Search PubMed⌕ Search

Biomedical subjects

Qutayba Hamid

Publications and source records attributed to Qutayba Hamid.

At least 73 records · Page 4Linked to original sources
PubMed2004

IL-4, IL-5 and IFN-gamma mRNA expression in pulmonary lymphocytes in equine heaves.

Heaves is a common condition of horses of cold climate that is characterized by small airway inflammation and obstruction following exposure of susceptible horses to moldy hay and straw. It has been shown that helper T lymphocytes (Th) orchestrate the inflammatory response in asthma and in various animal models of allergic lung diseases by the release of Th2-type cytokines. Results of previous studies indicate that a predominant expression of Th2-type response by airway cells may also be present in heaves. To evaluate the temporal mRNA expression of Th1 (IFN-gamma) and Th2 (IL-4, IL-5) type cytokines in heaves and their relationship to clinical disease, we studied the pulmonary mechanics and cytokine mRNA expression (IL-4, IL-5 and IFN-gamma) in bronchoalveolar lavage lymphocytes of horses with heaves (n=6) and control (n=6) before and after 24h and 9 days of continuous natural inhalation challenge. Starting 24h after challenge horses with heaves, but not control horses, had a significant increase in pulmonary elastance and the number of lymphocytes expressing mRNA for IL-4 and IL-5. These changes were further increased at 9 days, at which time the number of cells positive for IFN-gamma mRNA was decreased. In this study we have shown that BAL lymphocytes of horses with heaves during clinical exacerbation have a predominant Th2-type cytokine response and that this response coincides in time with the presence of airway obstruction.

Animals↗
PubMed2004

Selective irrigation of the sinuses in the management of chronic rhinosinusitis refractory to medical therapy: a promising start.

BACKGROUND: Although endoscopic sinus surgery has been widely used for the treatment of chronic rhinosinusitis, some patients fail to derive clinical benefit from this procedure. We evaluated the efficacy of a treatment regimen consisting of selective irrigation of diseased sinus mucosa with topical antibiotics and steroids in conjunction with oral antibiotics and steroids. METHODS: Twenty patients suffering from chronic rhinosinusitis and resistant to medical treatment (mean duration 3.4 years) underwent intubations of the affected maxillary and/or ethmoid sinuses for irrigation for a duration of 21 to 30 days. A computed tomographic (CT) scan of the paranasal sinus was taken both pre- and post-treatment and staged according to the Lund-MacKay system. Clinical symptoms were scored for rhinorrhea, facial pain, nasal congestion, and smell at least 2 months prior to treatment and approximately 18 months after the follow-up. RESULTS: The clinical experience with the technique of intubation and irrigation was well tolerated by all patients. We found an improvement in all symptom scores, including rhinorrhea, nasal congestion, smell (n = 20; p < .001), and facial pain (n = 20; p < .01). Similar improvements were seen on the CT scans, with reduced staging from 14.6 +/- 1.1 to 5.6 +/- 1.1 (p < .001). Only three patients did not respond to selective irrigation of the sinuses and needed further surgery. CONCLUSION: These results suggest that sinus irrigation could provide a reasonable and effective alternative to ethmoidectomy with drainage procedures and offer promise for the treatment of patients with chronic rhinosinusitis who are resistant to medical treatment.

Adult↗
PubMed2003

S epsilon S mu and S epsilon S gamma switch circles in human nasal mucosa following ex vivo allergen challenge: evidence for direct as well as sequential class switch recombination.

