Chronic obstructive pulmonary disease (COPD) is a common, highly debilitating disease of the airways, primarily caused by smoking. Chronic inflammation and structural remodelling are key pathological features of this disease, in part caused by the aberrant function of airway smooth muscle (ASM) cells under the regulation of transforming growth factor (TGF)‐β. miRNA are short, noncoding gene transcripts involved in the negative regulation of specific target genes, through their interactions with mRNA. Previous studies have proposed that mRNA‐145 (miR‐145) may interact with SMAD3, an important downstream signalling molecule of the TGF‐β pathway. TGF‐β was used to stimulate primary human ASM cells isolated from healthy nonsmokers, healthy smokers and COPD patients. This resulted in a TGF‐β‐dependent increase in CXCL8 and IL‐6 release, most notably in the cells from COPD patients. TGF‐β stimulation increased SMAD3 expression, only in cells from COPD patients, with a concurrent increased miR‐145 expression. Regulation of miR‐145 was found to be negatively controlled by pathways involving the MAP kinases, MEK‐1/2 and p38 MAPK. Subsequent, overexpression of miR‐145 (using synthetic mimics) in ASM cells from patients with COPD suppressed IL‐6 and CXCL8 release, to levels comparable to the nonsmoker controls. Therefore, this study suggests that miR‐145 negatively regulates pro‐inflammatory cytokine release from ASM cells in COPD by targeting SMAD3.

Triggering receptor expressed on myeloid cells-1 (TREM-1) is expressed on neutrophils and monocyte/macrophages and amplifies Toll-like receptor-mediated inflammation during infection. TREM-1 also exists in an antagonistic soluble form (sTREM-1) that has been used as a peripheral biomarker in sepsis, though the mechanisms of its release are not entirely clear. The requirement of TREM-1 in single microbial infections is controversial, with some studies showing a protective role and others a contribution to immunopathology. Furthermore, the role of membrane-bound and sTREM-1 in polygenic infections is currently unknown. In a mouse co-infection model where preceding viral infection greatly enhances bacteria co-infection, we now determine a mechanisms for the striking increase in sTREM-1 and the loss of TREM-1 on surface of neutrophils. We identified a matrix metalloproteinase (MMP)-9 cleavage site in TREM-1 and that the increase of MMP-9 in bronchoalveolar lavage fluid mirrors sTREM-1 release. In vitro studies with neutrophils and MMP-9 and the reduction of sTREM-1 in vivo after MMP-9 inhibition verifies that this enzyme cleaves TREM-1. Intriguingly, MMP-9 inhibition significantly reduces bacterial load and ensuing immunopathology in a co-infection model. This highlights MMP-9 inhibition as a potential therapeutic via blocking cleavage of TREM-1.

Background: In cystic fibrosis (CF), genetic mutations in the CF transmembrane conductance regulator (CFTR) gene cause reduced chloride efflux from ciliated airway epithelial cells. This results in a reduction in periciliary liquid (PCL) depth of the airway surface liquid due to associated reduced water efflux. PCL layer dehydration reduces mucociliary clearance (MCC), leading to airway obstruction (reduced airflow and inflammation due to pathogen invasion) with mucus plug formation. Summary: Rehydrating mucus increases MCC. Mucus hydration can be achieved by direct hydration (administering osmotic agents to set up an osmotic gradient), using CFTR modulators to correct dysfunctional CFTR, or it can be achieved pharmacologically (targeting other ion channels on airway epithelial cells). Key Messages: The molecular mechanisms of several therapies are discussed in the context of pre-clinical and clinical trial studies. Currently, only the osmotic agent 7% hypertonic saline and the CFTR ‘potentiator' VX-770 (ivacaftor) are used clinically to hydrate mucus. Emerging therapies include the osmotic agent mannitol (Bronchitol), the intracellular Ca²⁺-raising agent Moli1901/lancovutide, the CFTR potentiator sildenafil [phosphodiesterase type 5 (PDE5) inhibitor] and the CFTR ‘corrector' VX-809 (lumacaftor). Other CFTR correctors (e.g. ‘chemical chaperones') are also showing pre-clinical promise.

an allogeneic mixed-lymphocyte reaction (MLR). Lymphocyte proliferation (flow-cytometric measurement of CFSE) and cytokine production (multiplex bead array) were assessed at day 5. The proportion of lymphocytes primed to produce IFNg was measured at day 7 (intracellular staining). Results UPM-stimulation increased DC expression of the maturation marker CD83 (p = 0.0038) and chemokine receptor CCR7 (p = 0.0018). It had no effect on CD40 or MHC Class I expression. UPM-stimulation of DCs also significantly increased CD8 lymphocyte proliferation (p = 0.020), and the production of IFNg, TNFa and IL-13 by CD8 lymphocytes in MLR at day 5 (all p < 0.05; Table 1). The proportion of CD8 lymphocytes primed to produce IFNg was also increased by UPM-stimulation of DCs (p = 0.034). Conclusion No evidence of an impaired Tc1 response was seen with UPM-stimulated DCs, in contrast to our previous findings with CD4 T lymphocytes. This may be because CD8 lymphocytes are more primed to respond and produce cytokines at baseline. However, UPM-treatment of DCs did significantly increase DC expression of CCR7, which directs DCs to lymph nodes, and increased the priming of Tc1 and Tc2 responses in the absence of any other stimulation. Inhalation of UPM may give rise to pathological CD8 responses to otherwise innocuous novel antigens. Introduction Increasing evidence suggests accelerated ageing as a pathogenic mechanism in COPD. Methods and results Telomere length in circulating WBC, a marker of biological ageing, was assessed in 200 ex-smoker COPD patients (108 male, age 61.5 ± 6.4 years, FEV 1 45.6 ± 17.1% predicted), 50 ex-smokers with normal lung function (27 male, age 59.9 ± 7.3 years, FEV 1 109.1 ± 13.4%predicted) and 50 non-smoker healthy subjects (27 male, age 59.3 ± 8.3 years, FEV 1 113.2 ± 13.1% predicted). TL was assessed by qPCR and expressed as relative T/S ratio. S49 TELOMERE ATTRITION IN CIRCULATING WHITE BLOOD CELLS IN COPD RELATES TO LUNG FUNCTION AND OUTCOMESTL was shorter in COPD (0.77 ± 0.2 relative T/S ratio) than in both ex-smokers (0.83 ± 0.2 relative T/S ratio) and nonsmokers (0.84 ± 0.2 relative T/S ratio) (p < 0.05). Furthermore TL correlated negatively with age (r -0.17, p 0.007), emphysema score (r -0.217, p 0.001), number of exacerbations in the previous year to inclusion in the study (r -0.129, p 0.04), number of hospitalisations over 3 years follow-up (r -0.167, p 0.004) and positively with FEV 1 (r 0.135, p = 0.03) and arterial oxygen saturation (r 0.161, p 0.01). Conclusion COPD patients have evidence of premature ageing (shortened TL) compared to normal subjects irrespective of their smoking history. TL relates to FEV 1 , SatO 2 , exacerbation rate and hospitalisations.