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Biomedical subjects

M A Spiteri

Publications and source records attributed to M A Spiteri.

At least 37 records · Page 2Linked to original sources
PubMed1997

Interferon-gamma (IFN-gamma) down-regulates the rhinovirus-induced expression of intercellular adhesion molecule-1 (ICAM-1) on human airway epithelial cells.

Human rhinoviruses (HRV) are a major cause of upper respiratory tract infections in man, and can exacerbate existing pulmonary disease. The major group of HRV attach to ICAM-1, which is expressed on nasal and bronchial epithelial cells. To study the influence of biological mediators on ICAM-1 expression, and consequently HRV attachment and infection, we compared the effects of various cytokines, alone and in combination, on ICAM-1 expression by an uninfected and HRV-infected bronchial epithelial cell line H292. Cytokines known to be released soon after viral infection, such as tumour necrosis factor-alpha (TNF-alpha), IL-1beta and the chemokine IL-8 increase ICAM-1 expression on uninfected cells. Epithelial cells infected with live HRV-14 displayed marked up-regulation of ICAM-1 compared with baseline. TNF-alpha further enhanced the HRV-induced increase in ICAM-1 expression on epithelial cells, peaking at day 4 after infection, whilst IL-8 exhibited a steady increase in ICAM-1 expression over 14 days. In contrast, IFN-gamma, a known Th1 antiviral lymphokine, whilst increasing the level of ICAM-1 on uninfected cells, induced a significant persistent down-regulation of ICAM-1 expression on HRV-infected epithelial cells. With combinations of TNF-alpha and IFN-gamma, ICAM-1 expression on HRV-infected cells was reduced to basal levels. The effects of IFN-gamma were paralleled by a reduction in viral titres. Our in vitro model has provided useful insights into the early pathogenic events of HRV infection at the level of the host cell-virus interaction. Our data confirm that biological mediators play a crucial role in the pathogenesis as well as the course of HRV infection which is modulated by the types, and time kinetics of inflammatory cytokines in the immediate microenvironment.

Bronchi↗
PubMed1996

Sarcoidosis.

Sarcoidosis is a multisystem granulomatous disorder of unknown aetiology. The condition commonly affects young adults and frequently presents with bilateral hilar lymphadenopathy with or without pulmonary infiltration, ocular or cutaneous lesions. The clinical presentation can be extremely varied depending upon the organs affected. The diagnosis is firmly established when recognised clinical and radiographic findings are supported by histological evidence of discrete non-necrotising epithelioid cell granulomata in one or more organs. Sarcoidosis is usually self-limiting with spontaneous resolution, although in a few patients there is a progressive downhill course, culminating in irreversible fibrosis and severe impairment of organ function.

Adult↗
PubMed1996

Pulmonary sarcoidosis: patterns of cytokine release in vitro.

This study was designed to investigate the ability of bronchoalveolar and blood mononuclear cells to produce inflammatory mediators in vitro in pulmonary sarcoidosis. Seventeen patients with pulmonary sarcoidosis (stage I n = 8; stage II/III n = 9) and 10 normal controls were investigated. Bronchoalveolar and peripheral blood mononuclear cells were cultured in serum-free medium, without stimulant, for 24 h, and the supernatants analysed for concentrations of interleukin (IL)-1 beta (IL-1 beta), IL-2, IL-6, tumour necrosis factor-alpha (TNF-alpha), granulocyte-macrophage colony-stimulating factor (GM-CSF), interferon-gamma (IFN-gamma) and neopterin. Bronchoalveolar lavage cells (BALC) of sarcoid patients released significantly higher amounts of TNF-alpha, IL-6, IFN-gamma and neopterin in comparison to normal controls. When smokers were excluded, there was also an increased release of IL-1 beta and GM-CSF. In the sarcoid group, the levels of IL-1 beta, IL-6, TNF-alpha and GM-CSF showed highly significant correlations between each other, but not with IL-2, IFN-gamma or neopterin. Sarcoid patients whose BALC released more TNF-alpha or GM-CSF had higher percentage counts of alveolar macrophages but fewer lavage lymphocytes. In sarcoid patients, peripheral blood mononuclear cells (PBMNC) also released higher amounts of IL-1 beta, TNF-alpha, IL-6 and GM-CSF but less neopterin than normal controls. Patients whose PBMNC produced more IL-1 beta, IL-6 and GM-CSF had higher absolute and relative lavage neutrophil counts. No relationships were observed between cytokine release and radiographic or physiological markers of disease severity. We conclude from this study that sarcoid inflammation is associated with an increased and concerted release of monocyte/macrophage-derived cytokines not only in the lung but also in the peripheral blood. We speculate that the lymphokines, IFN-gamma and IL-2, are not the primary triggers.

