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Biomedical subjects

K Fan Chung

Publications and source records attributed to K Fan Chung.

At least 19 recordsLinked to original sources
PubMed2003

Mitogen-activated protein kinase modulation of nuclear factor-kappaB-induced granulocyte macrophage-colony-stimulating factor release from human alveolar macrophages.

Granulocyte macrophage-colony-stimulating factor (GM-CSF), released from alveolar macrophages (AM), is an important regulator of eosinophil, T cell, and macrophage function and survival. We determined the mechanisms of GM-CSF regulation in AM from normal volunteers activated by lipopolysaccharide (LPS) by examining the role of nuclear factor-kappaB (NF-kappaB), and of p38 mitogen-activated protein (MAP) kinase and MAP kinase kinase (MKK-1). PD 098059 (10 microM), an inhibitor of upstream activator of MKK-1, inhibited GM-CSF expression, but the expression of GM-CSF was not inhibited by SB 203580 (10 microM), an inhibitor of p38-MAP kinase. Phosphorylation of extracellular signal-regulated kinase-1 (ERK-1), ERK-2, and p38 MAP kinase by LPS were demonstrated on Western blot analysis. LPS increased NF-kappaB:DNA binding as examined by electrophoretic mobility shift assay, but this was not suppressed by PD 098059 or by SB 203580. LPS induced an increase in NF-kappaB activation as examined by p50 translocation assay without suppression by PD 098059 or by SB 203580. SN50 (100 microM), an inhibitor of NF-kappaB translocation and the specific IKK-2-Inhibitor (AS602868; 10 microM), also prevented GM-CSF expression and release induced by LPS, indicating that GM-CSF release is NF-kappaB-dependent. PD 098059, but not SB 203580, inhibited LPS-induced histone acetyltransferase (HAT) activity, indicating chromatin modification. Furthermore, AS602868 and SN 50 suppressed LPS-induced HAT activity. TSA (10 ng/ml), an inhibitor of histone deacetylase (HDAC), reversed the inhibitory effect of PD 098059, SB 203580, SN 50 and AS602868 on GM-CSF release. GM-CSF expression and release in AM is controlled by NF-kappaB activation, and this is modulated by phosphorylation of MKK-1 and p38 MAP kinase acting on histone acetylation.

Acetyltransferases↗
PubMed2003

Role of c-jun N-terminal kinase in the induced release of GM-CSF, RANTES and IL-8 from human airway smooth muscle cells.

1. Human airway smooth muscle cells (HASMC) contribute to airway inflammation in asthma by virtue of their capacity to produce several inflammatory mediators including IL-8, GM-CSF and RANTES. The intracellular signal pathway underlying the production of these cytokines in HASMC is not entirely elucidated. 2. We examined the role of the mitogen-activated protein kinase (MAPK) c-jun N-terminal kinase (JNK) in TNFalpha- and IL-1beta-induced GM-CSF, RANTES and IL-8 production in HASMC by using a novel specific inhibitor for JNK (SP600125). 3. Confluent HASMC were treated with TNFalpha or IL-1beta (10 ng ml(-1)) for 24 h in the presence or absence of SP600125 (1-100 micro M). JNK activity was determined by a kinase assay. Phosphorylation of JNK, p38 MAPK and ERK was examined by Western blotting. Culture supernatants were assayed for GM-CSF, RANTES and IL-8 content by ELISA. 4. Maximum TNFalpha- or IL-1beta-induced phosphorylation of JNK in HASMC occurred after 15 min and returned to baseline levels after 4 h. SP600125 inhibited TNFalpha- and IL-1beta-induced JNK activity in HASMC as shown by the reduced phosphorylation of its substrate c-jun. Furthermore, GM-CSF, RANTES and to a lesser extent IL-8 release from HASMC treated with TNFalpha and IL-1beta was inhibited dosedependently by SP600125. 5. JNK activation is involved in TNFalpha- and IL-1beta-induced GM-CSF, RANTES and IL-8 production from HASMC. JNK may therefore represent a critical pathway for cytokine production in HASMC.

Cells, Cultured↗
PubMed2003

Effects of cyclosporin A and a rapamycin derivative (SAR943) on chronic allergic inflammation in sensitized rats.