B cells switch to IgE under the influence of IL-4, IL-13, and CD40 costimulation through a multistep process involving epsilon germline transcription and class switch recombination. Classically, switching has been considered an event restricted to lymphoid tissues; however, epsilon germline transcripts (I(initiator)epsilon RNA) have been observed within lung, sinus, and nasal tissue of individuals with asthma, sinusitis, and rhinitis. Furthermore, nasal mucosal tissue from allergic rhinitics produces epsilon germline transcripts following ex vivo allergen challenge. Collectively, these studies raised the possibility that switching to IgE may occur locally, at sites of allergic inflammation. Although epsilon germline transcripts are considered necessary to target the IgE locus, it is class switch recombination that ultimately leads to de novo IgE production. In this study, we demonstrate that S epsilon S mu DNA switch circles (products of class switch recombination) as well as I epsilon and C epsilon RNA are produced within nasal tissue from allergic individuals following ex vivo allergen challenge. epsilon germline transcription was inhibited when tissue was cultured with a combination of allergen and neutralizing Abs against IL-4 and IL-13, indicating that de novo cytokine production mediated the isotype switch. We also show allergen-induced appearance of S epsilon S gamma DNA switch circles and up-regulation of C gamma 4 mRNA, illustrating that sequential switching to IgE also occurred. This work strongly suggests that B cells residing within the nasal mucosa undergo switching to IgE in the context of a local immune response to allergen.

Allergens↗
PubMed2003

Chlorine-induced injury to the airways in mice.

Exposure to chlorine gas (Cl2) causes occupational asthma that we hypothesized occurs through the induction of airway inflammation and airway hyperresponsiveness by oxidative damage. Respiratory mechanics and airway responsiveness to methacholine were assessed in A/J mice 24 hours after a 5-minute exposure to 100, 200, 400, or 800 ppm Cl2 and 2 and 7 days after inhalation of 400 ppm Cl2. Airway responsiveness was higher 24 hours after 400 and 800 ppm Cl2. Responsiveness after inhalation of 400 ppm Cl2 returned to normal by 2 days but was again elevated at 7 days. Airway epithelial loss, patchy alveolar damage, proteinaceous exudates, and inflammatory cells within alveolar walls were observed in animals exposed to 800 ppm Cl2. Macrophages, granulocytes, epithelial cells, and nitrate/nitrite levels increased in lung lavage fluid. Increased inducible nitric oxide synthase expression and oxidation of lung proteins were observed. Epithelial cells and alveolar macrophages from mice exposed to 800 ppm Cl2 stained for 3-nitrotyrosine residues. Inhibition of inducible nitric oxide synthase with 1400W (1 mg/kg) abrogated the Cl2-induced changes in responsiveness. We conclude that chlorine exposure causes functional and pathological changes in the airways associated with oxidative stress. Inducible nitric oxide synthase is involved in the induction of changes in responsiveness to methacholine.

Administration, Inhalation↗
PubMed2003

The CCR3 receptor is involved in eosinophil differentiation and is up-regulated by Th2 cytokines in CD34+ progenitor cells.

The involvement of chemokines in eosinophil recruitment during inflammation and allergic reactions is well established. However, a functional role for chemokines in eosinophil differentiation has not been investigated. Using in situ RT-PCR, immunostaining, and flow cytometric analysis, we report that human CD34+ cord blood progenitor cells contain CCR3 mRNA and protein. Activation of CD34+ progenitor cells under conditions that promote Th2 type differentiation up-regulated surface expression of the CCR3. In contrast, activation with IL-12 and IFN-gamma resulted in a significant decrease in the expression of CCR3. Eotaxin induced Ca2+ mobilization in CD34+ progenitor cells, which could explain the in vitro and in vivo chemotactic responsiveness to eotaxin. We also found that eotaxin induced the differentiation of eosinophils from cord blood CD34+ progenitor cells. The largest number of mature eosinophils was found in cultures containing eotaxin and IL-5. The addition of neutralizing anti-IL-3, anti-IL-5, and anti-GM-CSF Abs to culture medium demonstrated that the differentiation of eosinophils in the presence of eotaxin was IL-3-, IL-5-, and GM-CSF-independent. These results could explain how CD34+ progenitor cells accumulate and persist in the airways and peripheral blood of patients with asthma and highlight an alternative mechanism by which blood and tissue eosinophilia might occur in the absence of IL-5.

