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Biomedical subjects

P H Howarth

Publications and source records attributed to P H Howarth.

At least 19 recordsLinked to original sources
PubMed1992

Interleukin 4 is localized to and released by human mast cells.

Recent attention has focused on the T helper type 2 (Th2) lymphocyte as a source of interleukin 4 (IL-4) in allergic disease. However, Th2 cells themselves require a pulse of IL-4 to initiate this synthesis. Here we provide immunohistochemical evidence of IL-4 localization to human mast cells of the skin and respiratory tract, and demonstrate that immunoglobulin E-dependent stimulation of purified human lung mast cells leads to the rapid release of IL-4 into the extracellular environment. We propose that mast cell activation in an allergic response provides a rapid and local pulse of IL-4 into the local environment essential for the triggering of T lymphocytes into sustained IL-4 production and to initiate inflammatory cell accumulation and activation.

Culture Techniques↗
PubMed1992

The effect of inhaled allergen on circulating basophils in atopic asthma.

There is increasing evidence for the role of basophils in the allergen-induced late asthmatic response (LAR). To study the effect of inhaled allergen on basophil function in subjects with asthma, ex vivo basophil spontaneous histamine release (SHR) in peripheral blood and plasma histamine was measured before and 2, 5, 10, and 15 minutes, and 2, 4, 6, and 8 hours after allergen bronchial challenge (allergen study day) in six subjects with atopic asthma. Allergen inhalation induced an early response and LAR consisting of a mean (+/- SD) 32.5% (+/- 7.9%) and 28.8% (+/- 7.7%) fall in FEV1, respectively. As a control for the effects of bronchoconstriction, on another occasion, methacholine challenge was performed to produce a mean 33.4% (+/- 3.4%) fall in FEV1 during the early response and no LAR, and blood was obtained to measure basophil histamine release (HR) and plasma histamine. There was a small, but significant (p less than 0.05), rise in median SHR from 4.6% to 6.1% of total basophil histamine after allergen but not after methacholine inhalation. HR remained high after allergen inhalation during the 8 hours of study, whereas it demonstrated a steady, significant, decrease between 4 to 8 hours after methacholine inhalation. No significant changes in plasma histamine were recorded on either allergen or methacholine study days. On a third occasion, SHR was measured after challenge with physiologic saline to control for any effects of methacholine on SHR, and a decrease in HR was recorded during the day similar to HR observed after methacholine challenge. These studies suggest an enhancing effect of inhaled allergen on SHR.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

The influence of terfenadine and ipratropium bromide alone and in combination on bradykinin-induced nasal symptoms and plasma protein leakage.

Nasal instillation of bradykinin elicits many of the characteristic features of rhinitis. To assess the relevance of histamine release from metachromatic cells and the activation of cholinergic pathways, we investigated the effects of terfenadine, a histamine H1-receptor antagonist, and ipratroprium bromide, a selective antimuscarinic agent, on bradykinin induced rhinorrhoea, nasal airways resistance (NAR), nasal pain and plasma protein leakage. Oral terfenadine (120 mg) or matched placebo and nasal ipratropium bromide (80 micrograms) or matched placebo were administered at 4 hr and 30 min respectively prior to bradykinin nasal challenge in two randomized, double-blind and cross-over studies on eight non-rhinitic subjects. Thus subjects received either double-placebo, oral terfenadine and nasal placebo, oral placebo and nasal ipratopium bromide or oral terfenadine and nasal ipratropium bromide, as pretreatment. Bradykinin challenge induced mean maximal increases of 57%, 59%, 77% and 72% in NAR on the placebo, terfenadine, ipratropium bromide and terfenadine plus ipratropium bromide pretreatment days respectively. These increments were not significantly different. Similarly rhinorrhoea and nasal pain induced by bradykinin nasal challenge were not significantly different on the four challenge days. Bradykinin nasal challenge caused a mean maximal increase in albumin levels in recovered nasal lavages of 11.5, 13.0, 12.2 and 12.3 times of baseline levels on the placebo, terfenadine, ipratropium bromide and terfenadine plus ipratroprium bromide pretreatment days respectively. Similarly total protein levels achieved a mean maximal increase of 8.0, 8.2, 7.9 and 8.8 times of baseline levels on these challenge days. The increments in both albumin and total protein did not significantly differ on the 4 challenge days.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

Nasal effects of bradykinin and capsaicin: influence on plasma protein leakage and role of sensory neurons.

