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Biomedical subjects

C McSharry

Publications and source records attributed to C McSharry.

At least 19 recordsLinked to original sources
PubMed2006

Peroxisome proliferator-activated receptor-gamma agonists as potential anti-inflammatory agents in asthma and chronic obstructive pulmonary disease.

Inhaled corticosteroids are the most effective therapy for chronic persistent asthma and have a role in the treatment of chronic obstructive pulmonary disease (COPD). However, corticosteroids have reduced efficacy in some patients with asthma and fail to halt the progressive deterioration in lung function characteristic of COPD. Additional or alternative drug treatments to corticosteroids are required to improve control of inflammation in patients with therapy resistant airway disease. Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonists have displayed potent anti-inflammatory properties in experimental models of asthma and other airway diseases and as a result have the potential to become an additional treatment for asthma and COPD. We review the evidence from these experimental models and their applicability to asthma and COPD and the requirements for future clinical and experimental research.

Animals↗
PubMed2006

Potential therapeutic role for statins in respiratory disease.

Statins reduce cholesterol levels by inhibiting 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and have an established role in the treatment of atherosclerotic disease. Recent research has identified anti-inflammatory properties of statins. Statins appear to reduce the stability of lipid raft formation with subsequent effects on immune activation and regulation, and also prevent the prenylation of signalling molecules with subsequent downregulation of gene expression. Both these effects result in reduced cytokine, chemokine, and adhesion molecule expression, with effects on cell apoptosis or proliferation. This review considers the evidence for the anti-inflammatory properties of statins in the lung, and how these effects are being applied to research into the role of statins as a novel treatment of respiratory diseases.

Anti-Inflammatory Agents↗
PubMed2004

Interleukin-18 levels in induced sputum are reduced in asthmatic and normal smokers.

BACKGROUND: IL-18 is a cytokine which is known to have an important role in the development of a Th1 lymphocyte response. As such, it may have a regulatory role in asthma by modifying Th2 lymphocyte responses. Cigarette smoking may amplify the airway inflammation associated with asthma. OBJECTIVE: This study investigated if IL-18 could be detected in induced sputum from asthmatics and normal subjects and if smoking altered IL-18 levels. METHODS: Induced sputum was obtained from asthmatic (31 smokers, 35 non-smokers) and normal (20 smokers, 20 non-smokers) subjects. All smokers had a smoking history of > or =15 pack years. IL-18 levels in sputum supernatant were measured by ELISA. IL-18 mRNA expression and cellular localization were assessed by quantitative PCR and immunocytochemistry, respectively. RESULTS: Smoking was associated with a significant reduction in IL-18 levels (median (interquartile range) - smokers 20 (0-102) pg/mL vs. non-smokers 358 (50-876) pg/mL, P<0.001). This was more pronounced in asthmatics (smokers, 47 (40-64) pg/mL vs. non-smokers, 530 (30-1484) pg/mL; P<0.001) than in normal subjects (smokers, 25 (0-78) pg/mL vs. non-smokers, 247 (50-656) pg/mL; P<0.01). Within each of the smoking and non-smoking groups there was no significant difference in IL-18 levels between asthmatic and normal subjects. There was no correlation between sputum IL-18 levels and any specific cell type in the sputum samples nor serum IgE levels. IL-18 mRNA expression was reduced in asthmatic smokers compared with non-smokers. IL-18 production was localized to sputum macrophages by immunocytochemistry. CONCLUSIONS: IL-18 is detectable in induced sputum samples from both asthmatic and normal subjects. Cigarette smoking significantly reduces sputum IL-18 levels. This effect is more pronounced in asthmatics than in normal subjects.

Adult↗
PubMed2002

Takes your breath away--the immunology of allergic alveolitis.

Extrinsic allergic alveolitis (synonym: hypersensitivity pneumonitis) is caused by inhaling antigenic aerosols which induce hypersensitivity responses in susceptible individuals. It is an interstitial inflammatory disease affecting the distal, gas-exchanging parts of the lung, in contrast to allergic asthma where the inflammation is more proximal, affecting the conducting airways. The aims of this review are to describe current concepts of the immunology of this model of lung inflammation, to describe some of the constitutional and environmental characteristics which affect disease susceptibility and development, and to describe topics for prospective study.

Alveolitis, Extrinsic Allergic↗
PubMed2001

Effect of combination therapy on immunologic progression of human immunodeficiency virus at a population level.