Animals↗
PubMed2003

The effects of CD8+gammadelta T cells on late allergic airway responses and airway inflammation in rats.

BACKGROUND: Gamma-delta (gammadelta) T cells regulate immune responses to foreign protein at mucosal surfaces. Whether they can modify allergen-induced early (EAR) and late airway responses (LAR) is unknown. OBJECTIVE: We have tested the hypothesis that the CD8+ subtype of gammadelta T cells decreases allergen-induced LAR and airway eosinophilia in the rat. METHODS: Brown Norway rats were administered, intraperitoneally, 3.5 x 10(4) lymph node CD8+gammadelta T cells from naive or sensitized rats. The recipients were sensitized to ovalbumin (OVA) in Al(OH)(3) 3 days after cell transfer and challenged with aerosolized OVA 14 days later. Serum IgE was measured before allergen challenge. After challenge, lung resistance was monitored for 8 hours and then bronchoalveolar lavage (BAL) was analyzed for eosinophil major basic protein (MBP), IL-4, IL-5, IL-13, and IFN-gamma messenger RNA-expressing cells. RESULTS: gammadelta T cells from naive donors significantly decreased LAR in OVA-challenged sensitized rats, whereas MBP(+) eosinophils were decreased by both gammadelta T cells from naive and sensitized donors. EAR and serum IgE levels were unchanged. The expression of IL-4, IL-5, and IL-13 by BAL cells of gammadelta T cell recipients was attenuated compared with OVA-challenged controls. This was accompanied by an increase in the expression of IFN-gamma. CONCLUSIONS: Our results are consistent with a suppressive role of CD8+gammadelta T cells on allergic airway responses. However, only gammadelta T cells from naive donors inhibit LAR.

Adoptive Transfer↗
PubMed2003

5-oxo-6,8,11,14-eicosatetraenoic acid induces the infiltration of granulocytes into human skin.

BACKGROUND: 5-Oxo-6,8,11,14-eicosatetraenoic acid (5-oxo-ETE) is an arachidonic acid metabolite with potent in vitro chemoattractant effects on eosinophils and neutrophils. It has also been shown to induce pulmonary eosinophilia in Brown Norway rats, but it is not known whether it is active in human beings in vivo. OBJECTIVE: To determine whether 5-oxo-ETE can induce cellular infiltration in patients with atopic asthma and nonatopic control subjects after intradermal administration. METHODS: 5-Oxo-ETE was administered intradermally to 11 patients with atopic asthma and 10 nonatopic control subjects. Skin biopsy specimens were taken 6 or 24 hours later and examined by immunocytochemistry for cells expressing specific markers for eosinophils (major basic protein), neutrophils (elastase), macrophages (CD68), lymphocytes (CD3), and mast cells (tryptase). RESULTS: 5-Oxo-ETE (1.5 and 5 microg) elicited the infiltration of both eosinophils and neutrophils into the skin in both control and atopic asthmatic subjects. Increased numbers of eosinophils were observed at 6 and 24 hours after injection, whereas significantly elevated neutrophil numbers were present only after 24 hours. Eosinophils were >3 times higher in patients with atopic asthma compared with control subjects after injection of the highest dose of 5-oxo-ETE. Macrophage numbers were also elevated, but only at the highest dose of 5-oxo-ETE. No effects were observed on the numbers of either lymphocytes or mast cells. CONCLUSIONS: 5-Oxo-ETE elicits the infiltration of eosinophils and neutrophils into the skin of human beings in vivo after intradermal administration. Asthmatic subjects are more responsive to this substance than nonallergic control subjects. These results suggest that 5-oxo-ETE may be an important mediator of inflammation.

Arachidonic Acids↗
PubMed2003

The effects of IL-5 on airway physiology and inflammation in rats.

