation with serum MCP-1 in all asthmatic patients.

Conclusions

Serum RANTES may be used as a useful noninvasive marker of airway obstruction and a potential diagnostic tool for monitoring asthma severity. In this regard, identification and blocking of this chemokine and/or its receptor may be a promising therapeutic approach to asthmatic patients.

Key Words: Asthma, Chemokines, MCP-1, RANTES, Severity

 

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Introduction 

Asthma is a chronic inflammatory disorder of the airways characterized by bronchial hyperresponsiveness, reversible airflow obstruction, mucus hypersecretion, inflammatory cell migration into airways, bronchial epithelial desquamation and structural remodeling. The pathogenesis and etiology of asthma is very complex and not fully understood, although interactions between genetic and environmental factors have been suggested as important determinants of this disease 1, 2.

The immune response underlying the development of asthma has attracted considerable interest because many immune mediators have been shown to play a role in mediating the bronchial airway inflammation that accompanies allergic asthma (3). Chemokines are low molecular weight chemotactic cytokines comprised of four structurally different families—CXC, CC, CX3C, and C—on the basis of arrangement of the amino terminal cysteine residues (4). CC chemokines are involved in the initiation and amplification of allergic diseases such as atopic dermatitis, rhinitis, and asthma 5, 6, 7, 8, 9, 10.

A strong argument can be made for the CC chemokine ligand 5 (CCL5) known as RANTES (regulated upon activation, normal T-cell expressed and secreted) as a candidate mediator in asthma. It is produced by T lymphocytes, endothelial cells, fibroblasts, eosinophils, platelets and other cells. This mediator has the ability to attract several types of inflammatory cells including eosinophils, monocytes and memory T helper (Th) cells to the site of inflammation 11, 12. In addition, increased levels of RANTES have been detected in the nasal secretions of atopic patients exposed to local allergen challenge (13) and were found in higher levels in the bronchoalveolar lavage fluid (14) and exhaled breath condensate (15) of asthmatic patients. Furthermore, blocking antibodies to RANTES inhibit airway inflammation in a murine model of allergic airway disease (16).

In addition, polymorphisms in RANTES gene have been identified. Some studies indicated that some polymorphisms were associated with an increased risk of asthma. However, results from different studies were apparently conflicting. Lachheb et al. (17) suggested that −28 C/G and −403 G/A polymorphisms within the RANTES promoter region play an important role in asthma predisposition and in the severity of airway obstruction. Fryer et al. (18) reported that the −403 G/A polymorphism was associated with asthma risk. In contrast, there was no evidence of association between RANTES gene promoter polymorphisms and asthma in a Spanish population (19). Overall results are inconclusive. Therefore, a meta-analysis was carried out (20). However, larger studies including different ethnic groups with a careful matching between asthma patients and controls should be considered in the future. Monocyte chemoattractant protein-1 (MCP-1); the CC chemokine ligand 2 (CCL2), may play a significant role in allergic responses because of its ability to induce mast cell activation and leukotriene C4 release into the airway, which directly induces airway hyperresponsiveness (21). Neutralization of MCP-1 drastically reduces bronchial hyperreactivity, lymphocyte-derived inflammatory mediators, and T -cell and eosinophil recruitment to the lung (22).

In many studies performed using invasive (such as bronchoalveolar lavage -BAL) as well as semi-invasive (e.g., induced sputum) methods in asthmatic patients, an increased expression of local and systemic CC chemokines has been demonstrated 23, 24. However, these relatively invasive approaches are unsuitable for repeated monitoring of airway inflammation. Therefore, establishing a simple monitoring system of airway inflammation would be useful for asthma management. Given the importance of RANTES and MCP-1 in allergic inflammation, this study was conducted to assess their serum levels in Egyptian patients with atopic asthma and to evaluate their possible relation to the severity of airway obstruction.

