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Background: Therapeutic strategies to modulate the host response to bacterial pneumonia are needed to improve outcomes during community-acquired pneumonia. This study used mice with impaired Fas signalling to examine susceptibility to pneumococcal pneumonia and decoy receptor 3 analogue (DcR3-a) to correct factors associated with increased susceptibility., Methods: Wild-type mice and those with varying degrees of impairment of Fas (lpr) or Fas ligand signalling (gld) were challenged with Streptococcus pneumoniae and microbiological and immunological outcomes measured in the presence or absence of DcR3-a., Results: During established pneumonia, neutrophils became the predominant cell in the airway and gld mice were less able to clear bacteria from the lungs, demonstrating localised impairment of pulmonary neutrophil function in comparison to lpr or wild-type mice. T-cells from gld mice had enhanced activation and reduced apoptosis in comparison to wild-type and lpr mice during established pneumonia. Treatment with DcR3-a reduced T-cell activation and corrected the defect in pulmonary bacterial clearance in gld mice., Conclusions: The results suggest that imbalance in tumour necrosis factor superfamily signalling and excessive T-cell activation can impair bacterial clearance in the lung but that DcR3-a treatment can reduce T-cell activation, restore optimal pulmonary neutrophil function and enhance bacterial clearance during S pneumoniae infection.

Background: The death receptor ligand tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) shows considerable clinical promise as a therapeutic agent. TRAIL induces leukocyte apoptosis, reducing acute inflammatory responses in the lung. It is not known whether TRAIL modifies chronic lung injury or whether TRAIL has a role in human idiopathic pulmonary fibrosis (IPF). We therefore explored the capacity of TRAIL to modify chronic inflammatory lung injury and studied TRAIL expression in patients with IPF., Methods: TRAIL(-/-) and wild-type mice were instilled with bleomycin and inflammation assessed at various time points by bronchoalveolar lavage and histology. Collagen deposition was measured by tissue hydroxyproline content. TRAIL expression in human IPF lung samples was assessed by immunohistochemistry and peripheral blood TRAIL measured by ELISA., Results: TRAIL(-/-) mice had an exaggerated delayed inflammatory response to bleomycin, with increased neutrophil numbers (mean 3.19±0.8 wild type vs 11.5±5.4×10(4) TRAIL(-/-), p<0.0001), reduced neutrophil apoptosis (5.42±1.6% wild type vs 2.47±0.5% TRAIL(-/-), p=0.0003) and increased collagen (3.45±0.2 wild type vs 5.8±1.3 mg TRAIL(-/-), p=0.005). Immunohistochemical analysis showed induction of TRAIL in bleomycin-treated wild-type mice. Patients with IPF demonstrated lower levels of TRAIL expression than in control lung biopsies and their serum levels of TRAIL were significantly lower compared with matched controls (38.1±9.6 controls vs 32.3±7.2 pg/ml patients with IPF, p=0.002)., Conclusion: These data suggest TRAIL may exert beneficial, anti-inflammatory actions in chronic pulmonary inflammation in murine models and that these mechanisms may be compromised in human IPF.

Idiopathic pulmonary fibrosis is a progressive lung disease that carries a poor prognosis and for which there are no effective therapies. Although the excessive deposition of extracellular matrix, combined with evidence of recurrent injury to the alveolar epithelium, are well-described there is a pressing need to understand these processes better at a molecular level and thus to identify potential therapeutic targets in this intractable disease. This review considers some recent advances published in Thorax and elsewhere that have improved our understanding of the pathophysiology of idiopathic pulmonary fibrosis, using data both from human cells and tissue and from animal models of pulmonary fibrosis. The studies particularly address the fate of the alveolar epithelial cell and mechanisms of fibrogenesis, and identify mechanistic pathways shared with co-existing conditions such as lung cancer and pulmonary hypertension. The concepts of physiological biomarkers of disease progression and prognosis are also discussed.