Immunomodulators such as cyclosporin A (CsA) and SAR943 (32-deoxorapamycin) inhibit single allergen-induced allergic inflammation such as eosinophilic and lymphocytic infiltration and mRNA expression for interleukin (IL)-4 and IL-5. We examined the effects of CsA and SAR943, administered orally, on asthmatic responses in a rat model of chronic allergic inflammation. Sensitized Brown-Norway (BN) rats were exposed to ovalbumin (OVA) aerosol every third day on six occasions. CsA (5 mg/kg/day), SAR943 (2.5 mg/kg/day) or vehicle (Neoral) was administered orally, once a day, from days 10 to 21 (a total of 12 doses). We measured eosinophilic and T-cell inflammation in the airways, proliferation of airway cells by incorporation of bromodeoxyuridine (BrdU) and bronchial responsiveness to acetylcholine. CsA had no effects, while SAR943 inhibited airway smooth muscle (ASM, P < 0.05) and epithelial cell (P < 0.01) BrdU incorporation, and the number of CD4+ T cells (P < 0.05), without effects on BHR. ASM thickness was not significantly increased following chronic allergen exposure. Therefore, CsA and SAR943 have no effect on chronic eosinophilic inflammation, while SAR943, but not CsA, had a small effect on the proliferation of ASM and epithelium.

Acetylcholine↗
PubMed2003

Effect of acute and chronic inflammatory stimuli on expression of protease-activated receptors 1 and 2 in alveolar macrophages.

BACKGROUND: Protease-activated receptors 1 and 2 (PAR-1 and PAR-2) are 7-transmembrane G protein-coupled receptors activated by serine proteases in many cell types, including monocytes-macrophages, leading to the production of pro-inflammatory mediators, cytokines, and growth factors. OBJECTIVE: We determined the influence of chronic smoking and asthma on the expression of PAR-1 and PAR-2 receptors on alveolar macrophages (AMs). METHODS: We used RT-PCR and immunocytochemistry with confocal microscopy to determine mRNA and protein expression of PAR-1 and PAR-2 in AMs obtained from healthy smokers, asthmatic patients, and healthy subjects. In addition, we examined the effect of IL-1beta and LPS. RESULTS: PAR1 mRNA was decreased, whereas PAR2 mRNA was increased in 24-hour cultured AMs from smokers when compared with values in AMs from healthy subjects. Paradoxically, there was a higher degree of PAR-1 protein staining in AMs from smokers, whereas PAR-2 staining was similar in smokers and healthy subjects. PAR-1 and PAR-2 mRNA and protein expression were similar in asthmatic patients and control subjects. IL-1beta and LPS had no effect on PAR1 and PAR2 gene expression by AMs. CONCLUSIONS: There is a dissociation between gene and protein expression of PAR-1 and PAR-2. PAR-1 protein overexpression in AMs from smokers might be important in the pathophysiology of chronic airways disease.

Adult↗
PubMed2003

Distribution of respiratory mucin proteins in human nasal mucosa.

OBJECTIVES/HYPOTHESIS: The upper respiratory tract is involved in many acute and chronic respiratory tract diseases that present with the symptom of mucus hypersecretion. Mucin genes that encode for the backbone of glycoproteins contribute to the viscoelastic property of airway mucus. We examined the cellular expression and distribution of two major respiratory mucus-forming glycoproteins, MUC5AC and MUC5B, in normal human nasal tissues. METHODS: Immunohistochemical analysis using polyclonal antibodies against the mucins MUC5AC and MUC5B was performed in normal human nasal tissues. RESULTS: An abundant staining of submucosal mucus gland and epithelial goblet cells for MUC5B was found. Immunohistochemical analysis of MUC5AC showed staining of surface epithelium goblet cells, whereas there was no staining of glandular cells. Comparison of the expression to lower airways revealed a similar pattern of expression of both mucins. CONCLUSIONS: The data in the present study demonstrated the localization of the two major respiratory mucin proteins in human nasal mucosa with a similar distribution of expression of MUC5AC and MUC5B in normal upper and lower airways. Mucin protein expression parallels that of mucin messenger RNA expression.

Acute Disease↗
PubMed2003

Role of nitric oxide in chronic allergen-induced airway cell proliferation and inflammation.

