Rabih Halwani

King Saud University, Ar Riyāḑ, Ar Riyāḑ, Saudi Arabia

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Publications (43)137.78 Total impact

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    ABSTRACT: Abstract Objective. Rs37972 and rs37973 variants in the glucocorticoid-induced transcript 1 gene (Glcci1) have been associated with inhaled glucocorticosteroid responsiveness in asthmatics; however, some discrepancies have been also reported. This study aims to determine whether rs37972 and rs37973 SNPs are associated with asthma risk in Saudi Arabian asthmatics. Methods. Two hundred and seventy one diagnosed asthmatics (3-65 years old), and 387 healthy control subjects of equivalent age were recruited. DNA from peripheral blood was purified and genotyping of rs37972 and rs37973 SNPs was performed by PCR amplification of segments of interest, followed by Sanger sequencing. Results. The global frequencies of the minor ('risk') alleles were 28% ('T' allele, rs37972) and 30% ('G' allele, rs37973). Yates-corrected Chi-square (X(2)) tests revealed significant differences between asthmatic and healthy groups, in allele frequencies for rs37973 SNP only (X(2)=3.98, Yates' P-value=0.046). Regarding genotype frequencies, a significant difference between asthmatic and healthy groups was observed for variant rs37972 only (X(2)=8.19, Yates' P-value=0.016). To determine a possible association of the minor 'T' and 'G' alleles with asthma, both the recessive and dominant genetic models were tested. For rs37973, none of the genotypes were significantly associated with asthma. Concerning rs37972, the dominant model (C/T+T/T versus C/C) indicated a significant 'protective' association with asthma, in which C/T+T/T individuals had lower odds of being asthmatics than C/C individuals (OR=0.67; 95% CI=0.48-0.94; p=0.019*). Conclusions. The minor alleles 'T' and 'G' of rs37972 and rs37973 SNPs, respectively, were not significantly associated with increased asthma risk in asthma patients from Saudi Arabia.
    The Journal of asthma : official journal of the Association for the Care of Asthma. 08/2014;
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    ABSTRACT: The IL-4 receptor alpha subunit (IL-4Rα), when associated with the common gamma chain receptor, or the IL-13Rα1 subunit, transduces signals to STAT6 in response to IL-4 and IL-13 stimulations. This results in a number of cell-specific responses including Th2 differentiation, lymphocyte proliferation and IgE production. Given the prominent role of IL-4Rα in allergic disorders, several single-nucleotide polymorphisms (SNPs) have been found associated with asthma and other atopic disorders, including rs1805010 (I75V) and rs1801275 (Q576R) SNPs; however, lack of significant association have also been reported for some ethnic groups. The objective of this study was to determine whether IL-4Rα rs1805010 and rs1801275 polymorphisms are associated with asthma in patients from Saudi Arabia. One hundred and ninety severe asthmatic patients (11-70 years old) and 194 healthy subjects of equivalent age range were recruited for blood donation. DNA was purified and genotyping for rs1801275 and rs1805010 polymorphisms in the IL-4Rα gene was performed by PCR amplification, followed by cycle sequencing of the purified PCR fragments using BigDye chain terminator and capillary electrophoresis. Pearson's Chi-square tests showed that the minor alleles, G, for both rs1805010 and rs1801275 SNPs, were significantly more frequent in asthmatics than in the healthy group (Yates' P < 0.05); conversely, the major alleles, A, were significantly more frequent in healthy than in asthmatics (P < 0.05). Concerning association analysis, odds for A/G-G/G genotypes were significantly higher to be associated with asthma predisposition (rs1801275: OR = 2.12; 95% CI = 1.39-3.22; P < 0.001*; rs1805010: OR = 1.6; 95% CI = 1.01-2.53; P < 0.05*; dominant model). Analysis of gender-genotype interactions, with genders nested within A/G-G/G, indicated higher odds for females than males of significant association with asthma (rs1801275: OR = 5.19, 95% CI = 2.09-12.94*; rs1805010: OR = 3.73, 95% CI = 2.06-6.74*). Rs1805010 and rs1801275 were in linkage disequilibrium (D' = 0.27; P < 0.0004*), with G-G haplotype being more frequent in asthmatics than in healthy subjects (OR = 2.43, 95% CI = 1.59-3.71*). The risk alleles, G, of IL-4Rα rs1805010 and rs1801275 SNPs and corresponding A/G-G/G genotypes were significantly associated with asthma predisposition in asthmatics from Saudi Arabia.
