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Asthma and chronic obstructive pulmonary disease (COPD) are heterogeneous inflammatory disorders of the respiratory tract characterized by airflow obstruction. It is now clear that the environmental factors that drive airway pathology in asthma and COPD, including allergens, viruses, ozone and cigarette smoke, activate innate immune receptors known as pattern-recognition receptors, either directly or indirectly by causing the release of endogenous ligands. Thus, there is now intense research activity focused around understanding the mechanisms by which pattern-recognition receptors sustain the airway inflammatory response, and how these mechanisms might be targeted therapeutically. One pattern-recognition receptor that has recently come to attention in chronic airways disease is the receptor for advanced glycation end products (RAGE). RAGE is a member of the immunoglobulin superfamily of cell surface receptors that recognizes pathogen- and host-derived endogenous ligands to initiate the immune response to tissue injury, infection and inflammation. Although the role of RAGE in lung physiology and pathophysiology is not well understood, recent genome-wide association studies have linked RAGE gene polymorphisms with airflow obstruction. In addition, accumulating data from animal and clinical investigations reveal increased expression of RAGE and its ligands, together with reduced expression of soluble RAGE, an endogenous inhibitor of RAGE signalling, in chronic airways disease. In this review, we discuss recent studies of the ligand-RAGE axis in asthma and COPD, highlight important areas for future research and discuss how this axis might potentially be harnessed for therapeutic benefit in these conditions. [ABSTRACT FROM AUTHOR]

Background. This study aimed to compare the effects of two small-group asthma education interventions (one delivered by specially trained pharmacists (group A) and one delivered by a pharmacist researcher trained as an asthma educator (group B)) with usual care provided by community pharmacists (group C) on clinical and humanistic outcomes for people with asthma. Methods. Pharmacies were randomly selected to provide either group A, B, or C interventions. Data were collected at baseline, post intervention (groups A and B) and at 6 and 12 weeks (final visit). Results. Forty-eight people with asthma were recruited into groups A (n = 16), B (n = 16), and C (n = 16) and there were no significant differences between the groups at baseline. At 12 weeks there was a significant decrease in the proportion of patients with severe asthma/poor control in groups A and B compared with group C (56%, 44% and 50% to 25%, 13% and 50% [n = 48, p < 0.05], respectively). In Groups A and B, the proportion of patients with optimal metered dose inhaler (MDI) technique improved from 9% and 14%, respectively, at baseline to 82% and 93% (n = 11, p = 0.02, n = 14, p < 0.001), respectively, at 12 weeks. The proportion of patients with optimal dry powder inhaler (DPI) technique improved in Groups A and B from 0% and 8%, respectively, at baseline to 86% and 92% (n = 7, p < 0.001; n = 13, p = 0.002), respectively, at 12 weeks. No change in inhaler technique was observed for Group C. There were significant improvements in asthma knowledge scores in Groups A and B compared to Group C over time. Conclusions. Small-group asthma education delivered by pharmacists appears to be more effective than usual care in improving clinical and humanistic asthma outcomes. [ABSTRACT FROM AUTHOR]

Human airway smooth muscle (ASM) plays an immunomodulatory role in asthma. Recently, IL-17A has become of increasing interest in asthma, being found at elevated levels in asthmatic airways and emerging as playing an important role in airway neutrophilia. IL-17A predominantly exerts its neutrophil orchestrating role indirectly via the induction of cytokines by resident airway structural cells. Here, we perform an in vitro study to show that although IL-17A did not induce secretion of the CXC chemokine IL-8 from ASM cells, IL-17A significantly potentiates TNF-α-induced IL-8 protein secretion and gene expression in a concentration- and time-dependent manner (P < 0.05). Levels of IL-8 protein produced after 24 h of incubation with TNF-α were enhanced 2.7-fold in the presence of IL-17A, and conditioned media significantly enhanced neutrophil chemotaxis in vitro. As IL-17A had no effect on the activity of NF-κB, a key transcriptional regulator of IL-8 gene expression, we then examined whether IL-17A acts at the posttranscriptional level. We found that IL-17A significantly augmented TNF-α-induced IL-8 mRNA stability. Interestingly, this enhanced stability occurred via a p38 MAPK-dependent pathway. The decay of IL-8 mRNA transcripts proceeded at a significantly faster rate when cells were pretreated with the p38 MAPK inhibitor SB-203580 (-0.05763 ± 0.01964, t1/2 = 12.0 h), compared with vehicle (-0.0 1030 ± 0.007963, t1/2 = 67.3 h) [results are expressed as decay constant (means ± SE) and half-life (t1/2 in h): P < 0.051. Collectively, these results demonstrate that IL-17A amplifies the synthetic function of ASM cells, acting via a p38 MAPK-dependent posttranscriptional pathway to augment TNF-α-induced secretion of the potent neutrophil chemoattractant IL-8 from ASM cells. [ABSTRACT FROM AUTHOR]

The extension of airway smooth muscle cell (ASMC) functions, from just contractile, to synthetic and/or proliferative states, is an important component of airway remodelling and inflammation in asthma. Whereas all these functions have been demonstrated in ASM, currently, it is not known whether ASMC can be differentiated on the basis of their proliferative and synthetic functions. We used flow-cytometric techniques to determine, first, whether human ASMC are phenotypically heterogenous with regard to their secretory function, and second, the proliferative status of secretory cells. ASMC were induced to synthesize GM-CSF by stimulation with IL-1β and TNF-α followed by 10% human serum. Flow-cytometric detection of intracellular GM-CSF revealed that only a proportion of cells in culture (∼ 20–60%) synthesize GM-CSF. To determine the proliferative status of GM-CSF producing cells, ASMC were pretreated with 5,6-carboxyfluorescein diacetate succinimidyl ester (CFSE), a fluorescein based dye used to track cell division, prior to cytokine/serum stimulation. Simultaneous analysis of intracellular GM-CSF and CFSE revealed that GM-CSF producing cells were present in both the divided and undivided ASMC populations. Thus, cytokine production and proliferation occurred in overlapping ASMC populations and prior progression through the cell cycle was not essential for ASMC cytokine production. [ABSTRACT FROM AUTHOR]