Chronic cellular inflammation and airway wall remodeling with subepithelial fibrosis and airway smooth muscle thickening are features of chronic asthma. We determined the role of nitric oxide in the pathogenesis of allergen-induced airway cell proliferation and inflammation by studying the effects of a relatively selective prodrug inhibitor of nitric-oxide synthase type 2 (NOS2), L-N6-(1-iminoethyl)-lysine-5-tetrazole amide (SC-51). Brown-Norway rats were sensitized to ovalbumin and were exposed to ovalbumin aerosol every 3rd day on six occasions and were treated orally with either vehicle or SC-51 (10 mg. kg(-1); 12 doses). We measured inflammatory cell accumulation in the airways and proliferation of cells by incorporation of bromodeoxyuridine. There was an increase in the total number of airway smooth muscle cells expressing bromodeoxyuridine from 1.3% of airway smooth muscle cells in saline exposed to 5.4% after allergen-exposure (P < 0.001) and airway epithelial cells from 3.3 cells/mm basement membrane to 9.6 after allergen-exposure (P < 0.001). SC-51 had no effect on airway smooth muscle or epithelial cell proliferation. SC-51 attenuated the allergen-induced increase in major basic protein (MBP+) eosinophil (P < 0.05) and CD4+ T-cell (P < 0.05) accumulation. We conclude that nitric oxide derived during allergic inflammation is involved in the expression of eosinophilic inflammation and not in epithelial or airway smooth muscle cell DNA synthesis induced by chronic allergen exposure.

Actins↗
PubMed2003

Current and future prospects for drugs to suppress cough.

Cough is an important defensive reflex of the airway and a common symptom of respiratory disease. After an upper respiratory tract virus infection, cough is transient, but is more persistent with conditions such as asthma, rhinosinusitis, gastroesophageal reflux, chronic obstructive pulmonary disease (COPD) and lung cancer. Treatment directed at these conditions may improve cough, but there remains a need to control cough directly. The most effective antitussives are opioids, such as morphine, codeine or pholcodeine, but they produce side effects including drowsiness, nausea, constipation and physical dependence. Opioids such as k- and d-opioid receptor agonists, non-opioids such as nociceptin, neurokinin and bradykinin receptor antagonists, vanilloid receptor VR(1) antagonists, blockers of sodium-dependent channels, and maxi-K calcium-dependent channel activators of afferent nerves may all represent novel antitussives and this needs to be confirmed in clinical trials.

Anesthetics, Local↗
PubMed2002

Role of nitric oxide in allergic inflammation and bronchial hyperresponsiveness.

The role of nitric oxide (NO) in allergic inflammation and bronchial hyperresponsiveness is unclear. We studied a selective prodrug nitric oxide synthase (NOS)-2 inhibitor, L-N(6)-(1-iminoethyl)lysine 5-tetrazole amide (SC-51). In ovalbumin-sensitized and challenged rats, exhaled NO levels increased by 3 h following challenge (3.73 +/- 0.74 ppb; P < 0.05), peaking at 9 h (11.0 +/- 2.75; P < 0.01) compared to saline controls (1.87 +/- 0.26; P < 0.05 and 2.81 +/- 0.18; P < 0.01). Immunoreactive lung NOS2 expression was increased in ovalbumin-challenged rats compared with ovalbumin-sensitized, saline-challenged rats at 8 h post-challenge. SC-51 (10 mg/kg; p.o.) inhibited allergen-induced increase in exhaled NO levels to 1.3 +/- 0.17 ppb. SC-51 inhibited bronchial hyperresponsiveness in ovalbumin-sensitized and challenged rats (P < 0.05). In sensitized non-exposed rats, SC-51 increased bronchial responsiveness (P < 0.05). SC-51 reduced the allergen-induced increase in bronchoalveolar lavage neutrophils, but caused a nonsignificant reduction in bronchial mucosal eosinophil numbers. NO generated through NOS2 contributes to allergen-induced bronchial hyperresponsiveness but not to bronchial eosinophilia, indicating that these are independently expressed.

Acetylcholine↗
PubMed2002

Repeated allergen inhalation induces phenotypic modulation of smooth muscle in bronchioles of sensitized rats.