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Materials and Methods 

Subjects 

Sixty Egyptian patients with atopic asthma were selected from those admitted to the Internal Medicine and Respiratory Medicine Departments in Tanta University Hospital (35 men and 25 women) with a mean age of 38.7 ± 12.5 years. Twenty healthy age- and gender-matched non-smoker volunteers (10 men and 10 women) with a mean age of 38.1 ± 14.3 years were recruited for participation as controls. They were selected from medical and paramedical staff and from blood donors in Tanta University Hospital. None of the control subjects had ever suffered from asthma or chronic respiratory symptoms. They had not undergone any respiratory tract infection during the month preceding the study. The study was approved by the scientific and ethics committees of the Tanta University Hospital, Tanta University, Tanta, Egypt, and informed consent was obtained from each subject before the start of this study. Diagnosis of asthma was based on the guidelines proposed by the American Thoracic Society (25). The clinical severity of asthma was assessed according to the Global Initiative for Asthma (GINA) guidelines (26). Positivity of the skin prick test (wheal diameter ≥3 mm greater than saline control) to one or more of common aeroallergen extracts (house dust mite, house dust, cotton dust, mixed pollens, cat fur, dog fur, feathers) and/or total serum IgE levels ≥100 IU/mL were used to define atopic status in all asthmatic patients (27). Also, positive family history of atopic dermatitis, rhinitis and asthma was taken into consideration. All asthmatic patients were stable and had been without regular asthma treatment including steroid therapy prior to the study, but rescue use of short-acting bronchodilator as needed for symptom relief was permitted. All patients were lifelong nonsmokers and none had suffered respiratory tract infection for at least 8 weeks prior to the study. All cases included in this study were subjected to careful history taking, complete clinical examination, laboratory investigations, radiological assessment, and pulmonary function tests.

Blood Collection and Laboratory Analyses 

Peripheral venous blood was collected aseptically from patients and control subjects. Absolute eosinophil counts were performed on an aliquot of the whole venous blood using a Sysmex SE-9000 Automated Hematology Analyzer (TOA Medical Electronics Co, Kobe, Japan). The remaining blood sample was allowed to clot at room temperature for 30 min and centrifuged at 3000 x g for 10 min. Serum was then aspirated and divided into aliquots in small plastic tubes. One aliquot was used for determination of total serum IgE levels using fluorescent enzyme immunoassay (AutoCAP System; Pharmacia Diagnostics AB, Uppsala, Sweden). The other aliquots were stored at −70°C until used for measurements of RANTES and MCP-1 levels.

Measurement of Serum Level of RANTES and MCP-1 

Serum RANTES and MCP-1 levels were measured with quantitative sandwich enzyme-linked immunosorbent assay (ELISA) according to the manufacturer’s instructions (28), using commercially available kits for both RANTES (Quantikine, Human RANTES Immunoassay Kit, DRN00B, R&D Systems, Minneapolis, MN) and MCP-1 (Quantikine, Human MCP-1/CCL2 Immunoassay Kit, DCP00, R&D Systems).

Pulmonary Function Tests 

Spirometric study was done for all cases using Morgan's transfer apparatus with Della computer (Buckingham, England) according to the American Thoracic Society standards (29). Forced expiratory volume in 1 sec (FEV1), forced vital capacity (FVC), and the FEV1/FVC ratio were measured before and 15 min after the inhalation of salbutamol (Glaxo Operations Ltd., Greenford, UK). The results were recorded as the percentage of the predicted values. Asthmatic patients were categorized into severity groups by using level of FEV1 % predicted. The patients were classified as having mild (FEV1 >80%), moderate (FEV1 60–80%), or severe (FEV1 <60%) airflow obstruction.

Statistical Analysis 

Results were expressed as mean ± standard deviation (SD). Comparisons between groups were made using Student’s t- test for continuous variables. Correlation between parameters was determined by Pearson’s correlation coefficient (r); p value <0.05 was considered statistically significant.