There is accumulating evidence from clinical trials and cohort studies that highly active antiretroviral combination therapy is effective at halting immunologic and clinical progression of human immunodeficiency virus (HIV). Its impact at a population level is less well known because the regimes may be difficult to tolerate and compliance poorer. The authors make use of population data for almost all of the HIV-infected people in Scotland in 1997 who were under clinical care and monitor their response to therapy during the first year when these effective treatments became widely available. More than two thirds of the HIV-positive patients were on some form of antiretroviral therapy during the year. The authors show that all treated groups, even those who were on changing regimes, showed net improvement in immunologic status during the year. For the group of patients on triple or quadruple therapy, there was an average increase of more than 100 CD4 cells/mm(3) over the year, with other treatment groups showing more modest, but significant, increases.

Anti-HIV Agents↗
PubMed2001

Immuno-regulatory cytokines in asthma: IL-15 and IL-13 in induced sputum.

BACKGROUND: The importance of Th2-type lymphocyte function in asthmatic airway inflammation is well recognized, but less is known about the factors which regulate the function of these lymphocytes in asthma. The macrophage-derived cytokine, interleukin (IL)-15 has a number of T cell regulatory properties which might be of relevance to asthma and its treatment. OBJECTIVE: The aims were to identify and quantify the T cell regulatory cytokine IL-15 in induced sputum samples from asthmatic patients, in comparison with IL-13, and to relate the levels of these cytokines to treatment with inhaled steroids. METHODS: Induced sputum was collected from 16 asthmatics (eight steroid and eight non-steroid treated) and eight normal controls. IL-15 and IL-13 levels were measured by enzyme-linked immunoassay (ELISA) in sputum. IL-15 levels were also measured in sputum cell culture supernatants and localized to specific sputum cells by immuno-cytochemistry. RESULTS: IL-15 levels were increased and IL-13 levels were decreased in sputum fluid from steroid-treated compared with non-steroid-treated asthmatics. IL-15 was localized specifically to macrophages and the proportion of these cells expressing IL-15 correlated with sputum fluid IL-15 and IL-15 levels in cell culture supernatants, and all were higher in the steroid-treated asthmatics. CONCLUSION: IL-15 and IL-13 production appears to be reciprocally regulated by steroid therapy in asthma patients. The steroid-associated increase in IL-15 may regulate a fundamental shift away from an inflammatory Th2-type environment in asthma and may be an essential component of the cytokine modulation underlying the therapeutic benefit of corticosteroids in this condition.

Adult↗
PubMed2001

Smoking and airway inflammation in patients with mild asthma.

STUDY OBJECTIVES: Cigarette smoking is common in asthmatic patients, and we investigated the impact of cigarette smoking on airway inflammation in asthma. DESIGN: Single-center observational study of airway inflammation in asthmatic and healthy smokers and nonsmokers. SETTING: Asthma research unit in a university hospital. PATIENTS OR PARTICIPANTS: Sixty-seven asthmatic and 30 nonasthmatic subjects classified as smokers or nonsmokers. Asthmatics had chronic, stable asthma and were not receiving inhaled or oral steroids at the time of the study. INTERVENTIONS: We examined induced-sputum cell counts and levels of interleukin (IL)-8 and eosinophilic cationic protein (ECP). Bronchial hyperreactivity was assessed using methacholine challenge. MEASUREMENTS AND RESULTS: Asthmatic smokers had higher total sputum cell counts than nonsmoking asthmatics and both smoking and nonsmoking healthy subjects. Smoking was associated with sputum neutrophilia in both asthmatics and nonasthmatics (median, 47% and 41%, respectively) compared with nonsmokers (median, 23% and 22%, respectively), and sputum IL-8 was increased in smokers compared with nonsmokers, both in subjects with asthma (median, 945 pg/mL vs 660 pg/mL, respectively) and in healthy subjects (median, 1,310 pg/mL vs 561 pg/mL, respectively). Sputum eosinophils and ECP levels were higher in both nonsmoking and smoking asthmatics than in healthy nonsmokers. In smoking asthmatics, lung function (FEV(1) percent predicted) was negatively related to both sputum IL-8 (r = - 0.52) and sputum neutrophil proportion (r = - 0.38), and sputum IL-8 correlated positively with smoking pack-years (r = 0.57) and percent neutrophil count (r = 0.51). CONCLUSIONS: In addition to the eosinophilic airway inflammation observed in patients with asthma, smoking induces neutrophilic airway inflammation; a relationship is apparent between smoking history, airway inflammation, and lung function in smoking asthmatics.

