Biomedical subjects

Qutayba Hamid

Publications and source records attributed to Qutayba Hamid.

At least 91 records · Page 5Linked to original sources

PubMed2003

Inflammatory cells in asthma: mechanisms and implications for therapy.

Recent clinical studies have brought asthma's complex inflammatory processes into clearer focus, and understanding them can help to delineate therapeutic implications. Asthma is a chronic airway inflammatory disease characterized by the infiltration of airway T cells, CD(+) (T helper) cells, mast cells, basophils, macrophages, and eosinophils. The cysteinyl leukotrienes also are important mediators in asthma and modulators of cytokine function, and they have been implicated in the pathophysiology of asthma through multiple mechanisms. Although the role of eosinophils in asthma and their contribution to bronchial hyperresponsiveness are still debated, it is widely accepted that their numbers and activation status are increased. Eosinophils may be targets for various pharmacologic activities of leukotriene receptor antagonists through their ability to downregulate a number of events that may be key to the effector function of these cells.

Anti-Asthmatic Agents↗

PubMed2003

Inflammation and remodeling of the sinus mucosa in children and adults with chronic sinusitis.

OBJECTIVES/HYPOTHESIS: The sinus mucosal inflammatory response in adult patients with chronic sinusitis is well documented in the literature. In contrast, little is known about the pathogenesis of this condition in children. The objective of the study was to compare the inflammatory cell profile and the extent of tissue remodeling in the sinus mucosa of children and adults with chronic sinusitis. STUDY DESIGN: Prospective design. METHODS: Children (n = 7) and adult patients (n = 7) with chronic sinusitis undergoing functional endoscopic sinus surgery were recruited for the study. Patients with no evidence of sinus disease (n = 6) were used as control subjects. Using immunohistochemical analysis, sinus mucosal specimens were assessed for the presence of T lymphocytes, eosinophils, basophils, mast cells, and neutrophils. The extent of submucosal collagen deposition was evaluated in histological sections using van Gieson stain. RESULTS: The number of T lymphocytes, eosinophils, and basophils and the amount of subepithelial collagen deposition are significantly higher in the mucosa of both adults and children with chronic sinusitis compared with normal control subjects (P <.01). The number of mast cells is significantly higher in the mucosa of children with chronic sinusitis compared with normal control subjects (P <.01). The number of eosinophils and neutrophils and the amount of subepithelial collagen deposition are significantly greater in adults compared with children with chronic sinusitis (P <.01). CONCLUSIONS: The sinus mucosal inflammatory profile is similar in adults and children with chronic sinusitis. However, the degree of tissue eosinophilia and remodeling is significantly greater in adult sinus specimens when compared with those of children with chronic sinusitis.

Adolescent↗

PubMed2003

Increased expression of interleukin-9, interleukin-9 receptor, and the calcium-activated chloride channel hCLCA1 in the upper airways of patients with cystic fibrosis.

OBJECTIVES/HYPOTHESIS: Mucus overproduction is commonly found in airway disease in patients with cystic fibrosis. Interleukin-9 (IL-9) has been shown to mediate airway hyper-responsiveness and mucus overproduction. Recently, the calcium-activated chloride channel hCLCA1 has been described to be upregulated by IL-9 and has been thought to regulate the expression of soluble gel-forming mucins. We sought to examine the expression of IL-9, interleukin-9 receptor (IL-9R), and hCLCA1 in the upper airway of patients with cystic fibrosis in comparison to healthy control subjects and to demonstrate the relationship of IL-9, IL-9R, and hCLCA1 expression with mucus production. STUDY DESIGN: Prospective design. METHODS: Biopsy samples from nasal polyps of four patients with cystic fibrosis, nasal mucosa of six patients with cystic fibrosis, sinus mucosa of eight patients with cystic fibrosis, and nasal mucosa of six healthy control subjects were stained with periodic acid-Schiff (PAS) to identify mucus glycoconjugates. IL-9, IL-9R, and hCLCA1 expression was determined by immunocytochemical study. RESULTS: We demonstrated significant increases in IL-9, IL-9R, and hCLCA1 immunoreactivity in the mucosa of patients with cystic fibrosis compared with that found in control subjects (P <.05). There were no significant differences between the different locations (nasal polyps, nasal mucosa, and sinus mucosa) in the patient group (P >.05). We also observed a significant increase in the number of mucus-producing cells in biopsy specimens from patients with cystic fibrosis in comparison to control subjects. A positive correlation was found between hCLCA1-positive cells and IL-9-positive cells (correlation coefficient [r] = 0.79, P <.05) or IL-9R-positive cells (r = 0.92, P <.05). Moreover, a positive correlation was also present between PAS-positive (mucus-producing) cells and hCLCA1-positive cells (r = 0.64, P <.05) or IL-9R-positive cells (r = 0.64, P <.05). CONCLUSIONS: Increased expression of IL-9 and IL-9R, as well as upregulation of hCLCA1, in mucus-overproducing epithelium of patients with cystic fibrosis supports the hypothesis that IL-9 contributes to mucus overproduction in cystic fibrosis. Expression of hCLCA1 may also be responsible, in part, for the overproduction of mucus. These preliminary findings suggest that hCLCA1 might be an interesting new therapeutic target to control mucus overproduction in airway disease in patients with cystic fibrosis.