Repeated ovalbumin (OA) or saline exposure of sensitized Brown Norway rats was examined on agonist reactivity, airway smooth muscle (ASM) content, and contractile protein expression in small bronchioles at 24 h, 7 days, and 35 days after challenge. OA increased ASM content (P < 0.05 vs. saline) at 24 h, which resolved by 7 days. Maximum developed tension (T(max)) to carbachol, KCl, and 4-beta-phorbol 12,13-dibutyrate was increased (P < 0.05) by OA in bronchioles at 24 h but was abrogated after correction for ASM. Differences in T(max) were not present at 7 days. In contrast, at 35 days, T(max) was increased (P < 0.05) after correction for ASM. Smooth muscle (sm)-alpha-actin, sm-myosin heavy chain (MHC) isoform 1, calponin, smoothelin-A, and sm-myosin light chain kinase expression were reduced (P < 0.05) by OA at 24 h in bronchioles but not in trachealis. Consistent with contraction findings, no difference in expression of these proteins was detected at 7 days. At 35 days, however, with the exception of sm-alpha-actin, their abundance was again reduced (P < 0.05) by OA. Nonmuscle MHC and beta-actin were unchanged throughout by OA. These findings indicate persistent changes in contractile protein content, consistent with ASM phenotypic modulation in vivo, which occur in response to repeated OA inhalation. Thus, OA exposure induces structural changes in bronchiole ASM content and in agonist responsiveness ex vivo that resemble remodeling in asthma.

Allergens↗
PubMed2002

Increased p21(CIP1/WAF1) and B cell lymphoma leukemia-x(L) expression and reduced apoptosis in alveolar macrophages from smokers.

Alveolar macrophages (AMs) are the predominant defense cells in the airway, and their numbers are increased in smokers and subjects with chronic obstructive pulmonary disease. This increase may result from increased recruitment, increased proliferation, or reduced cell death. Apoptosis regulates inflammatory cell survival, and p21(CIP1/WAF1) is an important inhibitory regulator of cycle progression after oxidative stress. We have investigated whether chronic smoke exposure influences the expression and localization of cell cycle and apoptotic proteins in AM and bronchial epithelial cells in vivo. The increased numbers of AMs seen in smokers were only partially due to enhanced proliferation. p21(CIP1/WAF1) protein expression was increased in AMs and biopsies isolated from smokers and was found predominantly within the cytoplasm. In addition, B cell lymphoma leukemia (Bcl)-x(L), an antiapoptotic regulator, was also highly expressed in macrophages from smokers compared with nonsmokers and subjects with asthma. Hydrogen peroxide, an oxidative stress, induced cytoplasmic expression of p21(CIP1/WAF1) and failed to induce apoptosis in an in vitro model. These results suggested that AM and bronchial epithelial cells from smokers, in contrast to those from normal subjects and subjects with asthma, have reduced cell death. Thus, oxidative stress induced by cigarette smoking may contribute to the chronicity of inflammation in the airway, through a reduction of apoptosis.

Adult↗
PubMed2002

Expression and activity of histone deacetylases in human asthmatic airways.

Asthma is a chronic inflammatory disease that is characterized by increased expression of multiple inflammatory genes. Chromatin modification plays a critical role in the regulation of these genes. Acetyaltion of histones by histone acetyltransferases (HATs) is associated with increased gene transcription, whereas hypocetylation induced by histone deacetylases (HDACs) is associated with suppression of gene expression. We have examined the expression and activity of HATs and HDACs in bronchial biopsies from normal subjects and subjects with asthma. There was no difference in the site of HDAC1-HDAC6 expression between normal subjects and subjects with asthma, but subjects with asthma had reduced HDAC enzymatic activity and reduced HDAC1 and HDAC2 protein expression, as measured by Western blotting. In contrast, subjects with asthma treated with inhaled steroids were found to have greater HDAC activity than untreated subjects with asthma, although still lower than control subjects. In contrast, although there was no change in the site of HAT (CREB binding protein and p300/CREB binding protein-associated factor) expression, HAT activity was increased in subjects with asthma. HAT activity was reduced to control levels in subjects with asthma treated with inhaled steroids. The increase in HAT activity and reduced HDAC activity in asthma may underlie the increased expression of multiple inflammatory genes, and this is reversed, at least in part, by treatment with inhaled steroids.

Administration, Inhalation↗
PubMed2002

A molecular mechanism of action of theophylline: Induction of histone deacetylase activity to decrease inflammatory gene expression.

The molecular mechanism for the anti-inflammatory action of theophylline is currently unknown, but low-dose theophylline is an effective add-on therapy to corticosteroids in controlling asthma. Corticosteroids act, at least in part, by recruitment of histone deacetylases (HDACs) to the site of active inflammatory gene transcription. They thereby inhibit the acetylation of core histones that is necessary for inflammatory gene transcription. We show both in vitro and in vivo that low-dose theophylline enhances HDAC activity in epithelial cells and macrophages. This increased HDAC activity is then available for corticosteroid recruitment and predicts a cooperative interaction between corticosteroids and theophylline. This mechanism occurs at therapeutic concentrations of theophylline and is dissociated from phosphodiesterase inhibition (the mechanism of bronchodilation) or the blockade of adenosine receptors, which are partially responsible for its side effects. Thus we have shown that low-dose theophylline exerts an anti-asthma effect through increasing activation of HDAC which is subsequently recruited by corticosteroids to suppress inflammatory genes.