    Annals of Thoracic Medicine 01/2014; 9(2):81-86. · 1.12 Impact Factor
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    ABSTRACT: Background The signal transducer and activator of transcription 6 (STAT6) transduces signals in response to IL-4 and IL-13 cytokine stimulations, resulting in many cell-specific responses. Some common STAT6 SNPs were associated with asthma predisposition and/or IgE levels, although discrepancies have also been reported. Objective To determine whether STAT6 rs324011 and rs324015 polymorphisms are associated with atopic asthma in Saudi Arabian patients. Methods A total of 536 Saudi individuals aged 11–70 years old (230 atopic asthmatics, 306 healthy subjects) were recruited. DNA was purified from peripheral blood and genotyping for rs324011 and rs324015 polymorphisms was performed by PCR amplification, followed by cycle sequencing of the purified PCR fragments using BigDye chain terminator and capillary electrophoresis. Results By the contrast of alleles tests, no significant differences between asthma and healthy groups were detected for both variants (rs324011: X2 = 0.25, Pearson’s P-value = 0.617; rs324015: X2 = 0.068, Pearson’s P = 0.814).When testing for genotypes, rs324011 homozygous T/T genotype was significantly associated with asthma, when the Recessive model is considered (T/T vs. C/C + C/T) (adjusted, OR = 2.49, 95% CI = 1.18–5.25, Pearson’s P = 0.014∗, Yates’ P = 0.022∗). In contrast, rs324015 variant was not significantly associated with asthma. Conclusions Rs324011 homozygous T/T genotype was significantly associated with asthma risk whereas rs324015 genotypes were not in the Saudi population.
    Human Immunology 01/2014; · 2.30 Impact Factor
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    ABSTRACT: Targeting and noninvasive imaging of a specific alveolar macrophage subpopulation in the lung has revealed the importance for early and better diagnosis and therapy of chronic obstructive pulmonary disease (COPD). In this study, the in vivo effect of pulmonary administration of iron oxide nanoparticles on the polarization profile of macrophages was assessed, and a noninvasive free-breathing magnetic resonance imaging (MRI) protocol coupled with the use of biocompatible antibody-conjugated superparamagnetic iron oxide (SPIO) nanoparticles was developed to enable specific targeting and imaging of a particular macrophage subpopulation in lipopolysaccharide-induced COPD mice model. Enzyme-linked immunosorbent assay, Real-time polymerase chain reaction, and flow cytometry analysis were performed to assess the biocompatibility of PEGylated dextran-coated SPIO nanoparticles. Specific biomarkers for M1 and M2 macrophages subsets were selected for conjugation with magnetic nanoparticles. MRI protocol using ultra-short echo time sequence was optimized to enable simultaneous detection of inflammation progress in the lung and detection of macrophages subsets. Flow cytometry and immunohistochemistry analysis were finally performed to confirm MRI readouts and to characterize the polarization profile of targeted macrophages. The tested SPIO nanoparticles, under the current experimental conditions, were found to be biocompatible for lung administration in preclinical settings. Cluster of differentiation (CD)86- and CD206-conjugated magnetic nanoparticles enabled successful noninvasive detection of M1 and M2 macrophage subpopulations, respectively, and were found to co-localize with inflammatory regions induced by lipopolysaccharide challenge. No variation in the polarization profile of targeted macrophages was observed, even though a continuum switch in their polarization might occur. However, further confirmatory studies are required to conclusively establish this observation. Coupling of magnetic iron oxide nanoparticles with a specific antibody targeted to a particular macrophage subpopulation could offer a promising strategy for an early and better diagnosis of pulmonary inflammatory diseases using noninvasive MRI.