Adult↗
PubMed1994

Alveolar macrophage-induced suppression of peripheral blood mononuclear cell responsiveness is reversed by in vitro allergen exposure in bronchial asthma.

Little information is available on the specific role of alveolar macrophages (AMs) in modulating local cellular reactions to inhaled allergens in atopic asthma. We investigated the influence of alveolar macrophages obtained by bronchoalveolar lavage (BAL) on the proliferative responses of lavage and peripheral lymphocytes from 12 patients with atopic asthma, 6 nonasthmatic symptomatic atopic subjects, and 6 nonatopic normal volunteers, in the context of in vitro exposure to relevant and nonrelevant allergens. Fresh nonadherent bronchoalveolar lavage cells from atopic asthmatic patients, depleted of alveolar macrophages, proliferated spontaneously more than nonadherent bronchoalveolar lavage cells from normal subjects. Addition of autologous asthmatic alveolar macrophages reduced this endogenous "activation". Asthmatic and normal alveolar macrophages also inhibited phytohaemagglutinin-stimulated proliferation of both autologous and allogeneic nonadherent peripheral blood mononuclear cells (PBMC). In contrast, autologous asthmatic alveolar macrophages induced strong proliferation of peripheral blood mononuclear cells when stimulated with allergen to which the patient was skin test and radio allergosorbent test (RAST) reactive; however, no response was seen with allergens to which the patient was insensitive. No such allergen-specific proliferation was seen with alveolar macrophages from nonasthmatic atopic subjects. These data support the presence of functionally-active alveolar macrophages within the airways of atopic asthmatic patients, that under normal stable conditions suppress the induction of peripheral blood mononuclear cell responses, and which only on contact with specific allergen appear to switch to inducer alveolar macrophages, with consequent peripheral blood mononuclear cell hyperactivation.

Adult↗
PubMed1994

Inhaled frusemide does not affect lung mucociliary clearance in healthy and asthmatic subjects.

Inhaled frusemide has been shown to protect against the bronchoconstrictor effect of several inhaled agents in asthmatic subjects by mechanism(s) that are unclear. Since loop diuretics can modulate Cl- transport in the airway epithelium, frusemide may alter the quality and/or the quantity of the periciliary layer, which in turn may affect lung mucociliary transport. We investigated the effect of a single inhalation of nebulized frusemide (40 mg) on lung mucociliary clearance in four healthy subjects and in seven stable, mild asthmatics using an objective radioaerosol technique. Frusemide or placebo was inhaled in a double-blind, randomized, cross-over manner half an hour after the inhalation of 5 microns polystyrene particles labelled with 99mTc, used for assessing mucociliary clearance. The pulmonary function and initial radioaerosol distribution were similar between frusemide and placebo runs within each of the two study groups. The areas under the tracheobronchial retention curves over the 6 h observation period were similar between frusemide and placebo runs for both groups. Our findings show inhaled frusemide, at a dose known to inhibit bronchoconstrictor responses, does not affect lung mucociliary clearance.

Administration, Inhalation↗
PubMed1992

Seasonal cryptogenic organising pneumonia with biochemical cholestasis: a new clinical entity.