BACKGROUND: There is evidence that the cytokine IL-5 is a prominent feature of airway inflammation in asthma. OBJECTIVE: The aim of this study was to determine whether exogenous IL-5 could cause changes in lung physiology, the early and late airway response after antigen challenge, and airway inflammation in rats that do not have a propensity to develop these changes after sensitization and challenge. METHOD AND RESULTS: Intratracheal administration of IL-5 to ovalbumin sensitized Brown Norway SSN rats increased the airway responsiveness to methacholine (AHR) 20 hours after administration of IL-5 at the same time as an increase in neutrophils occurred in the lung lavage. This effect was dose dependent and was not caused by endotoxin. Concurrent intratracheal administration of 50 ng of anti-IL-5 monoclonal antibody with 10 microg of recombinant human IL-5 decreased the AHR and neutrophil influx. Pretreatment with 3 microg of IL-5 had no effect on the early and late airway response or on AHR after ovalbumin challenge. However, IL-5 increased lung re-sistance 20 hours after antigen challenge. Although total lung cells and differential counts did not differ significantly 8 hours after antigen challenge, the blood lymphocyte CD4/CD8 ratio decreased in IL-5 pretreated rats (P <.05). In addition, in situ hybridization showed a significant increase in cells within the airway wall expressing IL-4 and IL-5 mRNA in IL-5 treated/challenged rats compared to controls (P <.05). CONCLUSION: The intratracheal administration of IL-5 causes only part of the physiologic changes that are associated with asthma. Other factors are necessary to obtain the complete asthma phenotype.

Animals↗
PubMed2003

Anti-IL-5 (mepolizumab) therapy induces bone marrow eosinophil maturational arrest and decreases eosinophil progenitors in the bronchial mucosa of atopic asthmatics.

BACKGROUND: Eosinophils develop from CD34(+) progenitors under the influence of IL-5. Atopic asthmatic individuals have increased numbers of mature eosinophils and eosinophil pro-genitors within their bone marrow and bronchial mucosa. We have previously reported that anti-IL-5 monoclonal antibody treatment decreases total bone marrow and bronchial mucosal eosinophil numbers in asthma. OBJECTIVE: Using an anti-IL-5 monoclonal antibody, we examined the role of IL-5 in eosinophil development within the bone marrow and bronchial mucosa in asthma. METHODS: Blood, bone marrow, and airway mucosal biopsy specimens were examined before and after anti-IL-5 (mepolizumab) treatment of asthmatic individuals in a double-blind, placebo-controlled trial. Numbers of mature and immature eosinophils were measured by histologic stain (bone marrow myelocytes, metamyelocytes, and mature eosinophils), flow cytometry (bone marrow and blood CD34(+)/IL-5Ralpha(+) cells), enumeration of bone marrow-derived eosinophil/basophil colony-forming units in methylcellulose culture, and sequential immunohistochemistry and in situ hybridization (bronchial mucosal CD34(+)/IL-5Ralpha mRNA(+) cells). RESULTS: Mepolizumab decreased mature eosinophil numbers in the bone marrow by 70% (P =.017) in comparison with placebo and decreased numbers of eosinophil myelocytes and metamyelocytes by 37% (P =.006) and 44% (P =.003), respectively. However, mepolizumab had no effect on numbers of blood or bone marrow CD34(+), CD34(+)/IL-5Ralpha(+) cells, or eosinophil/basophil colony-forming units. There was a significant decrease in bronchial mucosal CD34(+)/IL-5Ralpha mRNA(+) cell numbers in the anti-IL-5 treated group (P =.04). CONCLUSION: These data suggest that anti-IL-5 therapy might induce partial maturational arrest of the eosinophil lineage in the bone marrow. The reduction in airway CD34(+)/IL-5 mRNA(+) cell numbers suggests that IL-5 might also be required for local tissue eosinophilopoiesis.

Antibodies, Monoclonal↗
PubMed2003

Inhibition of allergic airways inflammation and airway hyperresponsiveness in mice by dexamethasone: role of eosinophils, IL-5, eotaxin, and IL-13.

