Judith C W Mak

The University of Hong Kong, Hong Kong, Hong Kong

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Publications (40)149.57 Total impact

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    ABSTRACT: Transplantation of mesenchymal stem cells (MSCs) holds great promise in the repair of cigarette smoke (CS)-induced lung damage in chronic obstructive pulmonary disease (COPD). As cigarette smoke leads to mitochondrial dysfunction, we therefore aimed to investigate the potential benefit of mitochondrial transfer from human-induced pluripotent stem cell-derived mesenchymal stem cells (iPSC-MSCs) to CS-exposed airway epithelial cells in vitro and in vivo. Rats were exposed to 4% CS for one hour daily for 56 days. At day 29 and day 43, human iPSC-MSCs or adult bone marrow-MSCs (BM-MSCs) were administered intravenously to CS-exposed rats. CS-exposed rats exhibited severe alveolar destruction with a higher mean linear intercept (Lm) than sham air-exposed rats (p < 0.001) that was attenuated in the presence of iPSC-MSCs or BM-MSCs (p < 0.01). The attenuation of Lm value and the severity of fibrosis was greater in the iPSC-MSC-treated group than the BM-MSC-treated group (p<0.05). This might be contributed to the novel observation of mitochondrial transfer from MSCs to rat airway epithelial cells in lung sections exposed to CS. In vitro studies further revealed that transfer of mitochondria from iPSC-MSCs to bronchial epithelial cells (BEAS-2B) was more effective than from BM-MSCs with preservation of adenosine triphosphate contents. This distinct mitochondrial transfer occurred via the formation of tunneling nanotubes (TNT). Inhibition of TNT formation blocked mitochondrial transfer. Our findings indicate a higher mitochondrial transfer capacity of iPSC-MSCs than BM-MSCs to rescue CS-induced mitochondrial damage. iPSC-MSCs may thus hold promise for the development of cell therapy in COPD.
    American Journal of Respiratory Cell and Molecular Biology 04/2014; · 4.15 Impact Factor
  • Qian Han, Sze C Yeung, Mary S M Ip, Judith C W Mak
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    ABSTRACT: Obstructive sleep apnea (OSA), characterized by intermittent hypoxia (IH) during sleep, is increasingly recognized as an independent risk factor of cardiovascular diseases. OSA is associated with changes in the levels of circulating oxidative stress/inflammatory markers and dyslipidemia, supporting their mediating roles in cardiovascular pathogenesis. Our aims were to investigate the effect of IH on heart tissue using an IH-exposed rat model and to explore the potential mechanisms involved in the occurrence of cardiac damage. Male Sprague-Dawley rats were exposed to IH and intermittent normoxia as control and sacrificed after 2 or 4 weeks. IH for 4 weeks caused elevation in serum malondialdehyde and cytokine-induced neutrophil chemoattractant-1 and reduction in serum adiponectin levels. In contrast, cardiac oxidative stress and pro-inflammatory markers were suppressed while cardiac adiponectin and cholesterol levels were elevated after IH exposure for 4 weeks. In parallel, there was an increase in apoptosis in the heart of IH-exposed rats, demonstrated by elevations of Bax and cleaved caspase-3 protein and TUNEL staining. Cardiac damage was further evident with decreased arterial vessel and capillary densities, increased cardiac fibrosis, and the loss of troponin I. Our data demonstrated that IH exposure paradoxically caused systemic oxidative and inflammatory responses and cardioprotective responses, i.e., anti-oxidative and anti-inflammatory responses. Despite such a local compensatory protective mechanism, cardiac damage was observed that might be due to IH-induced cholesterol accumulation in the heart and caspase-dependent apoptosis.
    Journal of physiology and biochemistry 10/2013; · 1.65 Impact Factor
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    ABSTRACT: Oxidative stress has been implicated in the pathogenesis of asthma. We aimed at investigating the biomarkers of oxidative stress, inflammation, and tissue damage in patients with asthma in acute exacerbation and remission. We recruited 18 asthmatics admitted to hospital with acute exacerbation and 18 healthy nonsmoking controls matched for age. We evaluated plasma levels of 8-isoprostane, C-reactive protein (CRP) and total matrix metalloproteinase- (MMP-) 9 by ELISA, and MMP-9 activity by zymographic analysis. Plasma levels of 8-isoprostane and CRP were significantly elevated in acute exacerbation and decreased in remission but remained significantly higher compared to healthy controls. The activities of pro-MMP-9 were also significantly higher in acute exacerbation and decreased in remission but remained significantly higher compared to healthy controls in parallel to plasma levels of total MMP-9. These data suggest that overproduction of MMP-9 along with highly elevated levels of oxidative stress and inflammation is implicated in asthma exacerbation and that measurements of these biomarkers can be a valid index in its management.