Biopsy↗

PubMed2003

Involvement of the cysteinyl-leukotrienes in allergen-induced airway eosinophilia and hyperresponsiveness in the mouse.

The leukotriene modifiers are a novel generation of therapeutic agents in the treatment of allergic asthma. However, the mechanisms by which the cysteinyl (cys) leukotrienes (LTs) participate in allergen-induced airway eosinophilia and airway hyperresponsiveness (AHR) are still unclear. In the present study, we have investigated the role of cys-LTs in ovalbumin (OVA)-induced airway responses in a murine model of asthma. Montelukast (3 or 10 mg/kg), a selective cys-LT1 receptor antagonist, reduced airway eosinophilia and AHR after OVA challenge. The levels of interleukin (IL)-5 and eotaxin in the bronchoalveolar lavage fluid (BALF) from montelukast-treated (3 mg/kg) mice were unaffected, although a decrease in IL-5 was observed with a dose of 10 mg/kg. LTD4 (50 ng) instilled intranasally to immunized mice augmented macrophages in the BALF, but in conjunction with OVA challenge it caused BALF eosinophilia and neutrophilia when given before challenge and BALF neutrophilia but not eosinophilia when given 2 h after challenge. However, there were no increases of IL-5 or eotaxin in BALF following LTD4 treatment. Repeated instillations of LTD4 to immunized mice, mimicking allergen challenge, did not induce AHR but in conjunction with OVA challenge LTD4 enhanced AHR. These results indicate that allergen-induced eosinophilia and AHR are in part mediated by the cys-LT1 receptor, and that, although LTD4 alone has no effect on airway eosinophilia, in conjunction with antigenic stimulation it potentiates the degree of airway inflammation and AHR.

Acetates↗

PubMed2003

Dissection of experimental asthma with DNA microarray analysis identifies arginase in asthma pathogenesis.

Asthma is on the rise despite intense, ongoing research underscoring the need for new scientific inquiry. In an effort to provide unbiased insight into disease pathogenesis, we took an approach involving expression profiling of lung tissue from mice with experimental asthma. Employing asthma models induced by different allergens and protocols, we identified 6.5% of the tested genome whose expression was altered in an asthmatic lung. Notably, two phenotypically similar models of experimental asthma were shown to have distinct transcript profiles. Genes related to metabolism of basic amino acids, specifically the cationic amino acid transporter 2, arginase I, and arginase II, were particularly prominent among the asthma signature genes. In situ hybridization demonstrated marked staining of arginase I, predominantly in submucosal inflammatory lesions. Arginase activity was increased in allergen-challenged lungs, as demonstrated by increased enzyme activity, and increased levels of putrescine, a downstream product. Lung arginase activity and mRNA expression were strongly induced by IL-4 and IL-13, and were differentially dependent on signal transducer and activator of transcription 6. Analysis of patients with asthma supported the importance of this pathway in human disease. Based on the ability of arginase to regulate generation of NO, polyamines, and collagen, these results provide a basis for pharmacologically targeting arginine metabolism in allergic disorders.