    International Journal of Nanomedicine 01/2014; 9:1491-503. · 4.20 Impact Factor
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    ABSTRACT: Noninvasive imaging of macrophages activity has raised increasing interest for diagnosis of chronic obstructive respiratory diseases (COPD), which make them attractive vehicles to deliver contrast agents for diagnostic or drugs for therapeutic purposes. This study was designed to monitor and evaluate the migration of differently polarized M1 and M2 iron labeled macrophage subsets to the lung of a LPS-induced COPD animal model and to assess their polarization state once they have reached the inflammatory sites in the lung after intravenous injection. Ex vivo polarized bone marrow derived M1 or M2 macrophages were first efficiently and safely labeled with amine-modified PEGylated dextran-coated SPIO nanoparticles and without altering their polarization profile. Their biodistribution in abdominal organs and their homing to the site of inflammation in the lung was tracked for the first time using a free-breathing non-invasive MR imaging protocol on a 4.7T magnet after their intravenous administration. This imaging protocol was optimized to allow both detection of iron labeled macrophages and visualization of inflammation in the lung. M1 and M2 macrophages were successfully detected in the lung starting from 2 hours post injection with no variation in their migration profile. Quantification of cytokines release, analysis of surface membrane expression using flow cytometry and immunohistochemistry investigations confirmed the successful recruitment of injected iron labeled macrophages in the lung of COPD mice and revealed that even with a continuum switch in the polarization profile of M1 and M2 macrophages during the time course of inflammation a balanced number of macrophage subsets predominate.
    PLoS ONE 01/2014; 9(3):e90829. · 3.53 Impact Factor
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    ABSTRACT: The main objective of this study was to evaluate CYP2D6 genetic polymorphism in a Saudi Arabian population by determining the frequencies of CYP2D6*41, CYP2D6*29, CYP2D6*3, CYP2D6*6 and CYP2D6*14 alleles. Genomic DNA was isolated from 192 healthy Saudis representing different geographical regions, and genotyping of the selected CYP2D6 variants was carried out by direct sequencing. The allelic frequency of CYP2D6*41 was found to be 18.4%, and that of CYP2D6*29 to be 2.9%. The other investigated alleles were either not detected or rarely present in the study population. In addition, two commonly shared single nucleotide polymorphisms (SNPs) and two very rare SNPs among CYP2D6 alleles were detected. Further studies are therefore, required to evaluate the metabolic and clinical relevance of CYP2D6*41 in Saudi Arabians.
    Environmental toxicology and pharmacology. 09/2013; 36(3):1063-1067.
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    ABSTRACT: Glucuronidation is an important phase II pathway responsible for the metabolism of many endogenous substances and drugs to less toxic metabolites, which undergo renal excretion. The aim of the current work was to evaluate genotype and allele frequencies of certain UDP-glucuronosyltransferase 1A1 (UGT1A1) variants in an Arab population. Genomic DNA was isolated from 192 healthy unrelated Saudi males of various geographic regions and genotyping of UGT1A1*6, *27, *36, *28, *37, and *60 was carried out using polymerase chain reaction (PCR) amplification followed by direct sequencing. The most common allele for (TA) repeats was the wild type (TA)6 with a frequency of 74.3% followed by the mutant (TA)7 (i.e., UGT1A1*28) with a frequency of 25.7%. The distribution of UGT1A1*60 allele was 62.4% among subjects with the homozygous mutant genotype of 35.4%, while the wild type variant represents 10.6% only. Both UGT1A1*6 and *27 were not detected as all screened subjects showed a homozygous wild type pattern. Similarly, UGT1A1*36* and *37 were either not present or rarely found, respectively. In comparison to other populations, the frequency of UGT1A1*60 and *28 in the studied population was less than that of African Americans but higher than Asians. The geographical origin of the study subjects also implied some differences in genotype distribution of (TA) repeats and UGT1A1*60. Our data indicate that Saudis harbor some important UGT1A1 mutations known to affect enzyme activity. Additional studies are warranted to assess the clinical implications of these gene polymorphisms in this ethnic group.