Adult↗
PubMed2002

Regulation of kinin receptors in airway epithelial cells by inflammatory cytokines and dexamethasone.

The two kinin receptors, B(1) and B(2), are upregulated in inflammation and may play a role in diseases such as asthma. In pulmonary A549 cells, TNF-alpha or interleukin-1 beta dramatically increased bradykinin B(1) and B(2) receptor mRNA expression and this response was prevented by dexamethasone. In primary human bronchial epithelial cells, bradykinin B(1) receptor mRNA expression showed a similar trend, whereas bradykinin B(2) receptor showed almost constitutive expression. Radioligand-binding studies revealed significant increases in bradykinin B(2) receptor protein expression following both interleukin-1 beta and TNF-alpha treatment of A549 cells; however, no evidence was found for bradykinin B(1) receptor. Functionally, the bradykinin B(2) receptor ligand, bradykinin, but not the B(1) ligand, des-Arg(10)-kallidin, produced a marked increase in prostaglandin E(2) release when administered following interleukin-1 beta treatment. Arachidonic acid release in response to bradykinin was markedly enhanced by prior incubation with interleukin-1 beta and this was prevented by the prior addition of dexamethasone.

Bronchi↗
PubMed2002

Effect of topical immunomodulators on acute allergic inflammation and bronchial hyperresponsiveness in sensitised rats.

We examined the effects of different immunomodulators administered topically on asthmatic responses in a rat model of asthma. Sensitised Brown-Norway rats were administered rapamycin, SAR943 (32-deoxorapamycin), IMM125 (a hydroxyethyl derivative of D-serine(8)-cyclosporine), and budesonide by intratracheal instillation 1 h prior to allergen challenge. Allergen exposure induced bronchial hyperresponsiveness, accumulation of inflammatory cells in bronchoalveolar lavage fluid, and also an increase in eosinophils and CD2+, CD4+ and CD8+ T cells in the airways. Interleukin-2, interleukin-4, interleukin-5, interleukin-10, and interferon-gamma mRNA expression was upregulated by allergen exposure. Budesonide abolished airway inflammation, suppressed the mRNA expression for interleukin-2, interleukin-4, and interleukin-5 (P<0.03), and bronchial hyperresponsiveness (P<0.05). IMM125 suppressed airway infiltration of eosinophils, and CD8+ T cells (P<0.02), and prevented the upregulated mRNA expression for interleukin-4, interleukin-5, and interferon-gamma (P<0.02). Rapamycin suppressed CD8+ T cell infiltration in airway submucosa (P<0.03), and mRNA expression for interleukin-2 (p<0.002), while SAR943 suppressed interleukin-2, interleukin-4, and interferon-gamma mRNA (P<0.05). IMM125, rapamycin and SAR943 did not alter airway submucosal CD2+ and CD4+ T cell infiltration, and bronchial hyperresponsiveness. CD8+ T cells, in contrast to CD4+ T cells, are more susceptible to the inhibition by IMM125 and rapamycin, which also caused greater suppression of Th1 compared to Th2 cytokine mRNA expression. In this acute model of allergic inflammation, differential modulation of Th1 and Th2 cytokines may determine the effects of various immunomodulators on airway inflammation and bronchial hyperresponsiveness.

Acetylcholine↗
PubMed2002

Attenuated production of intracellular IL-10 and IL-12 in monocytes from patients with severe asthma.

Interleukin (IL)-10 and IL-12 production is decreased in peripheral blood mononuclear cells of patients with mild asthma. Using whole blood culture and flow cytometry we examined whether monocyte heterogeneity influenced IL-10 and IL-12 production in subjects with severe asthma. We demonstrated that IL-10 release in LPS-stimulated whole blood culture was decreased in patients with severe persistent asthma compared to those with mild asthma and controls (P = 0.04 and P < 0.001, respectively). In asthmatic patients, the percentage of CD14(+)CD16(+) cells was higher than that from normal subjects (P = 0.04). Severe asthmatics showed significantly less positive staining for IL-10 and IL-12 (P < 0.001 and P = 0.02, respectively) after stimulation in monocytes, compared to mild asthmatics and controls in both CD14(+)CD16(+) and CD14(+)CD16(minus sign) cells. These results suggest that IL-10 synthesis is attenuated in severe persistent asthma compared to mild asthma and that this cannot be explained by the increase in the CD14(+)CD16(+) monocytes in asthma.

