Mucosal production of uric acid by airway epithelial cells contributes to particulate matter-induced allergic sensitization.

Exposure to particulate matter (PM), a major component of air pollution, contributes to increased morbidity and mortality worldwide. PM induces innate immune responses and contributes to allergic sensitization, although the mechanisms governing this process remain unclear. Lung mucosal uric acid has also been linked to allergic sensitization. The links among PM exposure, uric acid, and allergic sensitization remain unexplored. We therefore investigated the mechanisms behind PM-induced allergic sensitization in the context of lung mucosal uric acid. PM10 and house dust mite exposure selectively induced lung mucosal uric acid production and secretion in vivo, which did not occur with other challenges (lipopolysaccharide, virus, bacteria, or inflammatory/fibrotic stimuli). PM10-induced uric acid mediates allergic sensitization and augments antigen-specific T-cell proliferation, which is inhibited by uricase. We then demonstrate that human airway epithelial cells secrete uric acid basally and after stimulation through a previously unidentified mucosal secretion system. Our work discovers a previously unknown mechanism of air pollution-induced, uric acid-mediated, allergic sensitization that may be important in the pathogenesis of asthma.

Soluble RAGE is deficient in neutrophilic asthma and COPD.

The receptor for advanced glycation end-products (RAGE) is a pattern-recognition receptor involved in the host response to injury, infection and inflammation. It is a membrane receptor, but also has soluble forms (sRAGE). Deficiencies in sRAGE are linked to heightened inflammation in various chronic conditions. We determined whether airway and systemic levels of sRAGE and the RAGE ligands HMGB1 (high-mobility group box-1) and serum amyloid A (SAA) are related to neutrophilic inflammation in asthma and chronic obstructive pulmonary disease (COPD). Bronchial lavage fluid from subjects with moderate-to-severe persistent asthma (n = 16) or COPD (n = 37), or from healthy controls (n = 18), was analysed for neutrophils, total sRAGE, endogenous secretory RAGE (esRAGE), HMGB1 and SAA. We also determined systemic levels of sRAGE in a separate group of asthmatic (n = 101) and COPD (n = 34) subjects. Subjects with neutrophilic asthma or COPD had undetectable levels of lung sRAGE, while levels of sRAGE in asthma/COPD without neutrophilia were similar to those in controls. Systemic sRAGE was significantly decreased in subjects with neutrophilic asthma or COPD compared with those without airway neutrophilia. There was significant positive correlation between total sRAGE and esRAGE in the lung and systemically. HMGB1 levels were similar in all subject groups, while SAA was below detectable levels. Neutrophilic airway inflammation in asthma and COPD is associated with reduced sRAGE.

Treating asthma means treating airway smooth muscle cells.

Asthma is characterised by airway hyperresponsiveness, airway inflammation and airway remodelling. Airway smooth muscle cells are known to be the main effector cells of airway narrowing. In the present paper, studies will be discussed that have led to a novel view of the role of airway smooth muscle in the pathogenesis of asthma in which airway hyperresponsiveness, remodelling and inflammation are, at least in part, attributable to airway smooth muscle. Furthermore, how this new view may lead to a change in the phenotyping and treatment of patients with asthma will be discussed.

Regulation of human lung epithelial cell numbers by diesel exhaust particles.

Particulate air pollution is associated with respiratory morbidity and has cytotoxic and pro-inflammatory effects. The effects of diesel exhaust particles (DEP) on proliferation and apoptosis of A549 lung epithelial cells were examined. When deprived of serum (serum starvation), epithelial cell numbers fell, but DEP (5-200 microg.mL-1) prevented this. Using flow cytometric analysis of propidium iodide (PI) staining, DEP (10 microg.mL-1) increased cells in the S phase of cell cycle from 12.85 to 18.75% after 48 h, reversing serum starvation-induced G0/1 arrest. DEP also reduced the increase in apoptotic cells, as defined by double expression of annexin V/PI, observed after serum starvation (from 28.35 to 15.46%). The antioxidants, N-acetylcysteine (NAC; 33 mM) and AEOL10113 (10-100 microM), the N-terminal c-jun kinase inhibitor, SP600125 (33 microM), and nuclear factor-kappaB inhibitor, SN50 (33 microM), inhibited DEP-induced cell number increase. NAC inhibited DEP-induced reduction of G0/1 and increase in cells in the S and G2/M phases. Expression of p21CIP1/WAF1 mRNA and protein seen with serum starvation was reduced by DEP. In conclusion, diesel exhaust particles prevented serum starvation-led decreases in A549 epithelial cells by inducing cell cycle progression and preventing apoptosis, processes involving oxidative stress, inhibition of p21CIP1/WAF1 expression and stimulation of N-terminal c-jun kinase and nuclear factor-kappaB. Therefore, low-dose diesel exhaust particle exposure may lead to lung epithelial cell hyperplasia.