BACKGROUND: Glucocorticoids inhibit allergen-induced airway eosinophilia and airway hyperresponsiveness (AHR). Whether glucocorticoids mediate their effects on AHR by inhibiting eotaxin and IL-5, 2 of the principal mediators of eosinophilia, or through IL-13, an important mediator of AHR, has not been established. OBJECTIVE: We sought to investigate the effects of glucocorticoids on airway eosinophilia and the expression of IL-5, eotaxin, and IL-13 in relation to the induction of AHR in a murine model of allergic asthma. METHODS: Dexamethasone (4 mg/kg) and mAbs against eotaxin (80 micro g/kg) and IL-5 (100 micro g/kg) singly and in combination were administered to immunized mice before antigen challenge. Airway responsiveness to methacholine was measured in anesthetized and mechanically ventilated animals. Eotaxin, IL-5, and IL-13 in bronchoalveolar lavage fluid (BALF), lung homogenates, or both were measured by means of ELISA. RESULTS: A single antigen challenge induced AHR that lasted at least 10 days. Eotaxin protein and mRNA levels increased in lung tissue but not in BALF after challenge. IL-5 protein and mRNA levels increased both in BALF and in lung tissue. Dexamethasone reduced airway eosinophilia, AHR, and protein and mRNA for eotaxin and IL-5. Anti-murine eotaxin and anti-IL-5 antibodies alone and in combination reduced the ovalbumin-induced airway eosinophilia significantly but failed to inhibit AHR. Both dexa-methasone and anti-IL-5/anti-eotaxin inhibited the increases in lung IL-13 levels after ovalbumin challenge to a similar extent. CONCLUSION: These findings suggest that the inhibition of AHR by the glucocorticoid dexamethasone does not appear to be explained by effects on eosinophilia, eotaxin, IL-5, or IL-13.

Animals↗
PubMed2003

Advances in mechanisms of allergy.

This review summarizes selected "mechanisms of allergy" articles appearing between 2001 and 2002 in the Journal of Allergy and Clinical Immunology (JACI). Papers chosen include those dealing with human eosinophil and basophil biology from life to death, as well as studies with animal models of allergic disease, including knock-out mice, Brown Norway rats, and ovalbumin (OVA)-sensitized and challenged BALB/c mice, that further our understanding of mechanisms of allergic diseases. When appropriate, articles from other journals have been included to supplement the topics being presented.

Animals↗
PubMed2003

Airway remodeling-associated mediators in moderate to severe asthma: effect of steroids on TGF-beta, IL-11, IL-17, and type I and type III collagen expression.

BACKGROUND: Important features of airway remodeling in asthma include the formation of subepithelial fibrosis and increased deposition of types I and III collagen. TGF-beta, IL-11, and IL-17 are profibrotic cytokines involved in the formation of subepithelial fibrosis and are increased in patients with asthma, particularly in those with severe disease. OBJECTIVE: The purpose of this study was to investigate the effect of corticosteroids on the expression of these profibrotic cytokines and on extracellular matrix deposition. METHODS: We used immunocytochemistry to measure the expression of TGF-beta, IL-11, IL-17, and collagen types I and III in the airways of patients with mild asthma (n = 9), patients with moderate-to-severe asthma (n = 10), and control subjects without asthma (n = 6). Baseline bronchial biopsy specimens were obtained in all groups. In addition, repeat biopsies were obtained in the patients with moderate-to-severe asthma after a 2-week course of oral corticosteroids. RESULTS: TGF-beta expression was significantly higher in all groups with asthma, and it did not decrease after treatment with oral corticosteroids. Levels of IL-11 and IL-17 were increased in patients with moderate-to-severe asthma compared with patients with mild asthma and normal controls (P <.05). The expression of these cytokines decreased with oral corticosteroids in the moderate-to-severe group to levels that were comparable to those seen in the patients with mild asthma and in the normal controls (P <.005). Expression of types I and III collagens was higher in the patients with moderate-to-severe asthma than in the patients with mild asthma and the controls (P <.05; P <.001). Treatment with corticosteroids did not decrease the expression of types I and III collagens. CONCLUSIONS: These results confirm the association of increased levels of TGF-beta, IL-11, IL-17, and types I and III collagens with severe disease and suggest that the failure of cortico-steroids to decrease collagen deposition might be due to persistently elevated TGF-beta expression.