The term cryptogenic organising pneumonia has been used for the combination of dyspnoea, cough, pleuritic pain, widespread shadows on chest radiographs, and histological evidence of intra-alveolar organisation with buds of granulation tissue within the alveoli. We report 12 patients with seasonal recurrence of this disorder for between 3 and 11 years. In all 12 patients, symptoms recurred between late February and early May every year, tending to increase in severity each year, and resolved between June and January. Chest radiography and computed tomography showed bilateral consolidation. Lung biopsy samples showed intra-alveolar buds of granulation tissue. There were many neutrophils within the lumina of medium-sized airways and terminal bronchioles showed evidence of obstruction by granulation tissue. Functionally, the predominant defect was restrictive and only 2 patients (life-long non-smokers) had airflow limitation. All 12 patients had very high activities of liver enzymes, suggesting intrahepatic cholestasis, but no other evidence of liver disease. Cultures of blood, sputum, lung tissue, and bronchoalveolar lavage fluid, viral screening, and complement fixation tests were consistently negative. In all patients all abnormalities responded rapidly to oral steroid therapy. These findings suggest a seasonal syndrome of organising pneumonia and biochemical abnormalities indicative of intrahepatic cholestasis. No aetiological factor has been identified, but the nature and periodicity of the illness point to an inhaled agent present in the environment for a limited period every year.

Adult↗
PubMed1992

Effect of temazepam on tracheobronchial mucus clearance.

BACKGROUND: Tracheobronchial clearance of mucus from the lungs is reduced during sleep and, usually, by the administration of opiates. It seemed possible therefore that temazepam, a widely used potent benzodiazepine, retarded clearance. METHODS: The effect of 10 mg temazepam on mucociliary clearance was studied in eight healthy volunteers, aged 18-50 (mean 30) years, in a randomised, placebo controlled, double blind, cross-over study. Six subjects were female and two male. Six were non-smokers and two were light current smokers. Clearance was assessed from the change in radio-activity in the lungs after inhalation of 5 microns diameter polystyrene particles, labelled with technetium-99m, under controlled conditions. RESULTS: Tracheobronchial clearance was reduced by 22% after temazepam by comparison with placebo during the first three hours after drug ingestion; this is the period when circulating drug concentrations are highest. CONCLUSION: Temazepam should be prescribed with caution in patients with impaired lung mucociliary transport.

Adolescent↗
PubMed1992

Alveolar macrophages that suppress T-cell responses may be crucial to the pathogenetic outcome of pulmonary sarcoidosis.

The alveolar macrophage (AM) population is widely recognized to be heterogeneous; distinct subpopulations can be identified by the use of macrophage-specific monoclonal antibody (MoAb) probes. We have isolated a macrophage subset that appears to react with both MoAbs that have previously discriminated between dendritic cells and classic macrophages. In the bronchoalveolar lavage (BAL) of patients with active sarcoidosis the proportion of this specific AM subpopulation increases dramatically (30.4 +/- 4.01% compared to 6.14 +/- 1.56% in normal BAL). This AM subset not only increases in direct proportion to the lavage lymphocytosis, but also exhibits sarcoid-related differences in surface receptor expression, physiology and induction of T-cell responses. An increased number of these AM expressed a separate antigen RFD9 (which identified epithelioid cells), and had raised fibronectin content, increased phagocytosis, and high lysosomal enzyme activity. Of functional significance, we found that while in normal volunteers this specific AM subset was capable of down-regulating by as much as 40% the induction of T-cell responses set up by other stimulator macrophages, in sarcoid patients this suppressor activity was enhanced, such that T-cell responses were completely abolished. In some studies this action was masked by the reduced enhancing capacity of sarcoid inducer AM. We postulate that the presence of an increased proportion of these suppressor AM (together with their sarcoid-specific features) in active sarcoidosis is of crucial significance in determining the fate of granulomata in the lungs of these patients.

Adult↗
PubMed1992

Isolation of phenotypically and functionally distinct macrophage subpopulations from human bronchoalveolar lavage.