Adult↗
PubMed2001

Hypersensitivity pneumonitis: current concepts.

Hypersensitivity pneumonitis (HP), or extrinsic allergic alveolitis, is due to a hypersensitivity reaction after repeated inhalation of finely dispersed antigens, mainly organic particles or low molecular weight chemicals. The essence of this disease is an interaction between the host's immune system and external antigen, influenced by both genetic and environmental factors. In susceptible subjects, it leads to a combined type III allergic reaction of Gell and Coombs (with formation of precipitines) and a type IV lymphocytic reaction (with a granulomatous inflammation in the distal bronchioles and alveoli). This review gives an update on epidemiology, antigens, pathogenesis, host susceptibility, environmental factors, clinical features, diagnosis and treatment in HP. The list of aetiological agents is long and new sources of antigens are constantly being identified. Host risk factors are poorly characterized, with the exception of those linked to exposure factors. Environmental factors and cofactors may be critical for the pathogenesis of the disease. HP is not a uniform disease entity, but a complex dynamic clinical syndrome such that different patterns of disease emerge over time. The diagnosis is made from a combination of clinical features, radiographic abnormalities, lung function tests and immunological tests. The use of inhalation challenge tests for the diagnosis has been hampered by the lack of standardization. Antigen avoidance is the key element in the treatment. There is often an apparent beneficial response to corticosteroids, but it may be difficult to distinguish between the effects of treatment, the natural course of the disease and the effect of antigen avoidance.

Alveolitis, Extrinsic Allergic↗
PubMed2000

Intergenerational 20 year trends in the prevalence of asthma and hay fever in adults: the Midspan family study surveys of parents and offspring.

OBJECTIVE: To estimate trends between 1972-6 and 1996 in the prevalences of asthma and hay fever in adults. DESIGN: Two epidemiological surveys 20 years apart. Identical questions were asked about asthma, hay fever, and respiratory symptoms at each survey. SETTING: Renfrew and Paisley, two towns in the west of Scotland. SUBJECTS: 1,477 married couples aged 45-64 participated in a general population survey in 1972-6; and 2,338 offspring aged 30-59 participated in a 1996 survey. Prevalences were compared in 1,708 parents and 1,124 offspring aged 45-54. MAIN OUTCOME MEASURES: Prevalences of asthma, hay fever, and respiratory symptoms. RESULTS: In never smokers, age and sex standardised prevalences of asthma and hay fever were 3.0% and 5.8% respectively in 1972-6, and 8.2% and 19. 9% in 1996. In ever smokers, the corresponding values were 1.6% and 5.4% in 1972-6 and 5.3% and 15.5% in 1996. In both generations, the prevalence of asthma was higher in those who reported hay fever (atopic asthma). In never smokers, reports of wheeze not labelled as asthma were about 10 times more common in 1972-6 than in 1996. With a broader definition of asthma (asthma and/or wheeze), to minimise diagnostic bias, the overall prevalence of asthma changed little. However, diagnostic bias mainly affected non-atopic asthma. Atopic asthma increased more than twofold (prevalence ratio 2.52 (95% confidence interval 1.01 to 6.28)) whereas the prevalence of non-atopic asthma did not change (1.00 (0.53 to 1.90)). CONCLUSION: The prevalence of asthma in adults has increased more than twofold in 20 years, largely in association with trends in atopy, as measured indirectly by the prevalence of hay fever. No evidence was found for an increase in diagnostic awareness being responsible for the trend in atopic asthma, but increased awareness may account for trends in non-atopic asthma.

Adult↗
PubMed2000

Non-invasive markers of airway inflammation as predictors of oral steroid responsiveness in asthma.

BACKGROUND: Sputum eosinophil counts and exhaled nitric oxide (NO) levels are increased in asthma and both measurements fall in response to corticosteroids. METHODS: Exhaled NO levels and sputum eosinophil counts were assessed as non-invasive markers of the response to an oral steroid in 37 patients (19 women) with stable chronic asthma (mean (SD) age 48.6 (12.2) years, asthma duration 25. 9 (17.3) years, and baseline forced expiratory volume in one second (FEV(1)) 76.3 (21.9)% predicted). Spirometric tests, with reversibility to a beta agonist (2.5 mg nebulised salbutamol), and induced sputum (using nebulised 3% saline) were performed at recruitment and following treatment with 30 mg prednisolone/day for 14 days. RESULTS: Baseline NO levels correlated with the percentage improvement in FEV(1) from baseline to the post-steroid, post-bronchodilator value (r(s) = 0.47, p = 0.003), with an NO level of >10 ppb at baseline having a positive predictive value of 83% for an improvement in FEV(1) of > or =15% (sensitivity 59%, specificity 90%). Sputum eosinophilia (> or =4%) had a positive predictive value of 68% (sensitivity 54%, specificity 76%) for an increase in FEV(1) of > or =15%. A combination of sputum eosinophilia and increased NO levels resulted in a positive predictive value of 72% and a negative predictive value of 79% (sensitivity 76%, specificity 75%). CONCLUSION: Exhaled NO levels and sputum eosinophilia may be useful in predicting the response to a trial of oral steroid in asthma.