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Results 

The main clinical and laboratory parameters of asthmatic patients are shown in Table 1. There was significant lowering of pulmonary function parameters (FEV1, FVC and FEV1/ FVC) in asthmatic patients as compared with control subjects. The severity of asthma in the studied patients—according to the GINA guidelines based on daytime and nocturnal symptoms—and lung function, was as follows: intermittent in seven patients (11.67%), mildly persistent in 12 patients (20%), moderately persistent in 24 patients (40%), and severely persistent in 17 patients (28.33%).

Table 1. Clinical and laboratory parameters of asthmatics and control subjects
ParametersControls (n = 20)Asthmatic patients (n = 60)
Age (years)38.1 ± 14.338.7 ± 12.5
Gender (M/F)10/1035/25
FEV1 (% predicted)97.6 ± 7.9677.5 ± 5.2a
FVC (% predicted)89.7 ± 2.485.6 ± 4.1a
FEV1/ FVC (%)84.3 ± 0.578.5 ± 0.8a
Total serum IgE (IU/mL)33.2 ± 12.4480.7 ± 102a
Absolute eosinophil counts (cells/mm3)50 ± 15172 ± 60a
Serum RANTES (pg/mL)2930 ± 515.28139.6 ± 3543.8a
Serum MCP-1 (pg/mL)173.6 ± 85.2226.5 ± 93.8b

FEV1, forced expiratory volume in one second; FVC, forced vital capacity; RANTES, regulated upon activation, normal T -cell expressed and secreted; MCP-1, monocyte chemoattractant protein-1.

Data are expressed as mean ± standard deviation.

ap <0.001.

bp <0.05 asthmatic patients vs. controls.

Compared with control subjects, total serum IgE concentrations and absolute eosinophil counts were significantly increased in all asthmatic patients (p <0.001, for both); however, no significant difference was found among the different grades of asthma severity (Table 1, Table 2). Serum levels of CC chemokine RANTES were significantly higher in all asthmatic patients than the control subjects (p <0.001) as shown in Table 1. Moreover, RANTES levels were significantly increased in patients with moderate and severe asthma as compared to those with mild asthma (p <0.001, for both) (Table 2). Regarding MCP-1 in asthmatic patients, there was an increase in MCP-1 serum levels in all asthmatics as compared to the controls (p <0.05), whereas there was no significant difference among the different grades of asthma severity (Table 1, Table 2).

Table 2. Laboratory parameters according to grades of asthma severity
ParametersMild asthma (n = 19)Moderate asthma (n = 24)Severe asthma (n = 17)
Total serum IgE (IU/mL)479 ± 107489 ± 104495 ± 67
Absolute eosinophil counts (cells/mm3)130 ± 52156 ± 43178 ± 87
Serum RANTES (pg/mL)4498.3 ± 26257818.2 ± 3253.8a10740.6 ± 3410.2b, c
Serum MCP-1 (pg/mL)204.1 ± 81.6220.4 ± 68.5238.7 ± 72.2

RANTES, regulated upon activation, normal T -cell expressed and secreted; MCP-1, monocyte chemoattractant protein-1.

Data are expressed as mean ± standard deviation.

ap <0.001 moderate asthma vs. mild asthma.

bp <0.001 severe asthma vs. mild asthma.

cp <0.01 severe asthma vs. moderate asthma.

In the present study, serum RANTES in all asthmatic patients was positively correlated with absolute eosinophil counts (r = 0.611; p <0.001) and total serum IgE (r = 0.298; p <0.05) and negatively correlated with FEV1 (r = −0.385; p <0.01), whereas there was no significant correlation with serum MCP-1 as shown in Table 3. On the other hand, no significant correlations were found between serum MCP-1 and absolute eosinophil counts, total serum IgE, or FEV1.