    ISRN allergy. 01/2013; 2013:561831.
  • Qian Han, Sze Chun Yeung, Mary Sau Man Ip, Judith Choi Wo Mak
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    ABSTRACT: Intermittent hypoxia (IH) is a hallmark feature in obstructive sleep apnea (OSA) which is increasingly recognized as an independent risk factor for atherosclerosis. Oxidative stress, inflammation, and cell apoptosis are major pathological events initiating or accelerating atherogenesis. This study addressed whether IH would affect these proatherogenic factors in endothelial cells and the mechanistic pathways involved. EA.hy926 cells were exposed to intermittent normoxia or IH for different numbers of cycles (32, 64, or 96). IH exposure time-dependently raised cellular GSSG/GSH ratio, increased production of IL-6 and IL-8, and accelerated cell apoptosis and death, concurrent with activation of NF-κB and inhibition of Nrf2/HO-1 pathways. At 64 cycles, inhibition of NF-κB attenuated IH-induced cellular oxidative stress and accumulation of inflammatory cytokines in cell culture medium but aggravated IH-induced cell apoptosis, while stimulation of HO-1 suppressed IH-induced cellular oxidative stress and cell apoptosis without affecting accumulation of inflammatory cytokines in cell culture medium. We demonstrated that early stage of exposure to IH-induced oxidative and inflammatory stresses leading to acceleration of cell apoptosis via NF-κB and Nrf2/HO-1 pathways in endothelial cells, suggesting the potential mechanisms for IH-induced vascular pathogenesis, in resemblance to OSA.
    Cell biochemistry and biophysics 12/2012; · 3.34 Impact Factor
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    ABSTRACT: Our recent study has indicated that Chinese green tea (Lung Chen), in which epigallocatechin-3-gallate (EGCG) accounts for 60% of catechins, protected cigarette smoke-induced lung injury. We now hypothesized that Lung Chen tea may also have potential effect on lung oxidative stress and proteases/anti-proteases in a smoking rat model. Sprague-Dawley rats were exposed to either sham air (SA) or 4% cigarette smoke (CS) plus 2% Lung Chen tea or water by oral gavage. Serine proteases, matrix metalloproteinases (MMPs) and their respective endogenous inhibitors were determined in bronchoalveolar lavage (BAL) and lung tissues by gelatin/casein zymography and biochemical assays. Green tea consumption significantly decreased CS-induced elevation of lung lipid peroxidation marker, malondialdehyde (MDA), and CS-induced up-regulation of neutrophil elastase (NE) concentration and activity along with that of α(1)-antitrypsin (α(1)-AT) and secretory leukoproteinase inhibitor (SLPI) in BAL and lung. In parallel, significant elevation of MMP-12 activity was found in BAL and lung of the CS-exposed group, which returned to the levels of SA-exposed group after green tea consumption but not CS-induced reduction of tissue inhibitor of metalloproteinase (TIMP)-1 activity, which was not reversed by green tea consumption. Taken together, our data supported the presence of local oxidative stress and protease/anti-protease imbalance in the airways after CS exposure, which might be alleviated by green tea consumption through its biological antioxidant activity.
