IL-13-producing BLT1-positive CD8 cells are increased in asthma and are associated with airway obstruction.

BACKGROUND: The role of CD8 T lymphocytes in the pathogenesis of asthma is not well understood. We investigated whether a subset of IL-13-producing BLT1-positive CD8 T lymphocytes are present in asthmatic airways and are associated with impaired lung function. METHODS: Bronchoalveolar lavage (BAL) cells were obtained from asthmatic (n = 39) and healthy control (n = 28) subjects. Cells were stimulated with phorbol ester and ionomycin in the presence of brefeldin A and stained for CD8, BLT1, and intracellular IL-13. The frequency of IL-13-producing BLT1-positive CD8 T lymphocytes was compared between the two groups and related to lung function, serum IgE levels, and reticular basement membrane (RBM) thickness. RESULTS: A subset of CD8 T lymphocytes expressing BLT1 and producing IL-13 were detected in the airways of all asthmatic subjects. The frequency of this subset among recovered lymphocytes was significantly higher in the airways of asthmatic subjects compared with controls (mean ± SEM: 16.2 ± 1.4 vs 5.3 ± 0.5, respectively, P < 0.001) and correlated positively with serum IgE levels and RBM thickness. More importantly, the frequency of CD8 T lymphocytes co-expressing BLT1 and IL-13 was inversely related to FEV1 and FEF[25-75] percent predicted values (P < 0.001). CONCLUSIONS: A subset of CD8 T lymphocytes expressing BLT1 and producing IL-13 is present in the airways of asthmatics. The accumulation of these cells is associated with airway obstruction, suggesting that they may play a significant pathogenic role in bronchial asthma.

Obesity and the lung: 4. Obesity and asthma.

Over the past 30 years there has been an epidemic of both obesity and asthma in the western world. A large body of robust epidemiological data has linked obesity with the development and severity of asthma in both children and adults and weight reduction with improvements in asthma severity and symptoms. However, it remains unsettled whether this relationship is causal or confounded by some other factor(s) as mechanistic and physiological studies have produced heterogeneous and at times conflicting findings. This review examines the clinical and epidemiological relationship between obesity and asthma and the purported mechanisms that may link these two processes together.

Predicting worsening asthma control following the common cold.

The asthmatic response to the common cold is highly variable, and early characteristics that predict worsening of asthma control following a cold have not been identified. In this prospective multicentric cohort study of 413 adult subjects with asthma, the mini-Asthma Control Questionnaire (mini-ACQ) was used to quantify changes in asthma control and the Wisconsin Upper Respiratory Symptom Survey-21 (WURSS-21) to measure cold severity. Univariate and multivariable models were used to examine demographic, physiological, serological and cold-related characteristics for their relationship to changes in asthma control following a cold. Clinically significant worsening of asthma control was observed following a cold (mean+/-SD increase in mini-ACQ score of 0.69+/-0.93). Univariate analysis demonstrated that season, centre location, cold duration and cold severity measurements were all associated with a change in asthma control. Multivariable analysis of the covariates available within the first 2 days of cold onset revealed that the day 2 and cumulative sum of day 1 and 2 WURSS-21 scores were significant predictors of the subsequent changes in asthma control. In asthmatic subjects, cold severity within the first 2 days can be used to predict subsequent changes in asthma control. This information may help clinicians prevent deterioration in asthma control following a cold.

Targeting the distal lung in asthma: do inhaled corticosteroids treat all areas of inflammation?