Tumour necrosis factor-alpha potentiates contraction of human bronchus in vitro.

OBJECTIVE: Chronic inflammation of the airways is an important component in the induction of airway hyperresponsiveness (AHR) in asthma. The pro-inflammatory cytokines interleukin-1beta (IL-1beta) and tumour necrosis factor-alpha (TNF-alpha) have been implicated in the induction of AHR. Whether these cytokines directly modulate the contractile properties of human airway smooth muscle (ASM) has not been fully investigated. METHODOLOGY: The contractile response to acetylcholine (ACh) (10(-8) to 10(-3) mol/L) was determined in isolated human bronchial segments both prior to and following a 16-h incubation period with IL-1beta (10 or 20 ng/mL) and TNF-alpha (25 ng/mL), either alone or in combination. Incubation of human bronchial segments with IL-1beta/TNF-alpha was also performed in the presence of the COX-1/COX-2 inhibitor, indomethacin. RESULTS: Tumour necrosis factor-alpha potentiated the contractile response to ACh by approximately 27%, while IL-1beta or the cytokines in combination had no effect. Indomethacin had no modulatory effect on the contractile response to ACh in the cytokine-treated tissues. CONCLUSIONS: The relative concentrations of IL-1beta/TNF-alpha in the vicinity of ASM may ultimately determine their effects on ASM contraction in asthma.

GM-CSF production from human airway smooth muscle cells is potentiated by human serum.

Recent evidence suggests that airway smooth muscle cells (ASMC) actively participate in the airway inflammatory process in asthma. Interleukin-1beta (IL-1beta) and tumour necrosis factor-alpha (TNF-alpha) induce ASMC to release inflammatory mediators in vitro. ASMC mediator release in vivo, however, may be influenced by features of the allergic asthmatic phenotype. We determined whether; (1) allergic asthmatic serum (AAS) modulates ASMC mediator release in response to IL-1beta and TNF-alpha, and (2) IL-1beta/TNF-alpha prime ASMC to release mediators in response to AAS. IL-5 and GM-CSF were quantified by ELISA in culture supernatants of; (1) ASMC pre-incubated with either AAS, nonallergic non-asthmatic serum (NAS) or Monomed (a serum substitute) and subsequently stimulated with IL-1beta and TNF-alpha and (2) ASMC stimulated with IL-1beta/TNF-alpha and subsequently exposed to either AAS, NAS or Monomed. IL-1beta and TNF-alpha induced GM-CSF release in ASMC pre-incubated with AAS was not greater than that in ASMC pre-incubated with NAS or Monomed. IL-1beta and TNF-alpha, however, primed ASMC to release GM-CSF in response to human serum. GM-CSF production following IL-1beta/TNF-alpha and serum exposure (AAS or NAS) was significantly greater than that following IL-1beta/TNF-alpha and Monomed exposure or IL-1beta/TNF-alpha exposure only. Whilst the potentiating effects of human serum were not specific to allergic asthma, these findings suggest that the secretory capacity of ASMC may be up-regulated during exacerbations of asthma, where there is evidence of vascular leakage.

An approach to medical curriculum evaluation.

The advent of new trends in medical education makes it necessary for new and established medical schools to evaluate their curricula. The changing needs of society emphasize that this process should be continuous. There are, however, many difficulties which impede the initiation of curriculum evaluation. The College of Medicine and Allied Health Sciences at King Abdulaziz University initiated and carried out a plan for programme evaluation in 1984-85. The pathway selected for this experience was based on existing models which were modified to suit the local needs. The formulation of the plan was guided by general principles aiming at participation, communication, data-gathering from numerous sources and utilization of appropriate resources. The main direction of the evaluation was formative in nature and was carried out internally. The results were analysed and revealed major problems in the existing design and the teaching/learning environment. The recommendations for change were guided by educational criteria concerned with promotion of learning, problem-solving and community orientation. The main emphasis in the presentation of this report is on the process more than the content of curriculum evaluation.

Curriculum development: a strategy for change.