Developing new treatments for chronic obstructive pulmonary disease (COPD) is extremely challenging. This disease, chronic by definition, becomes apparent only after substantial-and probably irreversible-tissue damage has occurred. The observable phenotype is of a stable disease state whose progression is hard to influence and reversal of which appears almost impossible. Identifying key components of the pathological process, targeting of which will result in substantial clinical benefit, is a significant challenge. In this review the nature of the disease is examined and conceptual information and simple tissue models of inflammation are used to explore the pathological network that is COPD. From the concept of COPD as a disease network displaying the features of contiguous immunity (in which many processes of innate and adaptive immunity are in continual dialogue and evolution), refinements are suggested to the strategies aimed at developing effective new treatments for this disease.

Background: The persistent airway neutrophilia observed in chronic lung disease of prematurity (CLD) may reflect inappropriate suppression of neutrophil apoptosis., Methods: 134 bronchoalveolar lavage (BAL) samples were obtained from 32 infants requiring mechanical ventilation for respiratory distress syndrome (RDS): 13 infants (median gestation 26 weeks, range 23 to 28) subsequently developed CLD (CLD group), and 19 infants (gestation 31 weeks, range 25 to 39) recovered fully (RDS group). A further 73 BAL samples were obtained from 20 infants (median age 2 days, range 1 to 402) receiving extracorporeal membrane oxygenation (ECMO) for severe respiratory failure., Results: Neutrophil apoptosis was increased in the RDS group (mean (SEM) neutrophil apoptosis on day 7 BAL: RDS 17.0 (8.6)% v CLD 0.7 (0.2)% (p<0.05)). BAL fluid obtained from RDS but not CLD patients was proapoptotic to neutrophils (apoptosis ratio BAL fluid/saline control: day 1, RDS 9.8 (5.5) v CLD 1.2 (0.1) (p<0.05); day 2, RDS 4.32 (2.8) v CLD 0.5 (0.4) (p<0.05)). There were similar findings in the ECMO group: survivors had proapoptotic BAL fluid compared with non-survivors (apoptosis ratio day 1, survivors 7.9 (2.1) v non-survivors 2.1 (0.7) (p<0.05))., Conclusions: Inappropriate suppression of neutrophil apoptosis may be associated with a poor outcome in newborn infants with respiratory failure.

Background: The prevalence and severity of asthma is believed to increase with increasing socioeconomic deprivation. The relationship between asthma diagnosis, symptoms, diagnostic accuracy, and socioeconomic deprivation as determined by Townsend scores was determined in Sheffield schoolchildren., Methods: All 6021 schoolchildren aged 8-9 years in one school year in Sheffield were given a parent respondent survey based on International Survey of Asthma and Allergies in Childhood (ISAAC) questions., Results: 5011/6021 (83.2%) questionnaires were returned. Postcode data were available in 4131 replies (82.4%) and were used to assign a composite deprivation score (Townsend score). Scores were divided into five quintiles, with group 1 being least and group 5 being most deprived. A positive trend was observed from group 1 to group 5 for the prevalence of wheeze in the previous 12 months, wheeze attacks >or=4/year, nocturnal wheeze and cough (all p<0.001), cough and/or wheeze "most times" with exertion (p<0.03), current asthma (p<0.001), and significant asthma symptoms (p<0.001). No significant trend was observed for lifetime wheeze or attacks of speech limiting wheeze. There were no significant trends in the prevalence of current asthmatic children without significant symptoms (overdiagnosis) or children with significant asthma symptoms but no current asthma diagnosis (underdiagnosis) across the social groups. There was a significant negative trend in the ratio of asthma medication to asthma diagnosis from least to most deprived groups (p<0.001)., Conclusions: Asthma morbidity and severity increase according to the level of socioeconomic deprivation. This may be due to differences in environment, asthma management, and/or symptom reporting. Diagnostic accuracy does not vary significantly across deprivation groups but children living in areas of least deprivation and taking asthma medication are less likely to be labelled as having asthma, suggesting diagnostic labelling bias.