Inflammation of the distal lung, which consists of the small airways (internal diameter <2 mm) and alveolar tissue, is an important feature of the asthma clinical syndrome comprising airway inflammation, airway hyperresponsiveness and bronchodilator-responsive expiratory airflow limitation. Support for this assertion is derived from histologic studies which have demonstrated evidence of inflammation in this anatomic compartment, along with additional studies, which have elucidated the radiologic and physiologic correlates of distal lung inflammation. Delivering inhaled drugs to this area is challenging and is dependent on a number of drug- and delivery device-related factors, as well as on a patient's inhaler technique and bronchial anatomy. Newer chlorofluorocarbon-free formulations of inhaled corticosteroids such as hydrofluoroalkane propelled metered-dose inhalers and dry powder inhalers appear to have certain advantages with regard to drug delivery that facilitate improved drug delivery to the distal lung. Mounting evidence indicates that recognition and treatment of distal lung inflammation may be key components of appropriate asthma pharmacotherapy.

Inhaled corticosteroids reduce the progression of airflow limitation in chronic obstructive pulmonary disease: a meta-analysis.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a syndrome of chronic progressive airflow limitation which occurs as a result of chronic inflammation of the airways and lung parenchyma. However, the role of inhaled corticosteroids in the treatment of COPD is controversial. We hypothesised that inhaled corticosteroids reduce the progression of airflow limitation in COPD. METHODS: A comprehensive literature search was conducted and data were analysed using random effects methodology. The effect of inhaled steroids on annual change in forced expiratory volume in 1 second (FEV1) was determined for all trials, for trials with high dose treatment regimens, and for trials in subjects with moderate to severe airflow limitation. RESULTS: Data from eight controlled clinical trials of > or =2 years were included (n=3715 subjects). Meta-analysis of all study data revealed that inhaled corticosteroids reduce the rate of FEV1 decline by 7.7 ml/year (95% confidence interval (CI) 1.3 to 14.2, p=0.02). Meta-analysis of studies with high dose regimens revealed a greater effect of 9.9 ml/year (95% CI 2.3 to 17.5, p=0.01) compared with the meta-analysis of all studies. CONCLUSIONS: Inhaled corticosteroid treatment for > or =2 years slows the rate of lung function decline in COPD. The effect observed with high dose regimens is greater than that with all regimens combined. These data suggest a potential role for inhaled corticosteroids in modifying the long term natural history of COPD.

Analysis of disulphide bridge function in recombinant bovine prolactin using site-specific mutagenesis and renaturation under mild alkaline conditions: a crucial role for the central disulphide bridge in the mitogenic activity of the hormone.

We have previously described a method for isolating Escherichia coli-produced methionyl bovine prolactin (Met-bPRL) and its renaturation using thioredoxin. This report describes an alternative renaturation procedure in which extracted Met-bPRL is incubated in air at pH 10 and 20 degrees C. Within 1 h of such treatment essentially all of the reduced Met-bPRL was converted to the oxidized form; this was accompanied by an increase to full mitogenic activity in the Nb2 cell bioassay. It was also found that, to minimize contamination by high mol. wt Met-bPRL derivatives, it is essential to have a reducing agent (dithiothreitol) present during disruption of the bacteria and to extract the protein at neutral pH. The contribution of each of the three disulphide bridges in bPRL to its bioactivity was studied with Met-bPRL variants, prepared via site-specific mutagenesis, in which cysteines were replaced by serines to prevent disulphide bond formation. Variants lacking the C4-C11 bridge, the C191-C199 bridge or both these terminal bridges were as mitogenic as authentic bPRL. (Variants lacking the C191-C199 bridge had markedly increased solubility in the presence of deoxycholate.) In contrast, variants lacking the C58-C174 bridge had greatly reduced bioactivity, indicating that integrity of the large disulphide loop is crucial to the hormone's mitogenic activity.

Prognosis after renal transplantation: cumulative influence of combined risk factors.

Seven hundred sixty-seven primary renal allografts from a single center were divided into subgroups according to combinations of several major risk factors: donor source and histocompatibility match, age, and presence or absence of diabetes. The relative effect of diabetes on patient and graft survival decreased as histocompatibility differences increased. The influence of recipient age, however, dramatically decreased as histocompatibility differences decreased. In all groups donor source and histocompatibility match had the strongest relative effect in determining subsequent 2-year patient and graft survival.