Animals↗

PubMed2003

Contribution of the distal lung to the pathologic and physiologic changes in asthma: potential therapeutic target Roger S. Mitchell lecture.

Pathologic and physiologic evidence has emerged in the last few years suggesting that the airway inflammation and remodeling that characterize asthma occur not only in the central airways but extend to the distal lung and the lung parenchyma. The distal airways are capable of producing T helper (Th) type 2 cytokines and chemokines, and, more recently, they have been recognized as a predominant site of airflow obstruction in asthmatic patients. In the lung parenchyma, a similar Th2 cytokine profile and infiltration of inflammatory cells also has been reported. The inflammation at this distal site has been described as being more severe when compared to the large amount of airway inflammation, and evidence of remodeling in the lung periphery is emerging. The recognition of asthma as a disease of the entire respiratory tract has an important clinical significance highlighting the need to also consider the distal lung as a target in any therapeutic strategy for effective treatment of this disease.

Asthma↗

PubMed2003

T helper type 2 cytokine receptors and associated transcription factors GATA-3, c-MAF, and signal transducer and activator of transcription factor-6 in induced sputum of atopic asthmatic patients.

BACKGROUND: It is well-known that the expression of T helper (Th) type 2 cytokines such as interleukin (IL)-4 and IL-5, and their receptors, is up-regulated within the airways of allergic asthmatic patients. Furthermore, higher numbers of cells producing GATA-3, c-MAF, and signal transducer and activator of transcription factor (STAT)-6, which are transcription factors (TFs) that are implicated in the regulation and signaling of the Th2 cytokines, have been observed in bronchial biopsy specimens from asthmatic patients but not in those of healthy control subjects. METHODS: We examined whether these mediators also can be detected in induced sputum. Immunoreactivity for IL-4Ralpha, IL-5Ralpha, GATA-3, c-MAF, and STAT-6 was investigated in samples of induced sputum from asthmatic patients (n = 8) and healthy control subjects (n = 8). RESULTS: Our results showed that the numbers of cells expressing IL-4 receptor alpha (Ralpha) and IL-5Ralpha were higher in samples from asthmatic patients compared to those of control subjects (p < 0.01). More cells exhibiting GATA-3, c-MAF, and STAT-6 immunoreactivity also were found in asthmatic patients vs those in control subjects (p < 0.005). Furthermore, the expression of STAT-6 and IL-4Ralpha, GATA-3 and IL-5Ralpha, and c-MAF with both IL-4Ralpha and IL-5Ralpha was correlated (p < 0.05). CONCLUSIONS: This study demonstrated that induced sputum provides sufficient sensitivity for examining the pathways of cytokine signaling, cytokine receptor signaling, and intracellular signaling. Furthermore, these data show correlations between the expression of Th2 cytokine receptors and associated TFs in the human lung, which has not been documented previously.

Adult↗

PubMed2003

Marked up-regulation of T lymphocytes and expression of interleukin-9 in bronchial biopsies from patients With chronic bronchitis with obstruction.

STUDY OBJECTIVE: To examine the differences in the inflammatory cell and cytokine profile between patients with chronic bronchitis (CB) with and without airway obstruction compared to control subjects. DESIGN: We used bronchial biopsy samples from the patients and control subjects and analyzed them for the presence of CD3 T cells, CD68, major basic protein (MBP), elastase, and tryptase, as well as expression of messenger RNA (mRNA) coding for interleukin (IL)-4, IL-5, interferon (IFN)-gamma, IL-9, eotaxin, and IFN-gamma-inducible protein (IP)-10. The techniques of immunocytochemistry and in situ hybridization were used. Results were expressed as the number of immunoreactive and mRNA-positive cells per field. RESULTS: Increased number of elastase, CD68, and MBP-positive cells (n = 9, p < 0.01) was demonstrated in both groups of patients with CB compared to control subjects. In patients with CB and obstruction, the number of elastase, CD68, and the number of CD3-positive cells was significantly increased compared to patients with CB without obstruction (n = 9, p < 0.01). IFN-gamma mRNA expression was increased in both groups of patients with CB compared to control subjects (n = 9, p < 0.01). IL-9 mRNA was significantly increased only in patients with CB and obstruction (n = 9, p < 0.01). Co-localization studies demonstrated > 80% of all IL-9-positive cells to be CD3-positive T cells. IP-10 mRNA was significantly increased in both groups of patients with CB compared to control subjects (n = 9, p < 0.01). CONCLUSIONS: These results indicate a differential expression of inflammatory markers and cytokine mRNA in patients with obstructive CB. Increased presence of T lymphocytes and up-regulation of IL-9 and IP-10 mRNA expression in the bronchial biopsy samples may contribute to the airway obstruction in these patients.