Bronchoalveolar lavage was used to obtain alveolar macrophages (AM) from the lower respiratory tract of healthy normal volunteers. Monoclonal antibody (MoAb) probes specific against macrophage determinants were then applied, in conjunction with density separation techniques, to identify and isolate three relatively homogeneous subpopulations from the AM pool. The MoAbs used, RFD1 and RFD7, have previously been shown to differentiate between "dendritic" cells and mature macrophages, respectively, in normal tissue. In addition to these two phenotypically distinct AM subsets (RFD1+D7- and RFD1-D7+ AM), a third AM subpopulation was isolated, which appeared to express both markers (RFD1+D7+). All three separated macrophage subsets were morphologically similar but exhibited distinct differences in surface receptor expression, enzyme content and physiology. Isolated RFD1+D7- AM (the phenotype of "dendritic" cells) did not adhere to the glass, had weak expression of C3b and FcR1 receptors, low fibronectin content and lysosomal activity; only a small proportion of these cells exhibited phagocytosis. The other two isolated AM subsets adhered to glass, expressed C3b and FcR1 receptors, had high fibronectin and acid phosphatase content, and a large majority exhibited phagocytic capacity; qualitative and quantitative differences in these features existed between the two AM subtypes. Furthermore, a diverse spectrum of hexose monophosphate shunt activity was observed throughout all three AM subpopulations, with the highest activity being recorded in the non-adherent AM. These data support the concept of a dynamic heterogeneity within the AM population. The variation in surface antigen expression and physiological capabilities observed amongst the three isolated AM subsets implies the presence of functionally distinct AM within the human lung, which, during steady-state conditions, may be critically balanced under the influence of stimuli in their local microenvironment. In support, proportional and functional shifts have been witnessed amongst these three AM subpopulations with the advent of disease.

Adult↗
PubMed1991

Characterization of immune inducer and suppressor macrophages from the normal human lung.

Monoclonal antibodies (MoAbs) that are able to discriminate between dendritic cells (MoAb RFD1+) and mature macrophages (MoAb RFD7+) in normal tissues were used in combination with density separation techniques to isolate relatively homogeneous subpopulations of macrophages from human bronchoalveolar lavage (BAL). A characterization of surface antigen expression, and functional capacity was then carried out on each isolated alveolar macrophage (AM) subset. One population with the phenotype RFD1+RFD7- obtained from the non-adherent cell pool showed the characteristics of antigen-presenting cells having absent or poor expression of Fc and C3b receptors, a low content of lysozomal hydrolase and poor phagocytic capacity. This population strongly stimulated T lymphocytes in allogeneic mixed lymphocyte reactions (MLR). A second AM population, isolated by adherence and density centrifugation expressed the phenotype RFD1+RFD7+. These cells showed the same phenotypic characteristics of mature macrophages with strong expression of C3b and Fc receptors, and marked phagocytic capacity. Such AM were very poor stimulators of allogeneic MLR. Under certain circumstances the RFD1+RFD7+ cells were shown to actively repress the stimulatory capacity of the RFD1+RFD7- subpopulation. These results suggest that variations within the functional capacity of AM subsets may be capable of influencing the strength of acquired T cell immune responses of the lung.

Acid Phosphatase↗
PubMed1990

Immunological features of lung lavage cells from patients with primary biliary cirrhosis may reflect those seen in pulmonary sarcoidosis.

To investigate the basis of subclinical alveolitis in patients with primary biliary cirrhosis, 10 primary biliary cirrhosis patients were studied by bronchoalveolar lavage. Both bronchoalveolar lavage lymphoid and non-lymphoid cell populations were analysed using immunocytological methods to determine their proportions and phenotypic features in an attempt to gain information as to possible immune mechanisms active in the lung of these patients. Six of the 10 patients in our study showed evidence of an alveolitis (raised lymphocyte count: 27.6 (4.3)% of total count) on lavage. The results were compared with control groups of normal volunteers and patients with active pulmonary sarcoidosis. The six primary biliary cirrhosis patients with lymphocytosis had a raised CD4/CD8 T-cell ratio (4.13:1), similar to the sarcoid patients (5.60:1). A proportion of these T-lymphocytes expressed markers of activation (HLA-DR+ 7.5 (2.1)%); CD25 + 2.3 (0.9)%; CD7 + 5.8 (1.5)%. This increased T-cell activation was also seen in the sarcoid groups (HLA-DR+ 10.0 (1.9)%; CD25 + 3.0 (1.1)%; CD7 + 5.0 (0.2)%). This was not seen in the primary biliary cirrhosis patients without lymphocytosis and the normal volunteers. Within the non-lymphoid cell population, an increase in dendritic (RFD1+) cells was seen in primary biliary cirrhosis patients with lymphocytosis (31.2 (1.9)%) and sarcoid patients (46.3 (5.1)%) in contrast with the normal and primary biliary cirrhosis group without lymphocytosis. The primary biliary cirrhosis patients without lymphocytes had a relatively greater proportion of mature phagocytes (RFD7+). We postulate that these observations suggest the emergence in the lung of a granuloma producing mechanism similar to that occurring in the liver. By comparison, the alveolitis found in primary biliary cirrhosis is consistent with that observed in interstitial granulomatous lung disorders such as sarcoidosis.

