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Biomedical subjects

P H Howarth

Publications and source records attributed to P H Howarth.

At least 127 records · Page 7Linked to original sources
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↗
PubMed1991

Comparative nasal effects of bradykinin, kallidin and [Des-Arg9]-bradykinin in atopic rhinitic and normal volunteers.

1. The structure-activity relationship of kinins within the nose has been investigated in atopic rhinitic (n = 7) and non-rhinitic (n = 7) subjects. On 4 separate days, each separated by a week, subjects randomly underwent nasal challenge with incremental doses of either the B1 agonist [Des-Arg9]-bradykinin, the B2 agonists kallidin or bradykinin, or vehicle placebo in a double-blind comparative study. The nasal response was monitored objectively by measurement of nasal airways resistance (NAR) by active posterior rhinomanometry and subjectively by symptom reporting of nasal blockage, rhinorrhoea, nasal itch and nasal pain. 2. The B2 agonists kallidin and bradykinin both induced a dose-dependent increase in NAR (P less than 0.001) and were associated with symptomatic reporting of nasal blockage (P less than 0.05), rhinorrhoea (P less than 0.01) and nasal discomfort (P less than 0.05) compared to placebo. In contrast the effects of the B1 agonist [Des-Arg9]-bradykinin on NAR and symptom reporting were indistinguishable from placebo. No difference could be identified in the nasal response to kallidin and bradykinin between rhinitic and non-rhinitic subjects and there was no evidence of B1 receptor upregulation in the disease state. For the whole group the provocative dose of agonist inducing a 50% increase in NAR (PD50) was 1.77 x 10(-4) mol for bradykinin and 2.86 x 10(-4) mol for kallidin (P greater than 0.05). 3. These findings identify that the nasal effects of kinins are mediated through B2 receptors and the advent of B2 receptor antagonists will permit a further evaluation of the role of kinins in rhinitis.

Adult↗
PubMed1991

Allergic inflammation and its pharmacological modulation in asthma.

While most asthma occurs in association with atopy, the relationship of this to clinical expression of the disease is not clearly understood. Allergen provocation causes an immediate bronchoconstriction (early asthmatic reaction) due to the release of mast-cell-derived histamine, prostaglandin D2 and leukotriene C4. The late reaction and attendent increase in bronchial responsiveness are associated with eosinophil influx, activation and mediator secretion, resulting in mucosal swelling in addition to smooth muscle contraction. Endobronchial biopsy and broncho-alveolar lavage have provided compelling evidence that both mast cells and eosinophils contribute to disordered airway function in 'clinical' asthma and that these cells are under the control of T lymphocytes. Topical corticosteroids which produce beneficial clinical effects probably do so by inhibiting those factors that maintain mast cell and eosinophil populations and their enhanced activation. The most likely contenders for these regulatory functions are the cytokines, particularly interleukin-3, -4 and -5.

Adrenal Cortex Hormones↗
PubMed1991

Airway inflammation and atopic asthma: a comparative bronchoscopic investigation.

Flexible fibre-optic bronchoscopy under local anaesthesia has been used to investigate the cellular airway events in atopic asthma. The findings have been compared to those from atopic individuals without asthma and non-atopic healthy controls, in an attempt to discern those changes relevant to clinical disease expression. Immunohistochemical and electron-microscopic analyses of airway biopsies identified that an atopic diathesis is associated with tissue eosinophil infiltration and mast cell degranulation. The eosinophilia was greatest in those atopic individuals with asthma. Flow-cytometric analysis of airway lavage revealed significantly enhanced T lymphocyte activation in clinical asthma. These findings are consistent with the hypothesis that T lymphocyte activation, through cytokine release, amplifies the tissue eosinophilia in asthma and that this combination is associated with clinical disease expression.

Asthma↗
PubMed1991

Mucosal nerves in endobronchial biopsies in asthma and non-asthma.

To investigate neural events within the airways in asthma, endobronchial biopsies were obtained by fibre-optic bronchoscopy from 8 atopic asthmatic subjects and 8 non-atopic healthy controls. The biopsies were immediately fixed on sampling and subsequently analysed for nerves using specific indirect immunofluorescence with antisera to the neural marker PGP 9.5 and to the neuropeptides vasoactive intestinal peptide (VIP), substance P (SP) and calcitonin gene-related peptide (CGRP). Nerves were present in all the biopsies from both subject groups, with no significant difference between the asthmatic and non-asthmatics. VIP-immunoreactive nerves were equally present in both subject groups, being localized to smooth muscle and glandular sites. No immunoreactive nerves to SP or CGRP could be identified in any biopsy at any location. These in vivo findings do not identify an anatomical neuronal imbalance in asthma.