Adult↗
PubMed2002

Glucocorticoids reverse IL-1beta-induced impairment of beta-adrenoceptor-mediated relaxation and up-regulation of G-protein-coupled receptor kinases.

1. The aim of the present study was to examine the effects of glucocorticoid dexamethasone on airway responsiveness to albuterol after intratracheal instillation of saline or IL-1beta in Brown-Norway rats in vivo and to elucidate the molecular mechanism of this effect. 2. IL-1beta caused a significant reduction in albuterol-mediated relaxation to protect against MCh-induced bronchoconstriction. Dexamethasone attenuated the IL-1beta-induced impaired relaxation while alone had no effect when compared to rats treated identically with saline. 3. The density of beta(2)-adrenoceptors was significantly reduced in lung membranes harvested from IL-1beta-treated rats, which was associated with impaired isoproterenol- and forskolin-stimulated cyclic AMP accumulation and adenylyl cyclase (AC) activity ex vivo. Dexamethasone did not prevent IL-1beta-induced down-regulation of beta(2)-adrenoceptors but completely blocked IL-1beta-induced impairment of cyclic AMP accumulation and AC activity stimulated by isoproterenol and forskolin. 4. The inhibitory G-protein subtypes, G(ialpha1), G(ialpha2) and G(ialpha3), were detected in lung membranes prepared from all groups of rats but the intensity of G(ialpha1) and G(ialpha2) was markedly increased in IL-1beta-treated rats, which were not prevented by dexamethasone. 5. The activity of cytosolic GRK and the expression of GRK2 and GRK5 were elevated in the lung of IL-1beta-treated rats, which were completely abolished by dexamethasone. 6. These results indicate that treatment of rats with IL-1beta results in desensitization of pulmonary beta(2)-adrenoceptors. In light of data obtained in this study, we propose that both the decrease in AC activity and the increase in GRK activity, which are reversed by dexamethasone, may underlie beta(2)-adrenoceptor desensitization.

Adenylyl Cyclases↗
PubMed2002

Matrix metalloproteinase-9 expression in asthma: effect of asthma severity, allergen challenge, and inhaled corticosteroids.

BACKGROUND: Asthma is associated with remodeling of the extracellular matrix (ECM) and increased airway obstruction, and the mechanisms of this process are unknown. Matrix metalloproteinases (MMPs) are a group of enzymes capable of degrading the ECM. They are released along with their inhibitors, tissue inhibitor of MMP (TIMP). STUDY OBJECTIVE: s: To determine whether severe, persistent asthma is associated with increased levels of MMP-9 in the airway compared with mild asthma, and to assess the effect of both allergen exposure and steroid treatment on MMP-9 and TIMP-1 levels. DESIGN: Prospective analysis of levels and activity of MMP-9 and TIMP-1 in BAL fluid (BALF) and induced sputum obtained from asthmatics of differing disease severity. In patients with mild asthma, MMP-9 and TIMP-1 levels were studied in induced sputum following allergen challenge and in BALF after inhaled steroid therapy. PATIENTS: Eighteen patients with mild asthma, 10 patients with severe asthma, and 10 nonsmoking, atopic subjects had their sputum studied. Fourteen of the patients with mild asthma underwent allergen challenge. BAL was collected from 16 patients with mild asthma before and after 4 weeks treatment with inhaled budesonide, 800 micro g bid, or placebo. RESULTS: Patients with severe asthma had increased levels and activity of sputum MMP-9 in their sputum compared with patients with mild asthma and normal subjects. Allergen challenge increased the MMP-9/TIMP-1 ratio and MMP-9 activity. Inhaled budesonide had no effect on MMP-9 or TIMP-1 in patients with mild asthma. CONCLUSIONS: MMP-9 may play a role in chronic airway inflammation and remodeling in asthma, as concentrations are increased in severe, persistent asthma and following allergen challenge. Inhaled steroids may not affect MMP-9 and TIMP in patients with mild asthma, and additional studies in patients with more severe asthma are needed.

Administration, Inhalation↗