    Free Radical Research 05/2012; 46(9):1123-9. · 3.28 Impact Factor
  • Judith C W Mak
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    ABSTRACT: Green tea (from the plant Camellia sinensis), a beverage whose consumption started 5000 years ago in China, has important biological and pharmacological properties. The beneficial effects of green tea have been attributed to the presence of phenolic compounds that are powerful anti-oxidants and free iron scavengers. Of all the catechins found in green tea, namely (-)-epicatechin-3-gallate, (-)-epigallocatechin, (-)-epicatechin and (-)-epigallocatechin-3-gallate (EGCG), EGCG is the most abundant and powerful. It is widely believed that green tea may protect against death from all causes, especially cardiovascular diseases (coronary heart disease and stroke) owing to the presence of catechins associated with green tea consumption. Other health benefits include various types of cancer chemoprevention, weight loss and protective effects against neurodegenerative diseases (Alzheimer's disease and Parkinson's disease). Thus far, numerous pharmacological activities regulating disease-specific molecular targets have been reported in vitro for EGCG concentrations in the micromolar range, which are physiologically irrelevant. Although most of the studies have shown benefits with two to three cups of green tea per day, the optimal dose has not yet been established to enable any solid conclusions to be drawn regarding the various health benefits of green tea or its constituents in humans. With Phase I trials providing information on the safety profile and pharmacokinetics of EGCG, the window of opportunity is wider to undertake well-controlled long-term human studies to enable a full understanding of the protective effects of green tea catechins on various parameters in different settings.
    Clinical and Experimental Pharmacology and Physiology 03/2012; 39(3):265-73. · 2.16 Impact Factor
  • Jamie Chung Mei Lam, Judith Choi Wo Mak, Mary Sau Man Ip
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    ABSTRACT: OSA is increasingly recognized as a major health problem in developed countries. Obesity is the most common risk factor in OSA and hence, the prevalence of OSA is undoubtedly rising given the epidemic of obesity. Recent data also suggest that OSA is highly associated with the metabolic syndrome, and it is postulated that OSA contributes to cardiometabolic dysfunction, and subsequently vasculopathy. Current evidence regarding the magnitude of impact on ultimate cardiovascular morbidity or mortality attributable to OSA-induced metabolic dysregulation is scarce. Given the known pathophysiological triggers of intermittent hypoxia and sleep fragmentation in OSA, the potential mechanisms of OSA-obesity-metabolic syndrome interaction involve sympathetic activation, oxidative stress, inflammation and neurohumoral changes. There is accumulating evidence from human and animal/cell models of intermittent hypoxia to map out these mechanistic pathways. In spite of support for an independent role of OSA in the contribution towards metabolic dysfunction, a healthy diet and appropriate lifestyle modifications towards better control of metabolic function are equally important as CPAP treatment in the holistic management of OSA.
    Respirology 02/2012; 17(2):223-36. · 2.78 Impact Factor
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    ABSTRACT: Cigarette smoking is a major risk factor in the development of age-related chronic obstructive pulmonary disease (COPD). The serotonin transporter (SERT) gene polymorphism has been reported to be associated with COPD, and the degree of cigarette smoking has been shown to be a significant mediator in this relationship. The interrelation between circulating serotonin (5-hydroxytyptamine, 5-HT), cigarette smoking and COPD is however largely unknown. The current study aimed at investigating the mediation effects of plasma 5-HT on cigarette smoking-induced COPD and the relation between plasma 5-HT levels and age. The association between plasma 5-HT, age and COPD was analyzed in a total of 62 COPD patients (ever-smokers) and 117 control subjects (healthy non-smokers and ever-smokers). Plasma 5-HT levels were measured by enzyme-linked immuno assay (EIA). The elevated plasma 5-HT levels were significantly associated with increased odds for COPD (OR = 1.221, 95% CI = 1.123 to 1.319, p<0.0001). The effect remained significant after being adjusted for age and pack-years smoked (OR = 1.271, 95% CI = 1.134 to 1.408, p = 0.0003). Furthermore, plasma 5-HT was found to mediate the relation between pack-years smoked and COPD. A positive correlation (r = 0.303, p = 0.017) was found between plasma 5-HT levels and age in COPD, but not in the control subjects (r = -0.149, p = 0.108). Our results suggest that cigarette smoke-induced COPD is partially mediated by the plasma levels of 5-HT, and that these become elevated with increased age in COPD. The elevated plasma 5-HT levels in COPD might contribute to the pathogenesis of this disease.