    Archives of Medical Science 08/2013; 9(4):731-8. · 1.89 Impact Factor
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    ABSTRACT: Polymorphisms in the PXR gene play important roles in influencing the efficacy and toxicity of a large number of endogenous and exogenous substrates. Because of ethnic specificity, several studies have been directed toward the determination of PXR polymorphisms in various populations. In the current study, we determined the genotype and allele frequencies of 19 coding and regulatory polymorphisms in the PXR gene in Saudi Arabians by direct sequencing. Our results show that the frequencies of the regulatory PXR SNPs in Saudi Arabians differ from those in other ethnic groups, and the results endorse the commonly seen ethnic pattern of a paucity of the PXR coding SNPs.
    Biochemical Genetics 04/2013; · 0.94 Impact Factor
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    ABSTRACT: BACKGROUND: Subepithelial fibrosis is one of the most critical structural changes affecting bronchial airway function during asthma. Eosinophils have been shown to contribute to the production of pro-fibrotic cytokines, TGF-beta and IL-11, however, the mechanism regulating this process is not fully understood. OBJECTIVE: In this report, we investigated whether cytokines associated with inflammation during asthma may induce eosinophils to produce pro-fibrotic cytokines. METHODS: Eosinophils were isolated from peripheral blood of 10 asthmatics and 10 normal control subjects. Eosinophils were stimulated with Th1, Th2 and Th17 cytokines and the production of TGF-beta and IL-11 was determined using real time PCR and ELISA assays. RESULTS: The basal expression levels of eosinophil derived TGF-beta and IL-11 cytokines were comparable between asthmatic and healthy individuals. Stimulating eosinophils with Th1 and Th2 cytokines did not induce expression of pro-fibrotic cytokines. However, stimulating eosinophils with Th17 cytokines resulted in the enhancement of TGF-beta and IL-11 expression in asthmatic but not healthy individuals. This effect of IL-17 on eosinophils was dependent on p38 MAPK activation as inhibiting the phosphorylation of p38 MAPK, but not other kinases, inhibited IL-17 induced pro-fibrotic cytokine release. CONCLUSIONS: Th17 cytokines might contribute to airway fibrosis during asthma by enhancing production of eosinophil derived pro-fibrotic cytokines. Preventing the release of pro-fibrotic cytokines by blocking the effect of Th17 cytokines on eosinophils may prove to be beneficial in controlling fibrosis for disorders with IL-17 driven inflammation such as allergic and autoimmune diseases.
    Respiratory research 03/2013; 14(1):34. · 3.64 Impact Factor
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    ABSTRACT: BACKGROUND: Uncontrolled asthma remains a frequent cause of emergency department (ED) visits and hospital admissions. Improper asthma inhaler device use is most likely one of the major causes associated with uncontrolled asthma and frequent ED visits.Objectives To evaluate the inhaler technique among asthmatic patients seen in ED, and to investigate the characteristics of these patients and factors associated with improper use of inhaler devices and its relationship with asthma control and ED visits. METHODS: A cross-sectional study of all the patients who visited the ED with bronchial asthma attacks over a 9-month period was undertaken at two major academic hospitals in Saudi Arabia. Information was collected about demographic data and asthma management and we assessed the inhaler techniques for each patient using an inhaler technique checklist. RESULTS: A total of 450 asthma patients were included in the study. Of these, 176(39.1%) were males with a mean age of 42.3 ±16.7 years and the mean duration of asthma was 155.9 ± 127.1 weeks. The improper use of asthma inhaler devices was observed in 203(45%) of the patients and was associated with irregular clinic follow-ups (p = 0.0001), lack of asthma education (p = 0.0009), uncontrolled asthma ACT (score ¿ 15) (p = 0.001), three or more ED visits (p = 0.0497), and duration of asthma of less than 52 weeks (p = 0.005). Multiple logistic regression analysis revealed that a lack of education about asthma disease (OR =1.65; 95% CI: 1.07, 2.54) or a lack of regular follow-up (OR =1.73; 95% CI: 1.08, 2.76) was more likely to lead to the improper use of an asthma inhaler device. CONCLUSION: Improper asthma inhaler device use is associated with poor asthma control and more frequent ED visits. We also identified many avoidable risk factors leading to the improper use of inhaler devices among asthma patients visiting the ED.