Nasal insufflation with bradykinin induces nasal discomfort, rhinorrhea, and nasal blockage, all features of rhinitis. We recently showed these effects to be mediated by the B2-receptor subtype, which has been identified at neural and vascular sites. To investigate the relative contribution of capsaicin-sensitive sensory neural stimulation to the action(s) of bradykinin, two randomized double-blind placebo-controlled studies have been undertaken comparing the nasal effects of single-dose administrations of bradykinin (1.88 x 10(-3) M) and capsaicin (3.28 x 10(-5) M). In comparison with placebo, both bradykinin and capsaicin induced nasal pain/discomfort (P less than 0.01) and rhinorrhea (P less than 0.02). Bradykinin significantly increased nasal airways resistance (P less than 0.005) and plasma protein exudation (P less than 0.02). No such changes were identified after nasal challenge with capsaicin. These findings suggest that bradykinin-induced nasal discomfort and rhinorrhea are neurally mediated, whereas the effects on nasal airways resistance and plasma protein exudation are due to a direct vascular action. In addition, these findings question the role of capsaicin-sensitive sensory neurons in nasal vasculature responses, because no vascular effects of capsaicin could be identified in the human nasal mucosa.

Adult↗
PubMed1992

Effect of inhaled platelet-activating factor on bronchial inflammation in atopic non-asthmatic subjects.

We have investigated the effect of inhaled platelet-activating factor (PAF) on bronchial mucosal inflammation in 6 atopic non-asthmatic subjects in a double-blind, placebo-controlled, randomised and crossover study. On 2 study periods at least 4 weeks apart, fiberoptic bronchoscopy was performed 24 h after inhalation of either 200 micrograms PAF or methacholine (control) to obtain endobronchial biopsies. Immunocytochemistry using antibodies for trypase (AA1) and eosinophil cationic protein (EG2) was performed to enumerate mast cells and eosinophils, respectively, in the bronchial submucosa. Median values of AA1+ cells and EG2+ cells did not differ significantly after inhalation of PAF or control (23.8 vs. 39 and 6 vs. 8/mm2, respectively, PAF vs. control, non-significant). Our findings suggest that within 24 h of inhaling a bronchoconstrictor dose of PAF, this agonist does not induce bronchial hyperresponsiveness or mucosal inflammation in atopic non-asthmatic subjects. However, because of the small number of subjects studied, these preliminary data should be interpreted with caution.

Administration, Inhalation↗
PubMed1992

Effect of an inhaled corticosteroid on airway inflammation and symptoms in asthma.

The effect of inhaled corticosteroid therapy on airway mucosal inflammation was investigated in 10 symptomatic atopic asthmatic patients treated with inhaled albuterol and whose disease severity required preventative antiinflammatory treatment. Endobronchial biopsies were obtained by fiberoptic bronchoscopy before and after 6 wk of therapy with inhaled beclomethasone dipropionate (2,000 micrograms/day for 2 wk followed by 1,000 micrograms/day for 4 wk). Following treatment, there was a significant increase in mean morning peak expiratory flow (p less than 0.05) and baseline FEV1 measured on the day of methacholine challenge (p less than 0.05) and a decrease in asthma symptoms (p less than 0.01), peak expiratory flow variation (p less than 0.05), and albuterol usage (p less than 0.05). This was accompanied by a sevenfold decrease in airway responsiveness (p = 0.001). The clinical improvement in asthma was associated with a significant (p less than 0.05) reduction in epithelial and mucosal mast cells and eosinophils and submucosal T lymphocytes, but electron microscopy did not identify any changes in the extent of mast cell and eosinophil degranulation following treatment. Because of the association between the decrease in inflammatory cell numbers and the improvement in all the measured clinical and physiologic indices of asthma, we suggest that the beneficial effect of inhaled corticosteroids in asthma may be attributed to their antiinflammatory action in the bronchial mucosa.