    PLoS ONE 01/2012; 7(2):e31617. · 3.73 Impact Factor
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    ABSTRACT: The present study investigated the mechanism underlying the transient potentiation of vasoconstriction by hypoxia in isolated porcine coronary arteries. Isometric tension was measured in rings with or without endothelium. Hypoxia (Po(2) <30 mmHg) caused a transient further increase in tension (hypoxic augmentation) in contracted (with U46619) preparations. The hypoxic response was endothelium dependent and abolished by inhibitors of nitric oxide synthase [N(ω)-nitro-L-arginine methyl ester (L-NAME)] or soluble guanylyl cyclase (ODQ and NS2028). The addition of DETA NONOate (nitric oxide donor) in the presence of L-NAME restored the hypoxic augmentation, suggesting the involvement of the nitric oxide pathway. However, the same was not observed after incubation with 8-bromo-cyclic GMP, atrial natriuretic peptide, or isoproterenol. Assay of the cyclic GMP content showed no change upon exposure to hypoxia in preparations with and without endothelium. Incubation with protein kinase G and protein kinase A inhibitors did not inhibit the hypoxic augmentation. Thus the hypoxic augmentation is dependent on nitric oxide and soluble guanylyl cyclase but independent of cyclic GMP. The hypoxic augmentation persisted in calcium-free buffer and in the presence of nifedipine, ruling out a role for extracellular calcium influx. Hypoxia did not alter the intracellular calcium concentration, as measured by confocal fluorescence microscopy. This observation and the findings that hypoxic augmentation is enhanced by thapsigargin (sarco/endoplasmic reticulum calcium ATPase inhibitor) and inhibited by HA1077 or Y27632 (Rho kinase inhibitors) demonstrate the involvement of calcium sensitization in the phenomenon.
    AJP Heart and Circulatory Physiology 12/2011; 301(6):H2313-21. · 3.63 Impact Factor
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    ABSTRACT: Cigarette smoking is a major risk factor in chronic obstructive pulmonary disease (COPD) with chronic airway inflammation as a key feature. Blockade of serotonin receptor 2A (5-HTR(2A)) with ketanserin has been found to improve lung function in COPD patients. Furthermore, ketanserin has been shown to possess anti-inflammatory properties in vivo. In this study, we investigated the antioxidative and anti-inflammatory properties of ketanserin and its underlying mechanism of action on cigarette smoke-induced interleukin (IL)-8 release in vitro. Primary normal human bronchial epithelial cells and human bronchial epithelial cell line (BEAS-2B) were treated with or without ketanserin prior to exposure to cigarette smoke medium (CSM). Exposure to CSM caused elevation of both mRNA and release of IL-8 with increased phosphorylation of p38 and extracellular signal-regulated kinases 1 and 2 (ERK1/2). Consistently, CSM-induced IL-8 release was blocked by SB203580, U0126, or MEK1 small interfering RNA (siRNA) but not SP600125. On the other hand, CSM caused a dose-dependent decrease in the ratio of reduced glutathione to oxidized glutathione (rGSH/GSSG) together with an increased translocation of Nrf2 to the nucleus demonstrated by Western blot analysis. Knock down of Nrf2 by siRNA completely blocked CSM-induced IL-8 release. Ketanserin suppressed CSM-induced IL-8 release by inhibiting p38, ERK1/2 MAPK, and Nrf2 signaling pathways and partially inhibited CSM-induced reduction of rGSH/GSSG ratio. Our data demonstrated the novel antioxidative and anti-inflammatory role of ketanserin via the Nrf2 signaling pathway in CSM-exposed human bronchial epithelial cells. This may open up new perspectives in the development of novel therapeutic targets in the treatment of cigarette smoke-related COPD.
    Toxicological Sciences 11/2011; 125(2):569-77. · 4.33 Impact Factor
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    ABSTRACT: Adiponectin is an anti-inflammatory adipokine that may play a role in chronic obstructive pulmonary disease (COPD) pathogenesis. To investigate the relationship between adiponectin, interleukin (IL) 6, IL-8 and C-reactive protein (CRP) and COPD by evaluating these biomarkers in ever-smokers with or without the disease. Plasma levels of adiponectin, IL-6, IL-8 and CRP were measured using commercially available kits in COPD patients (n = 71), healthy ever-smokers (n = 62) and non-smokers (n = 51). There were significant increases in plasma adiponectin, IL-6 and CRP in COPD patients (median [IQR] 4.39 microg/ml [2.68-6.98], 4.19 pg/ml [<2.40-6.40], 8.75 mg/l [4.26-40.63], respectively) compared to healthy ever-smokers (1.90 microg/ml [0.86-2.86], <2.40 pg/ml [<2.40-2.77], 3.71 mg/l [1.97-10.37 mg/l], respectively, P < 0.001) and non-smokers (1.76 microg/ml [1.34-2.52], <2.40 pg/ml [<2.40-2.78], 3.12 mg/l [2.11-5.71], respectively, P < 0.001). COPD patients had lower plasma IL-8 levels than healthy ever-smokers. Among ever-smokers with or without COPD, plasma adiponectin, IL-6 and CRP levels were inversely correlated with forced expiratory volume in 1 second (% predicted) after adjustment for age, body mass index, smoking status and pack-years. Our findings suggest that in COPD patients, adiponectin might be associated with COPD pathogenesis.