    Allergy Asthma and Clinical Immunology 03/2013; 9(1):8.
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    ABSTRACT: Autosomal recessive interleukin (IL)-12 p40 (IL-12p40) deficiency is a rare genetic etiology of Mendelian susceptibility to mycobacterial disease (MSMD). We report the genetic, immunologic, and clinical features of 49 patients from 30 kindreds originating from 5 countries (India, Iran, Pakistan, Saudi Arabia, and Tunisia). There are only 9 different mutant alleles of the IL12B gene: 2 small insertions, 3 small deletions, 2 splice site mutations, and 1 large deletion, each causing a frameshift and leading to a premature stop codon, and 1 nonsense mutation. Four of these 9 variants are recurrent, affecting 25 of the 30 reported kindreds, due to founder effects in specific countries. All patients are homozygous and display complete IL-12p40 deficiency. As a result, the patients lack detectable IL-12p70 and IL-12p40 and have low levels of interferon gamma (IFN-γ). The clinical features are characterized by childhood onset of bacille Calmette-Guérin (attenuated Mycobacterium bovis strain) (BCG) and Salmonella infections, with recurrences of salmonellosis (36.4%) more common than recurrences of mycobacterial disease (25%). BCG vaccination led to BCG disease in 40 of the 41 patients vaccinated (97.5%). Multiple mycobacterial infections were rare, observed in only 3 patients, whereas the association of salmonellosis and mycobacteriosis was observed in 9 patients. A few other infections were diagnosed, including chronic mucocutaneous candidiasis (n = 3), nocardiosis (n = 2), and klebsiellosis (n = 1). IL-12p40 deficiency has a high but incomplete clinical penetrance, with 33.3% of genetically affected relatives of index cases showing no symptoms. However, the prognosis is poor, with mortality rates of up to 28.6%. Overall, the clinical phenotype of IL-12p40 deficiency closely resembles that of interleukin 12 receptor β1 (IL-12Rβ1) deficiency.In conclusion, IL-12p40 deficiency is more common than initially thought and should be considered worldwide in patients with MSMD and other intramacrophagic infectious diseases, salmonellosis in particular.
    Medicine 03/2013; 92(2):109-122. · 4.35 Impact Factor
  • Rabih Halwani, Saleh Al-Muhsen, Qutayba Hamid
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    ABSTRACT: T helper 17 (Th17) cytokines are now widely believed to be critical for the regulation of various chronic immune diseases. Investigations have revealed a significant role for IL-17 cytokines in regulating inflammation and modulating lung and airway structural cells in asthma and COPD. In this review, our current understanding of the role of Th17-associated cytokines in airway diseases is summarized. Therapeutic approaches targeting IL-17 during asthma and COPD are also discussed.
    Chest 02/2013; 143(2):494-501. · 7.13 Impact Factor
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    ABSTRACT: We compared the relative efficacy against simian immunodeficiency virus (SIV) challenge of three vaccine regimens that elicited similar frequencies of SIV-specific CD4(+) and CD8(+) T-cell responses but differed in the level of antibody responses to the gp120 envelope protein. All macaques were primed with DNA plasmids expressing SIV gag, pol, env, and Retanef genes, and boosted either once (1xMVA) or twice (2xMVA) with recombinant MVA expressing the same genes, or once with MVA followed by a single boost with replication-competent Ad5hr expressing SIV gag and nef genes but not Retanef or env (1xMVA/Ad5). While two of the vaccine regimens (1xMVA and 1xMVA/Ad5) protected from high levels of SIV replication only during the acute phase of infection, the 2xMVA, with the highest anti-SIV gp120 titers, protected during the acute and transiently in the chronic phase of infection, Mamu-A*01 macaques of this third group exhibited persistent Gag CD8(+)CM9(+) effector memory T-cells with low expression of surface Program Death-1 (PD-1) receptor,and high levels of expression of genes associated with MHC-I and II antigen. The fact that control of SIV replication was associated with both high titers of antibodies to the SIV envelope protein, and durable effector SIV-specific CD8(+) T-cells suggest the hypothesis that the presence of antibodies at time of challenge may increase innate immune recruiting activity by enhancing antigen uptake and result in improvement of the quality and potency of secondary SIV-specific CD8(+) T-cell responses.