Antigens, CD↗

PubMed2002

Distribution of nitric oxide synthase in normal and cirrhotic human liver.

Chronic liver disorders represent a serious health problem, considering that 300 million people worldwide are hepatitis B virus carriers, and 8,000-10,000 patients per year, in the U.S. alone, die as a result of liver failure caused by hepatitis C infection. Nitric oxide synthase (NOS) regulates hepatic vasculature; however, the patterns of expression and activity of NOS proteins in healthy and diseased human livers are unknown. Sections of diseased (n = 42) and control livers (n = 14) were collected during orthotopic liver transplants and partial hepatectomy. The diseased sections included alcoholic cirrhosis, viral hepatitis, cholestasis, acute necrosis, and uncommon pathologies including alpha(1)-anti-trypsin disorder. The endothelial NOS (eNOS), inducible NOS (iNOS), and neuronal NOS (nNOS) were studied by using the citrulline assay, Western immunoblot, immunohistochemistry, and in situ hybridization. The systemic generation of plasma NO metabolites was measured by HPLC. In control livers, Ca(2+)-dependent and -independent NOS activities were identified by Western analysis as eNOS and iNOS, respectively. The eNOS was uniformly distributed in the hepatocytes and also detected in the endothelium of hepatic arteries, terminal hepatic venules, sinusoids, and in biliary epithelium. The iNOS was detected in hepatocytes and localized mainly in the periportal zone of the liver acinus. This pattern of distribution of eNOS and iNOS in normal liver was confirmed by in situ hybridization. In diseased livers, there was a significant increase in Ca(2+)-independent NOS with the corresponding strong appearance of iNOS in the cirrhotic areas. The eNOS was translocated to hepatocyte nuclei. Thus, eNOS and iNOS proteins are differentially expressed in healthy human liver, and this expression is significantly altered in cirrhotic liver disorders.

Blotting, Western↗

PubMed2002

The immunomodulatory actions of prostaglandin E2 on allergic airway responses in the rat.

PGE(2) has been reported to inhibit allergen-induced airway responses in sensitized human subjects. The aim of this study was to investigate the mechanism of anti-inflammatory actions of PGE(2) in an animal model of allergic asthma. BN rats were sensitized to OVA using Bordetella pertussis as an adjuvant. One week later, an aerosol of OVA was administered. After a further week, animals were anesthetized with urethan, intubated, and subjected to measurements of pulmonary resistance (R(L)) for a period of 8 h after OVA challenge. PGE(2) (1 and 3 micro g in 100 micro l of saline) was administered by insufflation intratracheally 30 min before OVA challenge. The early response was inhibited by PGE(2) (3 micro g). The late response was inhibited by both PGE(2) (1 and 3 micro g). Bronchoalveolar lavage fluid from OVA-challenged rats showed eosinophilia and an increase in the number of cells expressing IL-4 and IL-5 mRNA. These responses were inhibited by PGE(2). Bronchoalveolar lavage fluid levels of cysteinyl-leukotrienes were elevated after OVA challenge and were reduced after PGE(2) to levels comparable with those of sham challenged animals. We conclude that PGE(2) is a potent anti-inflammatory agent that may act by reducing allergen-induced Th2 cell activation and cysteinyl-leukotriene synthesis in the rat.