Administration, Oral↗
PubMed2003

Effect of HFA-flunisolide on peripheral lung inflammation in asthma.

BACKGROUND: New hydrofluoroalkane (HFA) formulations of glucocorticoids have been shown to effectively control asthma. HFA glucocorticoids are deposited across all sizes of airways, including the small ones. However, it is not clear whether they can suppress peripheral airway inflammation. OBJECTIVE: We sought to determine whether HFA-flunisolide could suppress peripheral inflammation in asthma. METHODS: Twelve patients with mild to moderate asthma received HFA-flunisolide for 6 weeks. Transbronchial and endobronchial biopsy specimens were obtained before and after treatment, and spirometry was performed. Changes in inflammatory cells (eosinophils, neutrophils, lymphocytes, macrophages, basophils) and IL-5 and eotaxin were measured by using immunocytochemistry and in situ hybridization. RESULTS: Lung function significantly improved after treatment (P <.05). HFA-flunisolide significantly reduced eosinophils, IL-5, and eotaxin in both peripheral and central airways (P <.01). Neutrophils significantly increased after treatment in peripheral and central airways (P <.05). The numbers of lymphocytes remained unchanged. CONCLUSIONS: These results show that HFA-flunisolide effectively suppressed eosinophilic inflammation in peripheral and central airways. These changes were accompanied by improvement in lung function.

Adult↗
PubMed2003

Modulation of allergic response in nasal mucosa by antisense oligodeoxynucleotides for IL-4.

BACKGROUND: The cytokine IL-4 is highly involved in T(H)2 inflammation, such as that seen in allergic rhinitis. IL-4 can induce IgE synthesis and eotaxin. Recent studies have shown that stimulation of allergic nasal tissue with ragweed allergen can induce local IL-4 mRNA production. OBJECTIVE: We set out to determine whether IL-4 antisense phosphorothioate-modified oligodeoxynucleotides (PS-ODNs) could inhibit IL-4 production and downstream events of IL-4. METHODS: Nasal mucosa biopsy specimens were obtained from patients with seasonal ragweed allergic rhinitis out of season, incubated ex vivo with or without PS-ODNs, and challenged with ragweed. FITC-labeled oligonucleotides were used to determine tissue uptake. By using immunocytochemistry, IL-4-, IL-13-, eotaxin 1-, and IFN-gamma-producing cells were enumerated, and by using in situ hybridization, epsilon germline transcript RNA- and IL-4 mRNA-positive cells were examined. RESULTS: The antisense PS-ODN was taken up by the tissue, and preincubation of the tissue with the IL-4 antisense PS-ODN caused a decrease in allergen-induced IL-4 mRNA and a decrease in the amount of IL-4 immunoreactivity (n = 7, P <.001). PS-ODNs had inhibitory effects on allergen-induced epsilon germline transcript RNA expression (n = 7, P <.001) and mucosa eotaxin 1 immunoreactivity (n = 7, P <.05). In contrast, the PS-ODNs increased the amount of IFN-gamma immunoreactivity (n = 7, P <.05), suggesting a nonspecific mechanism for reduced synthesis of IgE and eotaxin. CONCLUSIONS: Our results show that the IL-4 antisense PS-ODN effectively inhibits IL-4, IgE synthesis, and eotaxin, principal mediators of allergic inflammation, suggesting that PS-ODNs might offer a possible topical treatment for allergic rhinitis.

Allergens↗