Administration, Inhalation↗
PubMed1999

Sputum cellular and cytokine responses to inhaled endothelin-1 in asthma.

BACKGROUND: Endothelin (ET)-1 is a 21-amino acid peptide which has potent bronchoconstrictor activity. Animal studies show elevation of ET-1 during experimental airway inflammation, and inhibition of inflammation by endothelin-antagonists, suggesting pro-inflammatory activity for ET-1. OBJECTIVE: We wanted to assess any acute influence that bronchoconstrictor doses of inhaled ET-1 might have on cells, tumour necrosis factor (TNF)-alpha, interleukin (IL)-1beta, nitrite (NO2) and albumin in induced sputum in asthma. METHODS: Bronchial challenge was performed using nebulized ET-1 (nebulized dose range 0.96-15.36 nmol) and placebo in 10 adult asthmatic subjects in a randomized double-blind placebo-controlled cross-over study. Sputum induction was performed 30 min and 4 h after placebo or ET-1 bronchial challenge. RESULTS: All subjects experienced dose-dependent bronchoconstriction to inhaled ET-1 with a mean (range) PC15 forced expiratory volume in 1 s (FEV1) to ET-1 of 9.45 (1.2-21.7) nmol. Comparing ET-1 with placebo inhalation, there was no change in sputum differential cell counts, TNFalpha, IL-1beta, NO2 or albumin at 30 min or 4 h after inhalation, nor was there a difference in these parameters at 4 h compared with 30 min after ET-1 inhalation. There was no fall in FEV1 at 4 h after ET-1 inhalation, suggesting that ET-1 inhalation is not associated with a late bronchoconstrictor response. CONCLUSIONS: We conclude that inhaled ET-1 does not appear to stimulate an acute inflammatory response in asthma as assessed by differential cell count, TNFalpha, IL-1beta, NO2 and albumin concentrations in induced sputum.

Adult↗
PubMed1999

Mucosal immunity in extrinsic allergic alveolitis: salivary immunoglobulins and antibody against inhaled avian antigens among pigeon breeders.

BACKGROUND: Inhaled antigens from pigeons can cause extrinsic allergic alveolitis (EAA); a model disease of pulmonary inflammation. Among pigeon breeders, serum antibody and sensitized lymphocytes specific for these antigens have been described primarily, but not always, with disease. Antibody activity within the lung may have a closer association with disease, however, sampling by alveolar lavage at bronchoscopy is impractical for screening, therefore we used saliva to quantify the mucosal antibody response. OBJECTIVE: To establish: (a) if antibody activity against inhaled avian antigens was detectable in the saliva of pigeon breeders, (b) if the distribution of saliva antibody and total immunoglobulin levels were quantitatively or qualitatively different from serum, and (c) whether the hypersensitivity symptoms of EAA were associated more with the mucosal or the systemic humoral immune response. MEASURES: Saliva and serum total and avian antigen-specific IgG, IgA (IgA1 and IgA2) antibody activity in 87 pigeon breeders and 24 control subjects with no avian exposure. Albumin levels were used as a protein reference and cotinine levels confirmed smoking status. Specific hypersensitivity symptoms and various exposure indices to pigeons were established by interview. RESULTS: Absolute levels and relative proportions (vs albumin) of IgG, IgA and IgA1 in saliva, and IgG in serum, were significantly higher in pigeon breeders compared with controls, suggesting mucosal inflammation. Avian antigen-specific antibody of all isotypes was readily demonstrable in saliva (predominantly IgA) and serum (predominantly IgG) from pigeon breeders, and there were no significant titres in controls. The levels of IgG antibody in saliva and in serum correlated significantly (r = 0.52, P < 0.001), and both correlated with the raised immunoglobulin levels. In both saliva and serum the IgG rather than the IgA antibody activity was associated with symptoms of EAA. CONCLUSIONS: Antibody activity in saliva and serum, representing the mucosal and systemic responses, respectively, were both strongly stimulated by inhaled antigens. The IgG antibody titres of saliva and serum correlated significantly and were a useful index of inflammation, as measured by the raised total immunoglobulin levels, and symptoms. This suggests that IgG antibody in serum may reflect clinical and immunological sensitization of the lung mucosa. Collecting saliva is noninvasive, and saliva antibody measurement is a convenient method for monitoring EAA, especially in children, and will facilitate sampling for example in epidemiological studies of antibody prevalence.