Adjuvants, Immunologic↗

PubMed2002

Allergen-induced increases in bone marrow T lymphocytes and interleukin-5 expression in subjects with asthma.

Inhaled allergen challenge of subjects with atopic asthmatic increases bone marrow eosinophil progenitor cells. Interleukin-5 (IL-5) specifically induces growth and maturation of eosinophils. This study examined the effect of allergen challenge on the number of bone marrow total and CD3+ cells expressing IL-5 protein and IL-5 mRNA in subjects with asthma who developed either allergen-induced isolated early responses, or early and late asthmatic responses (dual responders). At 24 hours after allergen challenge, dual responders had significantly greater blood and airway eosinophilia compared with early responders. There were significant increases in the percentage of bone marrow CD3+ cells (p < 0.005) in both groups. However, there were significant differences in the increases in bone marrow IL-5 mRNA+ (p < 0.005), CD3+ (p < 0.005), and IL-5 mRNA+ CD3+ (p < 0.005) cells between the dual and early responder groups. These results suggest that, in subjects with atopic asthma, inhaled allergen causes trafficking of T lymphocytes to the bone marrow, and that in subjects who develop late responses and greater blood and airway eosinophilia after inhalation of allergen, there is a significant increase in the ability of bone marrow cells, particularly T lymphocytes, to produce IL-5.

Adult↗

PubMed2002

Cytokine profile of chronic sinusitis in patients with cystic fibrosis.

BACKGROUND: The inflammatory-cell and cytokine profiles of chronic sinusitis (CS) are well documented in the literature. In contrast, little is known about the pathogenesis of this condition in patients with cystic fibrosis (CF). OBJECTIVE: To determine whether patients with CF have inflammatory-cell and cytokine profiles that differ from other patients with CS. METHODS: Patients with CF (n = 7) and adults with CS (n = 7) undergoing functional endoscopic sinus surgery were recruited for the study. Patients with no allergies or sinus disease (n = 6) were used as controls. Using immunohistochemical analysis, we assessed sinus mucosal specimens for the presence of T lymphocytes, eosinophils, macrophages, and neutrophils. Using in situ hybridization, we assessed the expression of interleukin (IL) 4, IL-5, IL-8, IL-10, and interferon gamma. RESULTS: There was a higher number of neutrophils, macrophages, and cells expressing messenger RNA for interferon gamma and IL-8 in patients with CF than in patients with CS or in controls (P<.01). The number of eosinophils and cells expressing messenger RNA for IL-4, IL-5, and IL-10 was higher in patients with CS than in those with CF and controls (P<.01). CONCLUSIONS: Sinus disease in patients with CF presents different inflammatory-cell and cytokine profiles than that seen in other patients with CS. These results may explain the difference in response to treatment in the CF group.

Adult↗

PubMed2002

The role of the distal lung in asthma.

Accumulating patholological and physiological evidence in the last few years suggests that the airway inflammation and remodeling that characterize asthma occur not only in the central airways but extend to the distal lung and the lung parenchyma. The distal airways are capable of producing T-helper (Th)2 cytokines as well as chemokines, and more recently, they have been recognized as a predominant site of airflow obstruction in asthmatics. A similar TH2-type cytokine profile and infiltration of inflammatory cells has also been reported in the lung parenchyma. The inflammation at this distal site has been described as more severe when compared with the large airway inflammation, and evidence of remodeling in the lung periphery is emerging. Recognition of asthma as a disease of the entire respiratory tract has an important clinical significance highlighting the need also to consider the distal lung as a target in any therapeutic strategy for effective treatment of this disease.

Journal Article↗

PubMed2002

A calcium-activated chloride channel (HCLCA1) is strongly related to IL-9 expression and mucus production in bronchial epithelium of patients with asthma.