    The international journal of tuberculosis and lung disease: the official journal of the International Union against Tuberculosis and Lung Disease 09/2010; 14(9):1193-200. · 2.61 Impact Factor
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    Qian Han, Sze C Yeung, Mary S M Ip, Judith C W Mak
    International journal of cardiology 05/2010; 145(2):396-8. · 7.08 Impact Factor
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    ABSTRACT: Epigallocatechin-3-gallate (EGCG), which has been shown to have potent antioxidant effect, comprises 80% of catechins in Chinese green tea. This study was to investigate whether cigarette smoke (CS) exposure would induce lung morphological changes and oxidative stress in the CS-exposed rat model, and whether Chinese green tea (Lung Chen tea with EGCG as its main active ingredient) consumption would alter oxidative stress in sera and lung leading to protection of CS-induced lung damage. Sprague-Dawley rats were randomly divided into four groups, i.e. sham air (SA), 4% CS, 2% Lung Chen tea plus SA or 4% CS. Exposure to SA or 4% CS was performed for 1h/day for 56 days in ventilated smoking chambers. Sera and lung tissues were collected 24h after last CS exposure for histology and all biochemical assays. Airspace enlargement and goblet cell hyperplasia were observed after 56-day CS exposure alone, which were abolished in the presence of green tea consumption. Serum 8-isoprostane level was significantly elevated (p<0.01) as well as lung superoxide dismutase (SOD) and catalase activities in CS-exposed rats compared to SA-exposed rats (p<0.05), which returned to the levels of SA-exposed rats after Chinese green tea consumption. These results indicate that increased levels of systemic oxidative stress after CS exposure play an important role in the induction of lung damage. Chinese green tea may have the ability to suppress CS-induced oxidative stress that leads to protection of lung injury.
    Respiratory medicine 05/2009; 103(11):1746-54. · 2.33 Impact Factor
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    ABSTRACT: Rho kinase is involved in the pathogenesis of hypertension, which favors the occurrence of endothelium-dependent contractions. The present study was designed to determine the effects of two Rho kinase inhibitors, HA1077 [1-(5-isoquinolinesulfonyl)-homopiperazine (fasudil)] and Y27632 [(+)-(R)-trans-4-(1-aminoethyl)-N-(4-pyridyl) cyclohexane carboxamide dihydrochloride], on endothelium-dependent and -independent contractions. Isometric tension of 1-year-old spontaneously hypertensive rat and Wistar Kyoto aortae were measured. In the presence of N(omega)-nitro-L-arginine methyl ester, HA1077, and Y27632 reduced endothelium-dependent contractions caused by acetylcholine and the calcium ionophore 5-(methylamino)-2-[[2R,3R,6S,8S,9R,11R)-3,9,11-trimethyl-8-[(1S)-1-methyl-2-oxo-2-(1H-pyrrol-2-yl)-ethyl]-1,7-dioxaspiro[5.5]undec-2-yl]methyl]-4-benzoxazolecarboxylic acid (A23187). The Rho kinase inhibitors did not significantly affect prostacyclin production measured as 6-keto prostaglandin F(1alpha). They nearly abolished endothelium-independent contractions to (5Z)-7-[(1R,4S,5S,6R)-6-[(1E,3S)-3-hydroxy-1-octenyl]-2-oxabicyclo-[2.2.1]hept-5-yl]-5-heptenoic acid (U46619), prostaglandin F(2alpha), and phenylephrine. Western blotting revealed a comparable expression of Rho kinase in the aortae of the two strains. The reduction by Rho kinase inhibitors of endothelium-dependent contractions is mainly because of their direct effect on the vascular smooth muscle cells.