Adult↗
PubMed1991

The safety aspects of fiberoptic bronchoscopy, bronchoalveolar lavage, and endobronchial biopsy in asthma.

We have documented the physiologic effects of fiberoptic bronchoscopy with bronchoalveolar lavage (BAL) and endobronchial biopsy performed under local anesthesia in 20 asthmatic subjects, 8 healthy nonatopic control subjects, and 8 atopic nonasthmatic subjects. Premedication consisted of nebulized albuterol (2.5 mg; except for the study of atopic nonasthmatic subjects), ipratropium bromide (500 micrograms), and intramuscular atropine (0.6 mg). Intravenous midazolam was given for mild sedation, and oxygen was delivered via a nasal cannula. FEV1 was measured before and after premedication, immediately postbronchoscopy, and after 2 h recovery. There was a significant fall in mean (+/- SD) FEV1 immediately postbronchoscopy in both the asthmatic (26.2 +/- 16.7%; p less than 0.001) and normal (9 +/- 4.7%, p less than 0.05) groups, which in the asthmatic subjects correlated inversely with the concentration of methacholine provoking a 20% fall in FEV1 (PC20) measured 5 days prebronchoscopy (r = -0.74, p less than 0.001) but not with symptom scores, albuterol use, or peak expiratory flow (PEF) variation recorded during 2 wk before the investigation. There was significant arterial hemoglobin O2 desaturation during biopsy in the asthmatic subjects (median 3%, range -1 to 17% fall from baseline; p less than 0.01), which was not related to any of the measured indices of asthma severity. PC20, measured 5 days before and 5 days after bronchoscopy in the asthmatic subjects and 2 days before and 1 day after bronchoscopy in the atopic nonasthmatic subjects was not significantly affected by the procedure. We conclude that fiberoptic bronchoscopy with BAL and endobronchial biopsy can be conducted safely in asthmatic subjects, but requires caution in those with very responsive airways.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1990

Histamine and asthma: an appraisal based on specific H1-receptor antagonism.

H1-receptor antagonists have been utilized, following their initial chemical synthesis in 1933, both in the treatment of conditions in which histamine is considered to be of pathogenic importance and conversely to help elucidate the role of histamine in disease, through an evaluation of their influence on disease expression. While there is considerable indirect evidence to implicate histamine in the pathogenesis of asthma, a critical evaluation of H1-receptor antagonism in this condition has, until recently, proved difficult, as many of the early H1-receptor antagonists possessed additional actions, such as anti-cholinergic, local anaesthetic, alpha-adrenoceptor antagonistic and anti-serotonin activity. In addition, H1-receptor antagonists have been shown to have effects on mast cell function. In low concentrations in vitro, antihistamines have been found to inhibit immunologically stimulated mast cell mediator release, with the IC50 in the nanomolar to micromolar range, while at higher concentrations they induce histamine release. The potency of these drugs in producing such effects is unrelated to their H1-receptor blocking activity. Furthermore the sedative effects of these therapeutic agents limit the tolerable administrable dose and thus the degree of H1-receptor blockade achievable within the airways. The recent development of H1-receptor antagonists devoid of clinical sedative effects has enabled the administration of doses of H1-antihistamines which achieve a greater degree of H1-receptor blockade within the airways, thus permitting a better appraisal of the role of histamine in this condition. Furthermore, the receptor specificity of many of these agents has been focused such that terfenadine, astemizole, loratadine and cetirizine are devoid of anticholinergic activity and exhibit little alpha-antagonistic or anti-serotonin activity of clinical relevance. However, of these agents both loratadine and cetirizine possess additional actions likely to be of relevance to asthma. Pretreatment with loratadine has been shown to reduce the recovery of both histamine and prostaglandin D2 (PGD2) in nasal lavage fluid following nasal allergen challenge, a finding interpreted as indicative of in vivo mast cell stabilization, and cetirizine has been shown in vivo at therapeutic doses to inhibit allergen-induced eosinophil chemotaxis. Thus while both these agents offer the potential of an oral therapy for asthma based on an H1-receptor antagonist, their additional actions do not make them ideally suited to the exploration of the role of histamine in asthma.(ABSTRACT TRUNCATED AT 400 WORDS)

Asthma↗
PubMed1990

Quantitation of mast cells and eosinophils in the bronchial mucosa of symptomatic atopic asthmatics and healthy control subjects using immunohistochemistry.