BACKGROUND: One of the cardinal features of airway remodeling in asthma is mucus gland hyperplasia and mucus overproduction and hypersecretion. Recently, a calcium-activated chloride channel, HCLCA1, was described that is upregulated by IL-9 and thought to regulate the expression of soluble gel-forming mucins, such as MUC5A/C, a critical component of mucus in the airways. OBJECTIVE: We sought to examine the expression of HCLCA1 in bronchial biopsy specimens of asthmatic subjects compared with those of control subjects and to demonstrate its relationship with IL-9, IL-9 receptor (IL-9R), and markers of mucus production. METHODS: Bronchial biopsy specimens from asthmatic (n = 9) and control (n = 10) subjects were stained with periodic acid-Schiff to identify mucus glycoconjugates. IL-9- and IL-9R-positive cells were identified with immunocytochemistry, and HCLCA1 expression was detected by means of in situ hybridization with cRNA probes. RESULTS: We demonstrate significant increases in IL-9 (P <.001) and IL-9R (P <.05) immunoreactivity, as well as increased expression of HCLCA1 mRNA (P <.001), in the epithelium of asthmatic patients compared with that found in control subjects. There was also an increase in the number of mucusproducing cells in biopsy specimens from asthmatic subjects (P <.001). HCLCA1 mRNA was strongly and selectively colocalized with periodic acid-Schiff and IL-9R-positive epithelial cells. In particular, a strong positive correlation was observed between HCLCA1 mRNA expression and IL-9-positive (r = 0.69, P < 0.01) or IL9R-positive (r = 0.79, P <.01) cells. CONCLUSION: An upregulation of HCLCA1 in the IL-9- responsive mucus-producing epithelium of asthmatic subjects compared with that seen in control subjects supports the hypothesis that this channel may be responsible, in part, for the overproduction of mucus in asthmatic subjects. These preliminary findings suggest the inhibition of HCLCA1 may be an important new therapeutic approach to control mucus overproduction in chronic airway disorders.

Adult↗

PubMed2002

T(H)2 cytokine expression in atopic children with otitis media with effusion.

BACKGROUND: Otitis media with effusion (OME) is more common in atopic children. Few studies have looked for the presence of inflammatory mediators in the middle-ear effusions of this population. OBJECTIVE: We hypothesize that atopic children with OME have a different inflammatory cell and cytokine profile than nonatopic patients with the disease. METHODS: Twenty-six patients with OME undergoing myringotomy and ventilation tube placement were recruited at the McGill University Hospital Center. The atopic status was determined for each patient by using standard skin testing. By means of immunocytochemistry, fluid specimens were assessed for T lymphocytes (CD3), eosinophils (major basic protein), neutrophils (elastase), mast cells (tryptase), and basophils (BB1). By using in situ hybridization, the expression of IL-4, IL-5, and IFN-gamma was assessed. RESULTS: There is a higher percentage of eosinophils and T lymphocytes in atopic patients with OME (n = 8) compared with that seen in nonatopic patients (n = 18, P <.01). There is a higher percentage of neutrophils in nonatopic patients with OME compared with that seen in atopic patients (P <.01). In examining cytokine profiles, there is a higher percentage of cells expressing IL-4 and IL-5 in atopic patients with OME compared with that seen in nonatopic patients (P <.01). CONCLUSION: The predominance of eosinophils, T lymphocytes, and T(H)2 mediators in the middle-ear effusions of atopic children provides evidence that allergy might play a role in the pathogenesis of OME.

Basophils↗

PubMed2002

T-cell proliferation induced by local application of LPS in the nasal mucosa of nonatopic children.