    Journal of Pharmacology and Experimental Therapeutics 03/2009; 329(2):820-6. · 3.89 Impact Factor
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    ABSTRACT: Transforming growth factor-beta(1) (TGF-beta(1)), a multifunctional cytokine, has been implicated to be responsible for the increased deposition of extracellular matrix in the airways, and increased submucosal collagen expression in chronic obstructive pulmonary disease (COPD). We determined plasma TGF-beta(1) levels in patients with COPD and explored its association with common functional polymorphisms of TGF-beta(1) gene at C-509T and T869C in the development of COPD in a case-control study. Stable COPD patients who were ever smokers, and age and pack-years smoked matched healthy controls (n = 205 in each group) were recruited for measurement of plasma TGF-beta(1) levels using commercially available ELISA kit, and genotyped at C-509T and T869C functional polymorphisms of TGF-beta(1) gene using polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP). COPD patients had significantly elevated plasma TGF-beta(1) levels in comparison to healthy controls irrespective of the genotypes. Allele frequencies and genotype distributions at both polymorphic sites were not different among COPD patients or controls. TGF-beta(1) levels were inversely correlated (Pearson's correlation analysis) with FEV(1) (% predicted) (p < 0.001) and FVC (% predicted) (p < 0.001). The findings of elevated plasma TGF-beta(1) levels in patients with COPD suggest that TGF-beta(1) may play a role in COPD pathogenesis. The C-509T and T869C functional polymorphisms of TGF-beta(1) gene do not represent a genetic predisposition to COPD susceptibility in Hong Kong Chinese patients.
    Respiratory medicine 01/2009; 103(7):1083-9. · 2.33 Impact Factor
  • J C W Mak
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    ABSTRACT: Chronic obstructive pulmonary disease (COPD) represents a serious global health problem that affects the aged. This State of the Art article summarises previous studies on oxidative-antioxidative imbalance in patients with stable COPD or in acute exacerbations. Recent literature in this field reports conflicting findings. Several studies on markers of oxidative stress have demonstrated increased production of oxidants in exhaled air, breath condensates or induced sputum. The primary defence against oxidants is endogenous antioxidants, which are altered in COPD. Some studies have demonstrated a marked decrease in plasma antioxidant capacity, while other studies have shown opposite findings. A few studies have shown higher erythrocyte superoxide dismutase (SOD) activity in COPD patients and healthy smokers than those in healthy non-smokers. In contrast, we found no differences in erythrocyte SOD activity and elevated erythrocyte catalase activity in Chinese patients with COPD compared with healthy smokers matched for age and pack-years smoked. Possible reasons for such discrepancies could be related to differences in inter-individual variations in antioxidant capacity as a result of different populations and also differences in methodologies between studies.
    The international journal of tuberculosis and lung disease: the official journal of the International Union against Tuberculosis and Lung Disease 05/2008; 12(4):368-74. · 2.61 Impact Factor
  • J.C.W. Mak
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    ABSTRACT: Chronic obstructive pulmonary disease (COPD) represents a serious global health problem that affects the aged. This State of the Art article summarises previous studies on oxidative-antioxidative imbalance in patients with stable COPD or in acute exacerbations. Recent literature in this field reports conflicting findings. Several studies on markers of oxidative stress have demonstrated increased production of oxidants in exhaled air, breath condensates or induced sputum. The primary defence against oxidants is endogenous antioxidants, which are altered in COPD. Some studies have demonstrated a marked decrease in plasma antioxidant capacity, while other studies have shown opposite findings. A few studies have shown higher erythrocyte superoxide dismutase (SOD) activity in COPD patients and healthy smokers than those in healthy non-smokers. In contrast, we found no differences in erythrocyte SOD activity and elevated erythrocyte catalase activity in Chinese patients with COPD compared with healthy smokers matched for age and pack-years smoked. Possible reasons for such discrepancies could be related to differences in inter-individual variations in antioxidant capacity as a result of different populations and also differences in methodologies between studies.