    Journal of Virology 01/2013; · 5.08 Impact Factor
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    ABSTRACT: HIV-1 Nef protein down-regulates several cell surface receptors through its interference with the cell sorting and trafficking machinery. Here we demonstrate for the first time the ability of Nef to down-regulate cell surface expression of the negative immune modulator CTLA-4. Down-regulation of CTLA-4 required the Nef motifs DD175, EE155 and LL165, all known to be involved in vesicle trafficking. Disruption of the lysosomal functions by pH-neutralizing agents prevented CTLA-4 down-regulation by Nef, demonstrating the implication of the endosomal/lysosomal compartments in this process. Confocal microscopy experiments visualized the co-localization between Nef and CTLA-4 in the early and recycling endosomes but not at the cell surface. Overall, our results provide a novel mechanism by which HIV-1 Nef interferes with the surface expression of the negative regulator of T cell activation CTLA-4. Down-regulation of CTLA-4 may contribute to the mechanisms by which HIV-1 sustains T cell activation, a critical step in viral replication and dissemination.
    PLoS ONE 01/2013; 8(1):e54295. · 3.53 Impact Factor
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    ABSTRACT: BACKGROUND: Acute asthma attacks remain a frequent cause of emergency department (ED) visits and hospital admission. Many factors encourage patients to seek asthma treatment at the emergency department. These factors may be related to the patient himself or to a health system that hinders asthma control. The aim of this study was to identify the main factors that lead to the frequent admission of asthmatic patients to the ED. METHODS: A cross-sectional survey of all the patients who visited the emergency room with bronchial asthma attacks over a 9-month period was undertaken at two major academic hospitals. The following data were collected: demographic data, asthma control in the preceding month, where and by whom the patients were treated, whether the patient received education about asthma or its medication and the patients' reasons for visiting the ED.Result: Four hundred fifty (N = 450) patients were recruited, 39.1% of whom were males with a mean age of 42.3 +/- 16.7. The mean duration of asthma was 155.90 +/- 127.13 weeks. Approximately half of the patients did not receive any information about bronchial asthma as a disease, and 40.7% did not receive any education regarding how to use asthma medication. Asthma was not controlled or partially controlled in the majority (97.7%) of the patients preceding the admission to ED. The majority of the patients visited the ED to receive a bronchodilator by nebuliser (86.7%) and to obtain oxygen (75.1%). Moreover, 20.9% of the patients believed that the ED managed them faster than the clinic, and 21.1% claimed that their symptoms were severe enough that they could not wait for a clinic visit. No education about asthma and uncontrolled asthma are the major factors leading to frequent ED visits (three or more visits/year), p-value = 0.0145 and p-value = 0.0003, respectively. Asthma control also exhibited a significant relationship with inhaled corticosteroid ICS use (p-value =0.0401) and education about asthma (p-value =0.0117). CONCLUSION: This study demonstrates that many avoidable risk factors lead to uncontrolled asthma and frequent ED visits.
    BMC Pulmonary Medicine 12/2012; 12(1):80. · 2.76 Impact Factor
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    ABSTRACT: Asthma is characterized by eosinophilic airway inflammation and remodeling of the airway wall. Features of airway remodeling include increased airway smooth muscle (ASM) mass. However, little is known about the interaction between inflammatory eosinophils and ASM cells. In this study, we investigated the effect of eosinophils on ASM cell proliferation. Eosinophils were isolated from peripheral blood of mild asthmatics and non-asthmatic subjects and co-cultured with human primary ASM cells. ASM proliferation was estimated using Ki-67 expression assay. The expression of extracellular matrix (ECM) mRNA in ASM cells was measured using quantitative real-time PCR. The role of eosinophil derived Cysteinyl Leukotrienes (CysLTs) in enhancing ASM proliferation was estimated by measuring the release of leukotrienes from eosinophils upon their direct contact with ASM cells using ELISA. This role was confirmed either by blocking eosinophil-ASM contact or co-culturing them in the presence of leukotrienes antagonist. ASM cells co-cultured with eosinophils, isolated from asthmatics, but not non-asthmatics, had a significantly higher rate of proliferation compared to controls. This increase in ASM proliferation was independent of their release of ECM proteins but dependent upon eosinophils release of CysLTs. Eosinophil-ASM cell to cell contact was required for CysLTs release. Preventing eosinophil contact with ASM cells using anti-adhesion molecules antibodies, or blocking the activity of eosinophil derived CysLTs using montelukast inhibited ASM proliferation. Our results indicated that eosinophils contribute to airway remodeling during asthma by enhancing ASM cell proliferation and hence increasing ASM mass. Direct contact of eosinophils with ASM cells triggers their release of CysLTs which enhance ASM proliferation. Eosinophils, and their binding to ASM cells, constitute a potential therapeutic target to interfere with the series of biological events leading to airway remodeling and Asthma.