BACKGROUND: Recently, there has been a great deal of interest in the role of bacterial products in altering the allergic immune response in early life. OBJECTIVE: We sought to develop a model of bacterial inflammation in human subjects to characterize the ex vivo response to LPS in the nasal mucosa of young nonatopic children. METHODS: Using the explant technique, we cultured nasal mucosa in the presence or absence of increasing concentrations of LPS (0.001-1 microg LPS/mL) for 24 hours. Immunocytochemistry and in situ hybridization were used to phenotype the cells and cytokines in the explant, and immunofluorescence was used to study proliferation of T cells in explants cultured with LPS and 5-bromo-2'-deoxyuridine (BrdU). RESULTS: CD68, CD3, tryptase, elastase, IFN- gamma IL-12, and IL-10 immunoreactivity was detected in unstimulated tissue. LPS stimulation caused a dose-dependent increase in the number of CD3(+) (n = 7, P <.05), CD68(+) (n = 7, P <.01), elastase-positive (n = 7, P <.01), tryptase-positive (n = 7, P <.05), IL-2 -positive (n = 6, P <.05), IL-12 -positive (n = 6, P <.05), and IFN- gamma-positive (n = 6, P <.05) cells compared with media alone. LPS had no effect on major basic protein, IL-4, IL-5, or IL-13 immunoreactivity. LPS (0.1 microg/mL) caused an increase in the number of BrdU-positive cells as early as 2 hours after incubation (n = 8, P <.001). The maximal BrdU immunoreactivity was seen 24 hours after incubation with LPS, at which time approximately 70% of BrdU- positive cells were CD3(+) T cells. CONCLUSIONS: Our results suggest that LPS is capable of inducing local inflammation, T(H)1 cytokine immunoreactivity, and proliferation of CD3(+) activated T cells in the absence of de novo cell recruitment. This model holds promise for future studies investigating the importance of bacterial products in regulating local immune function in young atopic children.

Administration, Intranasal↗

PubMed2002

Site-specific sensitization in a murine model of allergic rhinitis: role of the upper airway in lower airways disease.

BACKGROUND: Allergic rhinitis (AR) is the most common atopic disease with strong links to asthma. We have developed a murine model of AR to study nasal, bronchial, and systemic immune response to local allergen stimulation. OBJECTIVES: The purpose of this study was to develop and characterize a murine model of AR. METHODS: Six- to 8-week-old BALB/c mice were sensitized by means of intranasal (local) application of ovalbumin (OVA) or systemic intraperitoneal injection. They were then challenged with intranasal OVA, and allergic response was assessed. RESULTS: Intranasal particle deposition was found to be exclusively in the nares. All sensitized animals showed increased levels of OVA-specific serum IgE and IgG after challenge, although the timing to maximal response varied with the route and dose of allergen used. Histology of the upper and lower airways showed marked eosinophilic infiltration, and analysis of bronchoalveolar lavage fluid showed increased IL-5 and PMN infiltrates after challenge. CONCLUSION: Using exclusive local sensitization and challenge of mouse nares, we were able to demonstrate inflammatory changes in both the upper and lower airways, even though distribution of allergen particles appeared to be only in the nares of these animals. This provides further evidence for the importance of the upper airway in lower airways disease. We have shown that the route of administration greatly affects the characteristics of the subsequent immune responses.

Animals↗

PubMed2002

Injurious ventilation induces widespread pulmonary epithelial expression of tumor necrosis factor-alpha and interleukin-6 messenger RNA.

OBJECTIVE: We examined the hypothesis that injurious strategies of mechanical ventilation alter the expression and distribution within the lung of tumor necrosis factor-alpha and interleukin-6 that are both duration and ventilation strategy dependent. SUBJECTS: Male Sprague Dawley rats. INTERVENTIONS: Lungs from rats were preserved immediately after death or were randomized to ex vivo ventilation with either a) noninjurious ventilation; b) high end-inspiratory lung volume with positive end-expiratory pressure (PEEP); c) high end-inspiratory lung volume without PEEP; or d) intermediate lung distension without PEEP, for periods ranging from 30 mins to 3 hrs. MEASUREMENT AND MAIN RESULTS: Changes in cytokines were assessed by in situ hybridization, immunocytochemistry, simultaneous in situ hybridization and immunocytochemistry, Northern analysis, and enzyme-linked immunosorbent assay. Whereas minimal expression of tumor necrosis factor-alpha and interleukin-6 mRNA was found in lungs subjected to noninjurious ventilation, the three injurious strategies resulted in a diffuse increase in expression of tumor necrosis factor-alpha and interleukin-6. The principal cells involved were the bronchial, bronchiolar, and alveolar epithelium. The changes in tumor necrosis factor-alpha mRNA and protein expression were dependent on both duration of ventilation and the ventilation strategy used. CONCLUSIONS: The vast pulmonary epithelium is a major contributor to ventilation-induced changes in cytokine production and may play an important role in the pathogenesis of lung injury and systemic sequelae in ventilated subjects.

Animals↗