    The international journal of tuberculosis and lung disease: the official journal of the International Union against Tuberculosis and Lung Disease 03/2008; 12(3 in the series]" class="no-underline contain" target="_blank">PDF 97.6kb):368-374. · 2.61 Impact Factor
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    ABSTRACT: The airway epithelium participates in chronic airway inflammation by expressing adhesion molecules that mediate the transmigration of neutrophils into the inflamed airways. We hypothesize that, in patients with bronchiectasis, cytokines in their bronchial secretions enhance the expression of intercellular cell adhesion molecule (ICAM-1) in the bronchial epithelium and thus contribute to sustained recruitment of neutrophils into the inflamed airways. In the present study, we investigated the effect of bronchial secretions on the regulation of ICAM-1 in bronchial epithelial cells, and its modulation by pharmacologic agents. The expression of ICAM-1 mRNA and protein in human bronchial epithelial cells upon exposure to sputum sol from subjects with bronchiectasis were evaluated by reverse transcription-polymerase chain reaction (RT-PCR) and ELISA, respectively. Modulating effects of dexamethasone, ibuprofen, MK-663 or triptolide on ICAM-1 regulation were investigated in vitro. We demonstrated that changes in ICAM-1 expression correlated with levels of TNF-alpha in the sputum sol, and treatment of sol samples with TNF-alpha antibodies attenuated both the increase in ICAM-1 mRNA and protein. The role of TNF-alpha was further demonstrated when TNF-alpha elicited dose dependent increase in ICAM-1 expression. The sputum effect could also be suppressed dose-dependently by pre-incubation of bronchial epithelial cells with dexamethasone, ibuprofen, MK-663 or triptolide. Evidence is thus provided for the upregulation of bronchial epithelial ICAM-1 expression by airway secretions in bronchiectasis and a specific role for TNF-alpha in the secretions. The success of drug attenuation of this upregulation provides insight into possible therapeutic paradigms in the management of the disease.
    Respiratory Medicine 03/2008; 102(2):287-98. · 2.59 Impact Factor
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    ABSTRACT: Susceptibility to tuberculosis (TB) may be affected by host genetic factors. Elevated levels of transforming growth factor-beta 1 (TGF-beta(1)) were found in plasma of patients with active TB compared with those of healthy contacts. To investigate the association of TGF-beta(1) gene polymorphisms (C-509T and T869C) and plasma levels with the risk of TB in Hong Kong Chinese adults, a case-control study was carried out on 174 active TB patients and 174 healthy controls matched for age, gender and smoking. Blood samples from 180 blood donors served as another control group. Genotyping was carried out on genomic DNA using polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP). Plasma TGF-beta(1) was measured by commercially available ELISA kit. We found no differences in the distribution of genotypes or alleles of TGF-beta(1) gene polymorphisms at C-509T and T869C between patients and either group of healthy controls. Patients with TB had elevated plasma TGF-beta(1) levels compared with healthy controls irrespective of their genotypes (p<0.001). In conclusion, TGF-beta(1) gene polymorphism at C-509T and T869C is not associated with TB susceptibility in Hong Kong Chinese adults, but elevated plasma TGF-beta(1) levels suggests that this cytokine may play a role in the pathogenesis of tuberculosis.
    Cytokine 12/2007; 40(3):177-82. · 2.52 Impact Factor
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    ABSTRACT: Increased oxidative stress has been implicated in the pathogenesis of chronic obstructive pulmonary disease (COPD). This study investigated the risk of COPD and the substitution of alanine 16 with valine (Ala16Val) polymorphism of manganese-superoxide dismutase (Mn-SOD) and the cytosine to thymidine transition of nucleotide -262 (-262C>T) polymorphism of the catalase gene, and the activity of erythrocyte SOD and catalase. The subjects were stable COPD patient ever smokers (n = 165) and healthy controls, matched for age and cigarette consumption. Genotyping of Mn-SOD at Ala16Val and the catalase gene at -262C>T was performed, and the functional activity of SOD and catalase in erythrocytes determined. There were no significant differences in the distribution of the different genotypes or allele frequencies between patients and controls for both the Mn-SOD and catalase genes. Among healthy controls or COPD patients, no differences were observed in erythrocyte SOD and catalase activity, irrespective of genotype. Significantly higher erythrocyte catalase activity was found in COPD patients than in healthy controls. The T/T catalase genotype and Ala/Ala Mn-SOD genotype were uncommon in the present Chinese population. The increase in erythrocyte catalase activity in Chinese patients with chronic obstructive pulmonary disease probably indicates dysfunction of the oxidant/antioxidant defence system, but it is unclear whether this increase is compensatory or a pathogenic factor.
    European Respiratory Journal 10/2007; 30(4):684-90. · 6.36 Impact Factor