Table 3. Correlation between serum RANTES, serum MCP-1 and other parameters in asthmatic patients
FEV1 (% predicted)Absolute eosinophil counts (cells/mm3)Total serum IgE (IU/mL)Serum MCP-1 (pg/mL)
Serum RANTES (pg/mL)r = −0.385 p <0.01r = 0.611 p <0.001r = 0.298 p <0.05r = 0.192 p>0.05
Serum MCP-1 (pg/mL)r = −0.214 p>0.05r = 0.221 p>0.05r = 0.127 p>0.05-

RANTES, regulated upon activation, normal T -cell expressed and secreted; MCP-1, monocyte chemoattractant protein-1; FEV1, forced expiratory volume in one second.

p value <0.05 was considered significant.

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Discussion 

Asthma is a complex disorder of the airways that is increasing in prevalence and can result in significant morbidity and mortality (30). Much attention has recently been focused on the role of allergic inflammatory reaction in asthma. Chemokines are a family of cytokines that are believed to be involved in the pathogenesis of asthma, possibly by recruiting leukocytes to the inflammatory site (31). CC chemokine RANTES has been implicated in allergic inflammation of asthma by promoting migration and activation of inflammatory cells, including eosinophils (32). A growing body of evidence suggests that many cell types present in asthmatic airways have the capacity to generate RANTES (6). However, the exact role of RANTES in airway allergic inflammation has been somewhat controversial.

This study was designed to investigate the potential contribution of serum levels of the CC chemokines RANTES and MCP-1 to the pathogenesis of atopic asthma and to evaluate their relationship with the severity of airway obstruction. The study revealed that serum levels of RANTES were significantly higher in all asthmatic patients than in control subjects and RANTES levels were significantly increased in patients with moderate and severe asthma as compared to those with mild asthma. These results are in agreement with the findings of Lun et al. (33) who observed that the plasma concentration of RANTES was significantly higher in both atopic and onatopic asthmatic patients than the controls and correlated positively with the GINA severity score in all asthmatic patients. This suggested its involvement in the severity of the disease. RANTES has also been found at significantly higher levels in patients during asthma attacks than in those with asymptomatic stages or in control subjects (34). This observation is supported by Ying et al. (35) who showed that RANTES expression was higher in bronchial mucosa from both atopic and nonatopic asthmatics.

Also of note, Berkman et al. (36) reported that RANTES was constitutively expressed in the airways and RANTES mRNA was elevated in patients with asthma. Moreover, increased expression of mRNA encoding RANTES in the bronchial mucosa in atopic asthma was found by Powell et al. (37). Zietkowski et al. (15) reported that RANTES levels in exhaled breath condensate were significantly higher in asthmatic patients than in healthy controls and higher in patients with unstable asthma than in those with stable asthma, indicating that RANTES can be used as a diagnostic tool for detection and monitoring of asthma. This observation is confirmed by previous studies performed by Tillie-Leblond et al. (38) who revealed that CC chemokines (including RANTES) were present at high levels in bronchoalveolar lavage (BAL) fluid from patients with severe asthmatic exacerbation than in patients with mild asthma. Conversely, Erten et al. (39) found no difference in RANTES levels in asthmatic patients compared to the control group. This finding may be attributed to the usage of inhaled corticosteroids in these patients, which was shown to repress RANTES by inhibition of NF-κB-dependent transcription (40).

Our current data also showed that serum RANTES in all asthmatic patients was positively correlated with absolute eosinophil counts, and total serum IgE and negatively correlated with FEV1, which is an index of airflow limitation. Meanwhile, Teran et al. (41) reported that RANTES is a major eosinophil attractant in BAL fluid of asthmatic patients exposed to an allergen challenge, and that the concentration of RANTES strongly correlated with eosinophil count. Also, a previous report showed that RANTES-positive sputum eosinophils and the percentage of FEV1 after allergen challenge were significantly correlated in asthmatic patients, which is compatible with our results (42). Eosinophils cause tissue damage and promote allergic disease in the lung through the release of toxic proteases, lipid mediators, cytokines, and oxygen free radicals (43).