Background: The prevalence of childhood asthma is increasing but few studies have investigated trends in asthma severity. We investigated trends in asthma diagnosis and symptom morbidity between an eight year time period in a paired prevalence study., Methods: All children in one single school year aged 8-9 years in the city of Sheffield were given a parent respondent questionnaire in 1991 and 1999 based on questions from the International Survey of Asthma and Allergy in Children (ISAAC). Data were obtained regarding the prevalence of asthma and wheeze and current (12 month) prevalences of wheeze attacks, speech limiting wheeze, nocturnal cough and wheeze, and exertional symptoms., Results: The response rates in 1991 and 1999 were 4580/5321 (85.3%) and 5011/6021 (83.2%), respectively. There were significant increases between the two surveys in the prevalence of asthma ever (19.9% v 29.7%, mean difference 11.9%, 95% confidence interval (CI) 10.16 to 13.57, p<0.001), current asthma (10.3% v 13.0%, mean difference 2.7%, 95% CI 1.44 to 4.03, p<0.001), wheeze ever (30.3% v 35.8%, mean difference 5.7%, 95% CI 3.76 to 7.56, p<0.001), wheeze in the previous 12 months (17.0% v 19.4%, mean difference 2.5, 95% CI 0.95 to 4.07, p<0.01), and reporting of medication use (16.9% v 20%, mean difference 3.0%, 95% CI 1.46 to 4.62, p<0.001). There were also significant increases in reported hayfever and eczema diagnoses., Conclusions: Diagnostic labelling of asthma and lifetime prevalence of wheeze has increased. The current 12 month point prevalence of wheeze has increased but this is confined to occasional symptoms. The increased medication rate may be responsible for the static prevalence of severe asthma symptoms. The significant proportion of children receiving medication but reporting no asthma symptoms identified from our 1999 survey suggests that some children are being inappropriately treated or overtreated.

A patient in whom chylothorax was the presenting feature of sarcoidosis is reported. Mediastinal lymphadenopathy was shown by computed tomographic scanning. Obstruction of the thoracic duct by enlarged lymph nodes or fibrosis is the probable cause of chylothorax in this case. The association of chylothorax and sarcoidosis is extremely rare.

Background: Current treatment of patients with pulmonary arteriovenous malformations requires serial embolisations by means of steel coils or balloons. Measurement of right to left shunt is the most specific index of response to treatment. A new method of measuring shunt has been developed that is less invasive than traditional methods., Methods: Right to left pulmonary shunt (expressed as percentage of cardiac output) was measured at rest in 19 patients with pulmonary arteriovenous malformations and six normal subjects by using intravenously injected albumin microspheres labelled with technetium-99m. The technique was compared with a simultaneous shunt measurement in subjects breathing 100% oxygen while they rested. The microsphere technique was adapted to measure the right to left shunt during exercise in 12 patients and five normal subjects with a new method of quantification., Results: The mean (SD) shunt at rest as measured by the microsphere method was 23.2% (15.6%) in the patients and 2.7% (1.2%) in the normal subjects. When these values were compared with those of the 100% oxygen method the difference in mean values was 1% and the limits of agreement between the two methods -32% to +45%. The microsphere method is less invasive (arterial blood gas sampling is not required), quicker, and more comfortable for patients than the 100% oxygen method. In five of the normal subjects the mean (SD) 99mTc microsphere shunt increased from 2.9% (1.3%) at rest to 5.1% (2.9%) during exercise. In the 12 patients studied during exercise the shunt increased from 33.7% (12.7%) at rest to 41.7% (13.3%) during exercise in eight but decreased from 22.6% (2.4%) at rest to 17.6% (2.2%) during exercise in four. Arterial desaturation during exercise correlated with change in the size of the right to left shunt during exercise (r = +0.80)., Conclusions: The microsphere method allows measurement of right to left shunt at rest and during exercise. Serial measurements at rest provide a simple, safe assessment of the physiological response to embolisation in patients with pulmonary arteriovenous malformations.