Administration, Inhalation↗
PubMed1992

Lymphocyte activation in bronchoalveolar lavage and peripheral blood in atopic asthma.

To study the role of T lymphocytes in atopic asthma we have examined cell populations in peripheral blood and bronchoalveolar lavage (BAL) from 12 atopic asthmatics and 10 healthy volunteers using flow cytometry and a panel of monoclonal antibodies directed toward T-cell surface antigens. BAL from asthmatics contained more eosinophils (mean, 0.54 +/- 11.2 x 10(6) versus 0.06 +/- 0.08 x 10(6) absolute count, p less than 0.05), but no greater total or percent of T lymphocytes. There was no difference between the two groups in the relative numbers of CD4+ or CD8+ T cells. However, there was a significant increase in the mean number of BAL CD3+ lymphocytes expressing the activation markers interleukin-2 receptor (IL-2R, CD25) (8.48 versus 4.37%, p less than 0.01) and human lymphocyte antigen-DR (11.08 versus 7.74%, p less than 0.05) in the asthmatics. In contrast to lavage cells, there was no difference in CD3+ cell activation markers in the peripheral blood. These findings suggest that T-lymphocyte activation occurs within the airways in symptomatic atopic asthma.

Adult↗
PubMed1992

Early changes in T lymphocytes recovered by bronchoalveolar lavage after local allergen challenge of asthmatic airways.

To assess the role of T lymphocytes in the initiation of the allergic asthmatic response we have investigated T-cells subsets and their activation markers in bronchoalveolar lavage (BAL) fluid recovered 10 min after local challenge of the bronchial mucosa with allergen or saline. Endobronchial challenge was performed in 13 mildly atopic asthmatic patients (FEV1% predicted range, 78.2 to 116.5) and 10 normal volunteers. In all of the asthmatics but in none of the normal subjects allergen but not saline exposure resulted in visible bronchoconstriction. Analysis of BAL by flow cytometry showed no differences in the overall number of T cells (CD3+) and their CD4+ and CD8+ subsets per milliliter of BAL between the groups of normal subjects and asthmatics. However, within 10 min of allergen challenge, in the asthmatics but not in the normal subjects, there occurred a significant loss of CD3+ cells (p less than 0.01) comprising mostly CD4+ (p less than 0.05) but also CD8+ cells, with a consequent decrease in the CD4:CD8 ratio. At this early time point no differences in the extent of expression of the T-cell activation markers, IL-2 receptor, and HLA-DR were found. These results provide evidence to support a role of T lymphocytes early in the allergen-induced inflammatory response in asthma.

Adult↗
PubMed1992

The expression of leukocyte-endothelial adhesion molecules is increased in perennial allergic rhinitis.

Accumulating evidence supports the importance of leukocyte-endothelial cell adhesion molecule (CAM) expression as an initiating process in tissue inflammation. To investigate the relevance of CAM expression to allergic airways inflammation, nasal biopsies from patients with perennial allergic rhinitis (n = 8) and from nonatopic healthy volunteers (n = 8) were immunostained with monoclonal antibodies directed against the CAMs, intercellular adhesion molecule-1 (ICAM-1), endothelial cell adhesion molecule-1 (ELAM-1), and vascular cell adhesion molecule-1 (VCAM-1). The endothelial staining of these CAMs was related to the number of vessels within each biopsy, delineated by a monoclonal antibody against Ulex europaeus-1 lectin bound to endothelial cells, and to the number of tissue leukocytes staining for one of the ligands of ICAM-1, the beta 2 integrin, lymphocyte function-associated antigen (LFA-1). Expression of CAMs was related to the number of infiltrating neutrophils, eosinophils, and lymphocytes identified immunohistochemically within the biopsies. ICAM-1 was the most prominent CAM present on the endothelium of the normal nasal mucosa, with less expression of ELAM-1 and only minimal or absent expression of VCAM-1. In perennial rhinitis, both ICAM-1 (P less than 0.05) and VCAM-1 (P less than 0.01) expression on endothelial cells were increased and were positively correlated in their level of expression (P less than 0.002). The number of tissue LFA-1-positive cells was significantly greater (P less than 0.05) in the biopsies from the perennial rhinitics (median, 27.3/mm2) than from the healthy controls (median, 5.3 cells/mm2). LFA-1 expression significantly correlated with the number of ICAM-1-positive vessels (P less than 0.03).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

Intercellular adhesion molecule-1 (ICAM-1) and endothelial leucocyte adhesion molecule-1 (ELAM-1) expression in the bronchial mucosa of normal and asthmatic subjects.