Albumins↗
PubMed1999

Natural immunity to Ascaris lumbricoides associated with immunoglobulin E antibody to ABA-1 allergen and inflammation indicators in children.

Children putatively immune to the large roundworm Ascaris lumbricoides were identified in an area of Nigeria where infection is hyperendemic. Immunity was associated with higher levels of serum ferritin, C-reactive protein, and eosinophil cationic protein, indicating ongoing acute phase or inflammatory processes. In contrast, children who were susceptible to the infection had little serological evidence of inflammation despite their high parasite burdens. Immunoglobulin G (IgG) antibody activity in all subclasses was present in high titer in most children but appeared to have no protective function. Despite exceptionally high total IgE levels, there was no evidence that atopic responses to local common allergens was associated with natural immunity to Ascaris. Among those individuals who produced IgG antibody to recombinant ABA-1 allergen of Ascaris, the naturally immune group had significantly more IgE antibody to the allergen than did those susceptible to the infection. IgE antibody responses in conjunction with innate inflammatory processes therefore appear to associate with natural immunity to ascariasis.

Adolescent↗
PubMed1999

T-Cell responses during Trypanosoma brucei infections in mice deficient in inducible nitric oxide synthase.

We have investigated the possibility that nitric oxide (NO) synthesis may affect the course of a trypanosome infection via T-cell responses using mice deficient in inducible NO synthase (iNOS). Parasitemia levels increased at the same rate in both iNOS-deficient homozygous and control heterozygous mice, and peak parasitemia values were the same in both groups. However, the heterozygous mice maintained higher parasitemia levels after the peak of an infection than the homozygous mice due to a decrease in the rate of clearance of parasites. In iNOS-deficient mice there was an increase in the numbers of total CD4(+) cells and activated (interleukin-2 receptor-expressing) CD4(+) cells in infected mice compared with the numbers in uninfected mice. Spleen cells from infected iNOS-deficient mice displayed increased proliferative responses and gamma interferon secretion when stimulated in vitro than those of control mice. These data suggest that NO production depresses T-helper 1-like responses generated during Trypanosoma brucei infections, thus promoting the survival of the parasite.

Animals↗
PubMed1999

Viral subtype and heterosexual acquisition of HIV infections diagnosed in Scotland.

OBJECTIVE: As at December 1998, 87% of the estimated 33 million people living with HIV throughout the world resided in Africa and South East Asia. In Scotland (and the United Kingdom), a major public health concern has been that non-B subtypes of HIV which predominate in the regions above might enter the country and spread heterosexually among the indigenous population. The authors conducted an investigation to determine if, and to what extent, such transmission had occurred. METHODS: Stored blood samples from people who were diagnosed as HIV positive in central Scotland during 1995-7 and who were reported to have acquired their infection heterosexually, were identified. Sequence data were sought from each sample and, where obtained, viral subtype was assigned. For each case, viral subtype was linked to corresponding epidemiological details on heterosexual risk. RESULTS: Viral sequence was obtained from specimens for 53 of 59 cases. For 43 of the 53 cases, information on region of sexual contact was known. All 19 cases who had a sexual risk in Africa or Asia had a non-B subtype (A, C, or E) while 20 of 24 cases who did not report sexual contact in these regions had a B subtype (p < 0.0001). Of the remaining 10 cases, nine had a subtype B and one a subtype C virus. CONCLUSION: There is no evidence that non-B viral strains from developing countries have yet disseminated appreciably among indigenous heterosexual men and women within Scotland. Continuing to collect both demographic and molecular data from indigenous heterosexuals who are newly diagnosed with HIV would improve the chances of detecting rapidly any appreciable dissemination of non-B subtypes among this population if it were to occur. Such information would be helpful in informing HIV prevention strategies.

DNA, Viral↗