We have used fiberoptic bronchoscopy to obtain endobronchial biopsies in which mast cells and eosinophils were enumerated using monoclonal antibodies directed against mast cell tryptase (AA1) and the eosinophil cationic protein (EG2). Eleven symptomatic atopic asthmatics treated with beta 2-agonists alone and six normal subjects were studied. Over a period of 2 wk prior to bronchoscopy, patients recorded asthma symptom scores, bronchodilator usage, and twice-daily peak expiratory flow. Five days before bronchoscopy, methacholine responsiveness was assessed. Two biopsies were taken from the subcarinae, one of which was processed into araldite for immunostaining by the streptavidin biotin immunoperoxidase method and the other into Spurr resin for electron microscopy. The number of AA1 staining mast cells present in the bronchial mucosa was not significantly different in the epithelium or submucosa between the asthmatic and the normal subjects. However, in the biopsies from asthmatics, there were significantly greater numbers of EG2-staining eosinophils in the epithelium (median, 1.2/mm versus zero; p less than 0.005) and in the submucosa (median, 50/mm2 versus 1/mm2; p less than 0.001). Electron microscopy showed morphologic features of mast cell and eosinophil degranulation in the asthmatics. No correlation could be established between mast cell or eosinophil numbers and indices of disease activity of PC20 methacholine, which points to the complexity of mechanisms responsible for the symptoms and the airway hyperresponsiveness of asthma.

Adult↗
PubMed1990

Myofibroblasts and subepithelial fibrosis in bronchial asthma.

A thickened bronchial epithelial basement membrane has long been regarded as a histopathologic characteristic of bronchial asthma. As we had previously demonstrated that this phenomenon is due to the deposition of interstitial collagens and fibronectin, we have now sought to determine the nature of the cell responsible for this process by studying endobronchial biopsies from eight normal and seven asthmatic volunteers by immunohistochemistry and electron microscopy. Biopsies were stained with PR 2D3, a monoclonal antibody to myofibroblasts of the pericrypt sheath of the colon and a monoclonal antibody to alpha-smooth muscle actin. The thickness of the subepithelial collagen and the organelle content of the cells therein were determined by electron microscopy. The subepithelial collagen thickness in the normal subjects ranged from 2.16 to 6.26 microns, while that in the asthmatic subjects ranged from 3.75 to 11.1 microns (Mann-Whitney test; P = 0.05). Elongated cells in the collagen layer were identified by staining with PR 2D3. As this antibody also stains smooth muscle, consecutive frozen sections were stained for alpha-smooth muscle actin and the number of positive cells per millimeter of basement membrane was subtracted from the count for PR 2D3. This yielded a count of 4.9 to 9.4 cells/mm in the normal subjects and 11.9 to 20.6 cells/mm in the asthmatics (P = 0.001). There was a highly significant correlation between the depth of subepithelial collagen and the number of PR 2D3-positive, alpha-smooth muscle actin-positive cells (Spearman rank correlation; r = 0.764 and P = 0.006). Electron microscopy confirmed the myofibroblastic nature of these cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Actins↗
PubMed1987

The relationship between mast cell-mediator release and bronchial reactivity in allergic asthma.

The relationship between mast cell-mediator release and nonspecific bronchial reactivity was investigated in allergen-induced asthma. Two groups of subjects with asthma, one group with markedly reactive airways (provocative concentration of methacholine causing a 20% fall in FEV1, 0.07 mg/ml) and the other group with less reactive airways (provocative concentration of methacholine causing a 20% fall in FEV1, 3.83 mg/ml), had allergen bronchoprovocation. After challenge, bronchoconstriction was measured as change in specific airway conductance (SGaw), and mast cell-mediator release was measured as change in both plasma histamine and serum neutrophil chemotactic activity (NCA). In the group with more reactive airways, allergen challenge, while it produced a mean fall in SGaw of 58.1%, was not associated with any significant increase in plasma histamine from a mean resting level of 3.69 nmol/L-1. In contrast, a comparable mean fall in SGaw of 52.4% in the group with less reactive airways was associated with a significant (p less than 0.005) increase in plasma histamine from 1.17 to 3.60 nmol/L-1, maximal 5 minutes after allergen challenge. There were, however, significant increments in serum NCA in both groups with asthma after allergen challenge. The changes in NCA in the group with less reactive airways (136.7 +/- 38.1% above baseline; p less than 0.01; 1% sera dilution) were significantly greater (p less than 0.05) than changes identified in the group with more reactive airways (68.3% above baseline; p less than 0.01; 20% sera dilution). These findings directly support the concept that both mast cell-mediator release and nonspecific bronchial reactivity are separate factors that influence the airway response to inhaled allergen in asthma.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