Summary: The airway epithelium plays an active role in acute lung inflammation by producing chemotactic factors and by expressing cell adhesion molecules involved in the migration of leucocytes to extravascular spaces. We have reported previously that neutrophil migration to airways can be down-modulated by exogenously administered vitamin E (α-tocopherol). The mechanism for this effect is not well understood, however. The action of α-tocopherol was investigated in human alveolar type II and bronchial epithelial cells stimulated with tumour necrosis factor-α. Treatment of alveolar epithelial cells with α-tocopherol resulted in down-regulated cell surface expression of intercellular adhesion molecule-1 (ICAM-1). On bronchial epithelial cells, both ICAM-1 and vascular adhesion molecule-1 were decreased, leading to diminished adherence of leucocytes to the cells. The production of the neutrophil chemoattractant interleukin-8 was attenuated in both alveolar and bronchial cells. These effects were preceded by reduced activation of the mitogen-activated protein kinases (MAPK), extracellular signal-regulated kinase (ERK1/2) and p38, as well as down-regulation of nuclear factor-κB. Comparing the effects of α-tocopherol with that of specific inhibitors of MAPK and protein kinase C (PKC) revealed that effects appear to be partly independent of PKC inhibition. These results implicate the anti-inflammatory action of α-tocopherol in addition to its anti-oxidant properties.

Background: Differences in the expression of regulatory T cells (Tregs) have been suggested to explain why some smokers develop COPD and some do not. Upregulation of Tregs in response to smoking would restrain airway inflammation and thus the development of COPD; while the absense of such upregulation would over time lead to chronic inflammation and COPD. We hypothesized that—among COPD patients—the same mechanism would affect rate of decline in lung function; specifically, that a decreased expression of Tregs would be associated with a more rapid decline in FEV₁. Methods: Bronchoscopy with BAL was performed in 52 subjects recruited from the longitudinal OLIN COPD study; 12 with COPD and a rapid decline in lung function (loss of FEV₁ ≥ 60 ml/year), 10 with COPD and a non-rapid decline in lung function (loss of FEV₁ ≤ 30 ml/year), 15 current and ex-smokers and 15 non-smokers with normal lung function. BAL lymphocyte subsets were determined using flow cytometry. Results: The proportions of Tregs with regulatory function (FoxP3⁺/CD4⁺CD25^bright) were significantly lower in COPD subjects with a rapid decline in lung function compared to those with a non-rapid decline (p = 0.019). This result was confirmed in a mixed model regression analysis in which adjustments for inhaled corticosteroid usage, smoking, sex and age were evaluated. No significant difference was found between COPD subjects and smokers or non-smokers with normal lung function. Conclusions: COPD subjects with a rapid decline in lung function had lower proportions of T cells with regulatory function in BAL fluid, suggesting that an inability to suppress the inflammatory response following smoking might lead to a more rapid decline in FEV₁. Trial registration Clinicaltrials.gov identifier NCT02729220

Diseases in the respiratory tract rank among the leading causes of death in the world, and thus novel and optimized treatments are needed. The lungs offer a large surface for drug absorption, and the inhalation of aerosolized drugs are a well-established therapeutic modality for local treatment of lung conditions. Nanoparticle-based drug delivery platforms are gaining importance for use through the pulmonary route. By using porous carrier matrices, higher doses of especially poorly soluble drugs can be administered locally, reducing their side effects and improving their biodistribution. In this study, the feasibility of mesoporous silica particles (MSPs) as carriers for anti-inflammatory drugs in the treatment of airway inflammation was investigated. Two different sizes of particles on the micron and nanoscale (1 µm and 200 nm) were produced, and were loaded with dexamethasone (DEX) to a loading degree of 1:1 DEX:MSP. These particles were further surface-functionalized with a polyethylene glycol–polyethylene imine (PEG–PEI) copolymer for optimal aqueous dispersibility. The drug-loaded particles were administered as an aerosol, through inhalation to two different mice models of neutrophil-induced (by melphalan or lipopolysaccharide) airway inflammation. The mice received treatment with either DEX-loaded MSPs or, as controls, empty MSPs or DEX only; and were evaluated for treatment effects 24 h after exposure. The results show that the MEL-induced airway inflammation could be treated by the DEX-loaded MSPs to the same extent as free DEX. Interestingly, in the case of LPS-induced inflammation, even the empty MSPs significantly down-modulated the inflammatory response. This study highlights the potential of MSPs as drug carriers for the treatment of diseases in the airways.

Regulatory T cells have been implicated in the pathogenesis of COPD by the increased expression of CD25 on helper T cells along with enhanced intracellular expression of FoxP3 and low/absent CD127 expression on the cell surface.

Cytotoxic lymphocytes are increased in the airways of COPD patients. Whether this increase is driven primarily by the disease or by smoking is not clear, nor whether it correlates with the rate of decline in lung function. Bronchoscopy with BAL was performed in 52 subjects recruited from the longitudinal OLIN COPD study according to pre-determined criteria; 12 with COPD and a rapid decline in lung function (loss of FEV1 ≥ 60 ml/year), 10 with COPD and a non-rapid decline in lung function (loss of FEV1 ≤ 30 ml/year), 15 current and ex-smokers and 15 non-smokers with normal lung function. BAL lymphocyte subsets were determined using flow cytometry. In BAL fluid, the proportions of NK, iNKT and NKT-like cells all increased with pack-years. Within the COPD group, NK cells – but not iNKT or NKT-like cells – were significantly elevated also in subjects that had quit smoking. In contrast, current smoking was associated with a marked increase in iNKT and NKT-like cells but not in NK cells. Rate of lung function decline did not significantly affect any of the results. In summary, increased proportions of NK cells in BAL fluid were associated with COPD; iNKT and NKT-like cells with current smoking but not with COPD. Interestingly, NK cell percentages did not normalize in COPD subjects that had quit smoking, indicating that these cells might play a role in the continued disease progression seen in COPD even after smoking cessation. Clinicaltrials.gov identifier NCT02729220 .