In the context of the development of persistent inflammation that underlies asthma-related physiological dysfunction, we postulate that because eosinophils recruited by RANTES are a major source of the reactive oxygen species released during the inflammatory process, chronically elevated levels of the chemokine RANTES may at least in part result in significant damage to the airway wall necessitating airway remodeling. Thus, RANTES may be important in determining the severity of inflammation leading to airway remodeling and bronchial response to inhaled allergen. These findings may be exploited clinically as RANTES antagonists could be of considerable therapeutic efficacy in modifying the underlying inflammation present in these patients.

In addition to targeting the eosinophil, it has been demonstrated that RANTES rapidly degranulates basophils and releases histamine (44), selectively enhances B-cell IgE production (45), and also participates in T-lymphocyte chemotaxis and activation (46). Therefore, RANTES may be involved in inflammatory cell recruitment and the induction of bronchoconstrictive mediators from cells, resulting in airflow limitation. These RANTES characteristics further support the proposed role in asthma pathogenesis.

Considering these observations, many studies have also shown an interesting link between RANTES polymorphisms and asthma, showing that the variant in the promoter region is associated with a high risk of asthma and severe airway obstruction 47, 48. All of these results indicate that RANTES is an attractive gene candidate for the genetic dissection of asthma.

As regards MCP-1 in our study, there was an increase in MCP-1 serum levels in all asthmatic patients as compared to the controls, whereas there was no significant difference among the different grades of asthma severity. It is possible that MCP-1 is secreted by alveolar macrophages when they are activated by toxic particles and attracts monocytes that can differentiate into macrophages, playing a key role in monocyte migration. Therefore, an increased serum MCP-1 may contribute to an increase in macrophages, increased monocyte differentiation, and more severe airway inflammation as in patients with COPD (49).

Our results are in accordance with the findings of Chan et al. (50) who reported that serum MCP-1 levels were significantly higher during the asymptomatic phase of asthma than that of normal controls and were significantly higher during acute asthma attacks, suggesting a possible role of MCP-1 in the pathogenesis of asthma. Furthermore, increased MCP-1 expression has been demonstrated in the bronchial epithelium of asthmatic patients (51), with marked elevation of sputum MCP-1 levels preceding exacerbation of acute asthma attacks in comparison to the asymptomatic state (52).

By investigating BAL fluid, Alam et al. (14) observed that MCP-1 levels were significantly higher in asthma patients than in control subjects. Moreover, it has been demonstrated that the levels of MCP-1 were increased in BAL fluid of ventilated subjects with status asthmaticus compared to mild to moderate asthmatics (38), suggesting that this CC chemokine may be an important factor in life-threatening asthma attacks. On the contrary, the findings of Holgate et al. (53) and Folkard et al. (54) failed to support the findings of Alam et al. that this chemokine was increased in BAL fluid from patients with stable asthma.

Interestingly, Szalai et al. (55) found an association between the MCP-1 −2518G allele and asthma susceptibility and severity. Although these results are encouraging, reproducibility is critical in gene association studies and confirmatory data from different ethnic populations are needed.

Together, chemokines have now emerged as potentially critical cytokines involved in the pathogenesis of asthma. This has provided the rationale for increased scientific investigation in the field and for the development of new therapeutic strategies targeting chemokine and/or chemokine receptor pathways involved in this socioeconomically important disease.

In conclusion, serum RANTES may be used as a useful noninvasive marker of airway obstruction and as a potential diagnostic tool for monitoring asthma severity. In this regard, identification and blocking of this chemokine and/or its receptor may be a promising therapeutic approach to asthmatic patients. However, future well-designed large studies are required to elucidate its therapeutic role in asthma.

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PII: S0188-4409(12)00036-7

doi:10.1016/j.arcmed.2012.01.009

Archives of Medical Research
Volume 43, Issue 1 , Pages 36-41, January 2012

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