Bronchoalveolar Lavage Fluid↗
PubMed1989

Inhaled corticosteroids can modulate the immunopathogenesis of pulmonary sarcoidosis.

We investigated the effect of inhaled corticosteroids on the phenotypes and functional capacity of macrophages obtained by bronchoalveolar lavage from patients with pulmonary sarcoidosis. The results were correlated with clinical status and therapeutic efficacy. Ten symptomatic sarcoid patients (previously untreated) with radiological parenchymal shadowing and abnormal pulmonary function received inhaled budesonide, 800 micrograms m twice daily via a Nebuhaler for 16 weeks. A placebo group included ten healthy volunteers and five sarcoid patients with similar features to the treated group. Drug distribution studies showed that 10% of the inhaled drug was deposited in the alveolar region. All ten treated sarcoid patients had symptomatic relief with no adverse effects. Three of these ten patients had significant resolution of their radiological shadowing. No significant difference in pulmonary function was observed. At the cellular level, a significant decrease in lavage lymphocytosis was seen after 16 weeks, during which time there was a concomitant change in the phenotype and functional characteristics of the alveolar macrophage population. No similar changes were observed in the placebo group. Our results suggest that inhaled budesonide can modulate the aberrant immunological reactions existent in the lung in pulmonary sarcoidosis, and produce concomitant symptomatic relief with no side effects. It is postulated that this effect may occur through action on the local alveolar macrophage population.

Administration, Inhalation↗
PubMed1989

The macrophage in sarcoid granuloma formation.

Sarcoid granulomata result from aberrant immunological reactions initiated by antigen--presenting macrophage--like cells, and maintained by other effector macrophages. These macrophages can be distinguished phenotypically by monoclonal antibodies RFD1 and RFD7 (which recognize dendritic cells and mature macrophages respectively). Active sarcoid BAL contains a high proportion of RFD1 + cells (mean 44.7% compared to 12% in normals). Much of this increase is accounted for by the emergence of macrophages with the double phenotype RFD1 + D7 + (27.2% compared to 7% in normals), the proportion of which increases with disease severity and returns to normal in remission. When isolated from BAL by using plastic plate adherence and metrizamide density gradient, this hitherto unknown RFD1 + D7 + subset displays distinctive phenotypic, physiological and functional features. Unlike RFD1 + D7-cells, RFD1 + D7 + macrophages adhere to plastic, are acid phosphatase positive with increased phagocytosis, have marked Fc and c3b receptor expression, and suppress T-lymphocyte reactivity. In active sarcoidosis, this suppressive action is accentuated, and a greater proportion of RFD1 + D7 + cells express Fc receptors as well as a separate antigen RFD9 (which identifies epithelioid cells). Furthermore we have observed that gamma-interferon, produced in high concentration by activated T-lymphocytes induces not only HLA-DR molecules on cells, but has also been shown in vitro to increase the proportion of RFD1 + cells developing while suppressing RFD7 expression. It therefore seems that the increased proportion of RFD1 + D7 + macrophages seen in active sarcoidosis could arise as a result of an increased induction of RFD1 expression on macrophages which express RFD7.(ABSTRACT TRUNCATED AT 250 WORDS)

Antibodies, Monoclonal↗
PubMed1989

The nature of latent pulmonary involvement in primary biliary cirrhosis.

Primary biliary cirrhosis is a disease of unknown aetiology, resulting in progressive granulomatous destruction of small intrahepatic bile ducts. The rate at which this occurs varies considerably producing a wide clinical spectrum of the disease itself, as well as expression in other organs. Pulmonary manifestations in PBC have only been intermittently reported. Nevertheless in practice, a vast array of pathophysiological mechanisms can be implicated for the pulmonary dysfunction seen in some of these patients. The observed clinical features can be attributed to pulmonary vascular abnormalities, to a secondary 'fibrosing alveolitis', or indeed to the emergence of a granulomatous disorder in the lungs similar to sarcoidosis. Physicians should thus be aware of such potential lung complications, which can occur not only during the course of the PBC but also following liver transplantation.

Humans↗