    Journal of Clinical Immunology 11/2012; · 3.38 Impact Factor
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    ABSTRACT: PURPOSE: Most asthmatic patients have well controlled symptoms with regular treatment, but some require much higher doses of inhaled and oral corticosteroids, or in rare cases fail to respond; these patients may present Th-17 cell infiltration and associated cytokines (IL-17A and -F) in the airways, sputum and peripheral blood. Because glucocorticoid receptor-beta (GR-beta) is associated with corticosteroid resistance, we investigated whether Th-17 associated cytokines induce steroid insensitivity in PBMCs via GR-beta up-regulation. METHODS: GR-alpha, GR-beta, GILZ and IL-6 expression were analyzed in PBMCs stimulated with IL-2/IL-4, IL-17A/IL-17F and IL-23 cytokines by quantitative RT-PCR. Dexamethasone-inhibition of PHA-induced proliferation and Dexamethasone-induced apoptosis were determined by either (3)H-thymidine or CFSE-labelled cells and by Annexin-V staining and flow cytometry. RESULTS: IL-17 and IL-23 cytokines significantly increased GR-beta expression. IL-2/IL-4 significantly decreased GR-alpha expression without affecting GR-beta. IL17, IL-23 and IL2 + 4 stimulations significantly hampered Dexamethasone-inhibition of proliferation (Dex EC(50) for: IL-17A + F = 251 nM; IL-23 = 435 nM; IL2 + 4 = 950 nM; Medium = 90 nM). IL2 + 4 and IL17A + F but not IL-23, significantly hampered Dexamethasone-induced apoptosis (1400 and 320 nM Dex, respectively). Dexamethasone's trans-activation of GILZ and trans-repression of NF-kB-driven IL-6 expression were both inhibited by IL2 + 4; IL17 + IL23 antagonized Dex trans-repression in PBMC from asthmatics. CONCLUSIONS: GR-beta up-regulation by IL-17/IL-23 cytokines is associated with induced steroid insensitivity in PBMCs, observed as diminished Dexamethasone's effects on cell proliferation, apoptosis and gene regulation. Steroid resistance induced by IL-2/IL-4 was associated with decreased GR-alpha expression. This study supports the possibility that Th-17 lymphocytes and associated cytokines play a role in the mechanism of steroid hypo-responsiveness in severe asthmatics.
    Journal of Clinical Immunology 11/2012; · 3.38 Impact Factor
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    Molecular Biology Reports 11/2012; · 2.51 Impact Factor

Publication Stats

382 Citations
137.78 Total Impact Points

Institutions

  • 2010–2014
    • King Saud University
      • • College of Medicine
      • • College of Pharmacy
      Ar Riyāḑ, Ar Riyāḑ, Saudi Arabia
  • 2008–2013
    • Université de Montréal
      Montréal, Quebec, Canada
  • 2012
    • King Saud medical city
      Ar Riyāḑ, Ar Riyāḑ, Saudi Arabia
  • 2011
    • McGill University
      • Meakins-Christie Laboratories
      Montréal, Quebec, Canada
    • French Institute of Health and Medical Research
      • Unité de Génétique Humaine des Maladies Infectieuses U980
      Paris, Ile-de-France, France