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Background: Occupational asthma, induced by workplace exposures to low molecular weight agents such as toluene 2,4-diisocyanate (TDI), causes a significant burden to patients and society. Little is known about innate lymphoid cells (ILCs) in TDI-induced asthma. A critical regulator of ILC function is microRNA-155, a microRNA associated with asthma., Objective: To determine whether TDI exposure modifies the number of ILCs in the lung and whether microRNA-155 contributes to TDI-induced airway inflammation and hyperresponsiveness., Methods: C57BL/6 wild-type and microRNA-155 knockout mice were sensitised and challenged with TDI or vehicle. Intracellular cytokine expression in ILCs and T-cells was evaluated in bronchoalveolar lavage (BAL) fluid using flow cytometry. Peribronchial eosinophilia and goblet cells were evaluated on lung tissue, and airway hyperresponsiveness was measured using the forced oscillation technique. Putative type 2 ILCs (ILC2) were identified in bronchial biopsies of subjects with TDI-induced occupational asthma using immunohistochemistry. Human bronchial epithelial cells were exposed to TDI or vehicle., Results: TDI-exposed mice had higher numbers of airway goblet cells, BAL eosinophils, CD4 + T-cells and ILCs, with a predominant type 2 response, and tended to have airway hyperresponsiveness. In TDI-exposed microRNA-155 knockout mice, inflammation and airway hyperresponsiveness were attenuated. TDI exposure induced IL-33 expression in human bronchial epithelial cells and in murine lungs, which was microRNA-155 dependent in mice. GATA3 + CD3 - cells, presumably ILC2, were present in bronchial biopsies., Conclusion: TDI exposure is associated with increased numbers of ILCs. The proinflammatory microRNA-155 is crucial in a murine model of TDI asthma, suggesting its involvement in the pathogenesis of occupational asthma due to low molecular weight agents., Competing Interests: Conflict of interest: E.E. Blomme reports grants from Fund for Scientific Research in Flanders (projects G053516N and G0G2318N) and Ghent University (BOF19-GOA-008), during the conduct of the study. Conflict of interest: S. Provoost has nothing to disclose. Conflict of interest: E. Bazzan has nothing to disclose. Conflict of interest: H.P. Van Eeckhoutte has nothing to disclose. Conflict of interest: M.P. Roffel has nothing to disclose. Conflict of interest: L. Pollaris has nothing to disclose. Conflict of interest: A. Bontinck has nothing to disclose. Conflict of interest: M. Bonato has nothing to disclose. Conflict of interest: L. Vandenbroucke has nothing to disclose. Conflict of interest: F. Verhamme has nothing to disclose. Conflict of interest: G.F. Joos reports grants and personal fees from AstraZeneca and GlaxoSmithKline, personal fees from Bayer, Eureca and Teva, grants from Chiesi, outside the submitted work; all payments were made to his employer. Conflict of interest: M.G. Cosio has nothing to disclose. Conflict of interest: J.A.J. Vanoirbeek has nothing to disclose. Conflict of interest: G.G. Brusselle has nothing to disclose. Conflict of interest: M. Saetta reports grants from Laboratori Guidotti SpA and Chiesi Farmaceutici SpA, outside the submitted work. Conflict of interest: T. Maes reports grants from Ghent University (concerted research action BOF-GOA-008) and Fund for Scientific Research in Flanders (projects G053516N and G0G2318N), during the conduct of the study; personal fees for advisory board work from GlaxoSmithKline, outside the submitted work; and is shareholder of Oryzon Genomics and Mendelion Lifesciences SL., (Copyright ©ERS 2020.)

Investigations toward the understanding of chronic obstructive pulmonary disease (COPD) have been directed, so far, to the study of mechanisms leading to the disease. We believe that understanding why ~80% of smokers evade COPD and how this evasion is accomplished might be a fruitful endeavour that could advance knowledge of the development of the disease. Since the inflammatory infiltrate smokers develop seems to be the key element leading to the lung destruction in COPD, the understanding of the possible ways inflammation can be dampened, as well as its consequences, ought to be important. We review here some of the mechanisms by which inflammation is controlled: by the post-translational regulons, by the mechanisms preventing full activation of dendritic cells and by the regulatory T-cells. The potential role of the M2 alveolar macrophage phenotype and the newly described myeloid-derived suppressor cells is mentioned. We also point out that evasion comes at a price, as healthy smokers might be immunosuppressed to some extent and unable to prevent the development of cancer, certainly less so than in severe COPD, where immunity is heightened. Probably, the knowledge of the mechanisms of evasion from COPD could add significantly to the understanding of those leading to the disease.

A mild-to-moderate increase in pulmonary arterial pressure is often associated with severe chronic obstructive pulmonary disease (COPD). Transforming growth factor (TGF)-beta is a cytokine involved in the maintenance of integrity of vasculature. The aim of the study was to investigate whether the TGF-beta pathway might be involved in the development of pulmonary hypertension associated with COPD. Surgical specimens from 14 patients undergoing lung transplantation for very severe COPD (forced expiratory volume in one second 17 +/- 2% of the predicted value) and from seven donors were examined. The expression of TGF-beta1 and TGF-beta type II receptor (TGF-betaRII), cell proliferation index and structural changes in pulmonary arteries were quantified immunohistochemically. In severe COPD patients, increased expression of TGF-betaRII was observed in both the tunica media and intima, which was associated with a normal proliferation index in both layers. Conversely, significant thickening of the tunica intima, which was not present in the tunica media, was observed, suggesting that mechanisms other than cell proliferation may be involved in intimal thickening. In conclusion, in the pulmonary arteries of patients with severe chronic obstructive pulmonary disease, there is upregulation of transforming growth factor-beta type II receptor expression associated with a normal proliferation index. These findings suggest the activation of an antiproliferative pathway, which might explain the relatively low degree of pulmonary hypertension observed in these subjects.

The aim of the study was to investigate the expression of basic fibroblast growth factor (bFGF) and its receptor, fibroblast growth factor receptor (FGFR)-1, in the central airways of smokers with chronic bronchitis. The lobar bronchi from 17 subjects undergoing thoracotomy for solitary nodules were examined. All had a history of cigarette smoking, nine had symptoms of chronic bronchitis and airflow limitation, and eight were asymptomatic with normal lung function. Using immunohistochemical methods, bFGF and FGFR-1 expression in the total airway wall and the different airway compartments, i.e. bronchial glands, submucosal vessels and smooth muscle, was quantified. Moreover, to investigate the role of bFGF in angiogenesis, the number of submucosal vessels was quantified. Smokers with chronic bronchitis had an increased bFGF expression in the total airway wall compared with asymptomatic smokers, which was mainly due to bFGF upregulation in bronchial glands. By contrast, the expression of FGFR-1 and the number of submucosal vessels was similar in the two groups of subjects examined. In conclusion, smokers with chronic bronchitis have an increased expression of basic fibroblast growth factor in the central airways, which is mainly due to an increased expression in bronchial glands, suggesting the involvement of this growth factor in the pathogenesis of chronic bronchitis.