It is generally accepted that educational methods have a lot to offer to the development of teaching and learning in medical colleges. However, it is frequently reiterated that these offerings are theoretical and are either not feasible or have little impact in most settings. This conclusion comes as an inevitable result of frustrations associated with well-meaning attempts to introduce change in the teaching and learning environment. The main purpose of this article is to share with the reader some of the experiences of one medical college in the introduction of change. In this article the decisions and implementation of change in the teaching programme are described. An evaluation of curriculum development was based on the impact or outcome of these strategies. The criteria used in this evaluation were student orientation, problem-solving, integration and community orientation. In the early stages of this experience the main strategy focused on teacher-training, which aimed at 'critical mass development'. A cohesive core group of teachers was formed. Further strategies for the introduction of change were used and modified according to need. Utilization of sources of power and influence was resorted to so as to draw attention to issues and to expedite academic decisions. In many instances group activities utilized emotionally detached 'academic' settings to resolve curriculum issues. Conflicts were mainly dealt with in this setting. The advantages and disadvantages of these strategies for change are discussed.

An approach to the question of relevance of medical physiology courses.

One of the problems of designing basic science courses is to define objectives relevant to the future needs of the graduates. A simple approach is described whereby a series of clinical problems were identified by physiologists and practising physicians. Priority areas were then identified to provide a basis for defining objectives for the medical physiology courses and for the selection of materials and methods. It is argued that the question of relevance, emotional involvement and effective facilitation of learning will be served by the approach described. Finally, the usefulness of this exercise to the selection and orientation of appropriate evaluation tools is discussed.

Age-independent anthropometry: an examination of data from rural Khartoum, Sudan.

The data collected in a mixed cross-sectional longitudinal survey of children in a village in rural Khartoum, Sudan, were analysed in order to identify age-independent anthropometric indices. The mean values of weight/height, weight/height, mid arm circumference, mid arm fat area and triceps skinfold thickness all change little with age over certain parts of the age range. 15% of the boys and 22% of the girls had weights less than 75% of standard weight for age. The ability of age-independent indices to identify these low-weight individuals was investigated in terms of their sensitivity and specificity. Weight/height discriminated best, correctly classifying 85% of the low weight boys and 78% of the normal weight boys in the under-five age group. Weight/height and mid arm circumference were also useful, but triceps skinfold thickness and mid arm fat area did not discriminate usefully. All tests performed better in the under-five age group than in the older age bands.

An assessment of anti-schistosomal treatment on physical work capacity.

Acting as their own controls, village subjects from the Gezira are of the Sudan with relatively high levels of schistosomiasis infection were first tested in an exercise laboratory in Khartoum and the tests were then repeated after a period of about 1 yr during which time the subjects were treated with hycanthone and periodically monitored to ensure that they had remained free of the disease. In the meantime they were also given anti-malarial prophylaxis. Laboratory tests showed a significant improvement in physiological work capacity of up to 20% after treatment compared with untreated controls. An overall improvement in pulmonary function, particularly forced vital capacity, was observed as well as a significant increase in mean haemoglobin concentration by 1.1 g/100 ml of blood in the treated group. Apart from these improvements in physical working capacity, the treated subjects subjectively felt better after the exercise tests, as expressed by the disappearance of fatiguability.

Growth velocity in children in rural Khartoum, Sudan.

The results of a mixed cross-sectional and longitudinal anthropometric survey of Sudanese children up to the age of sixteen years are reported. Weight velocity, height velocity, mid arm circumference velocity, and mid arm muscle circumference velocity, and the age at which 50% of females have reached menarche have been calculated. Growth velocities are lower than for English children and the puberty growth spurts occurs about one year later in Sudanese than in English children

Anthropometric survey of children in rural Khartoum, Sudan.

The results of a cross-sectional anthropometric survey of Sudanese children up to the age of thirteen years and six months is reported. Children in whom a quick clinical examination revealed pathology were excluded, as were children who did not have a true birth certificate. Height, weight and mid-arm circumference were measured in all children, head and chest circumference were measured in children up to the age of 5 years and 6 months. Skinfold thickness at biceps, triceps, subscapular and suprailiac sites were measured in children above the age of 30 months. The children were found to be shorter and lighter, and to have less subcutaneous fat than British children. The findings are also compared with those from other African populations. Comparison with a survey performed in the same village seven years earlier reveals that the heights and weights of the children have hardly changed despite a considerable improvement in economic status. The children have a lower weight for height than British and other African populations.