Bronchial lavage and biopsy studies suggest the involvement of eosinophils and T-lymphocytes in allergic inflammation in asthma. There is evidence suggesting that the expression of adhesion molecules on endothelial cells and of their receptors on leucocytes is involved in this process. To investigate these mechanisms we have obtained bronchial mucosal biopsies from 10 normal subjects and from 10 symptomatic atopic asthmatics. Six of the asthmatics were re-biopsied after 6 weeks of inhaled beclomethasone dipropionate (BDP) during which time their clinical response was monitored. Frozen sections were stained by the immunoperoxidase method using monoclonal antibody (MoAb) 6.5B5 to identify expression of intercellular adhesion molecule (ICAM-1) and MoAb 1.2B6 for endothelial leucocyte adhesion molecule (ELAM-1). Araldite-embedded sections were also stained for eosinophils using MoAb EG2 to identify eosinophilic cationic protein (ECP). A significant mucosal eosinophilia was apparent in the asthmatic but not in the normal biopsies. Immunostaining for ICAM-1 was observed in both the epithelium and endothelium and ELAM-1 in endothelium, with no significant differences being apparent between the asthmatic and normal subjects. Topical BDP markedly reduced the mucosal eosinophilia without affecting the expression of either adhesion molecule. Using this method, we conclude that there is basal expression of ICAM-1 and ELAM-1 in normal human bronchial mucosa, which is not significantly different from that in asthmatics, and that it is insensitive to suppression with corticosteroids at an inhaled dose that causes clinical improvement.

Adult↗
PubMed1992

Bronchial mucosal manifestations of atopy: a comparison of markers of inflammation between atopic asthmatics, atopic nonasthmatics and healthy controls.

We studied the role of atopy, as defined by positive skin tests to common inhalant allergens, in allergic bronchial inflammation. Endobronchial biopsies were taken via the fibreoptic bronchoscope in 13 symptomatic atopic asthmatics, 10 atopic nonasthmatics, and 7 normals. The numbers of mast cells, identified in the submucosa by immunohistochemistry using the AA1 monoclonal antibody against tryptase, were no different between the three groups, but electron microscopy showed that mast cell degranulation, although less marked in atopic nonasthmatics, was a feature of atopy in general. The numbers of eosinophils, identified by immunohistochemical staining using the monoclonal anti-eosinophil cationic protein antibody, EG2, were greatest in the asthmatics, low or absent in the normals and intermediate in the atopic nonasthmatics. In both atopic groups eosinophils showed ultrastructural features of degranulation. Measurements of subepithelial basement membrane thickness on electron micrographs showed that the collagen layer was thickest in the asthmatics, intermediate in the atopic nonasthmatics and thinnest in the normals. The results suggest that airways eosinophilia and degranulation of eosinophils and mast cells, as well as increased subepithelial collagen deposition, are a feature of atopy in general and suggest that the degree of change may determine the clinical expression of this immune disorder.

Adult↗
PubMed1991

Endothelin immunoreactivity of airway epithelium in asthmatic patients.

There is extensive pharmacological and physiological evidence that endothelin-1 influences airway calibre. In mammals, endothelin receptor occur on airway smooth muscle, local storage and release of the peptide have been demonstrated, and inhalation of endothelin-1 induces bronchoconstriction. To investigate the relation between endothelins and asthma the expression of this peptide in endobronchial biopsy specimens was examined immunohistochemically with an antiserum against endothelin-1. Biopsy specimens from 17 asthmatic patients and 11 atopic and non-atopic healthy controls revealed striking differences, with endothelin expression being evident in airways epithelium and vascular endothelium in 11 of the 17 asthmatic patients but in only 1 of 11 controls. These results suggest that endothelins may play a part in the exaggerated bronchomotor tone of asthma.

Adolescent↗