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Background: Epithelial damage, repair and remodelling are critical features of chronic airway diseases including chronic obstructive pulmonary disease (COPD). Interleukin (IL)-33 released from damaged airway epithelia causes inflammation via its receptor, serum stimulation-2 (ST2). Oxidation of IL-33 to a non-ST2-binding form (IL-33 ox ) is thought to limit its activity. We investigated whether IL-33 ox has functional activities that are independent of ST2 in the airway epithelium., Methods: In vitro epithelial damage assays and three-dimensional, air-liquid interface (ALI) cell culture models of healthy and COPD epithelia were used to elucidate the functional role of IL-33 ox . Transcriptomic changes occurring in healthy ALI cultures treated with IL-33 ox and COPD ALI cultures treated with an IL-33-neutralising antibody were assessed with bulk and single-cell RNA sequencing analysis., Results: We demonstrate that IL-33 ox forms a complex with receptor for advanced glycation end products (RAGE) and epidermal growth factor receptor (EGFR) expressed on airway epithelium. Activation of this alternative, ST2-independent pathway impaired epithelial wound closure and induced airway epithelial remodelling in vitro . IL-33 ox increased the proportion of mucus-producing cells and reduced epithelial defence functions, mimicking pathogenic traits of COPD. Neutralisation of the IL-33 ox pathway reversed these deleterious traits in COPD epithelia. Gene signatures defining the pathogenic effects of IL-33 ox were enriched in airway epithelia from patients with severe COPD., Conclusions: Our study reveals for the first time that IL-33, RAGE and EGFR act together in an ST2-independent pathway in the airway epithelium and govern abnormal epithelial remodelling and muco-obstructive features in COPD., Competing Interests: Conflict of interest: S. Strickson, V.A. Negri, Y. Ohne, T. Ottosson, R.B. Dodd, C.C. Huntington, T. Baker, J. Li, K.E. Stephenson, A.J. O'Connor, J.S. Sagawe, H. Killick, D.G. Rees, S. Koch, Y. Wang, M. Ghaedi, S. Saumyaa, G.P. Sims, I.C. Scott, X. Romero Ros and E.S. Cohen are employees of AstraZeneca and may hold stock or stock options in AstraZeneca. K.F. Houslay, T. Moore, E. Gubbins, R. Kolbeck and A.A. Humbles are former employees of AstraZeneca and may hold stock or stock options in AstraZeneca. C. Sanden has nothing to disclose. J.S. Erjefält is a founder and board member of Medetect AB., (Copyright ©The authors 2023.)

Regulatory T cells (Tregs) are the key cells regulating peripheral autoreactive T lymphocytes. Tregs exert their function by suppressing effector T cells. Tregs have been shown to play essential roles in the control of a variety of physiological and pathological immune responses. However, Tregs are unstable and can lose the expression of FOXP3 and suppressive functions as a consequence of outer stimuli. Available literature suggests that secreted proteins regulate Treg functional states, such as differentiation, proliferation and suppressive function. Identification of secreted proteins that affect Treg cell function are highly interesting for both therapeutic and diagnostic purposes in either hyperactive or immunosuppressed populations. Here, we report a phenotypic screening of a human secretome library in human Treg cells utilising a high throughput flow cytometry technology. Screening a library of 575 secreted proteins allowed us to identify proteins stabilising or destabilising the Treg phenotype as suggested by changes in expression of Treg marker proteins FOXP3 and/or CTLA4. Four proteins including GDF-7, IL-10, PAP and IFNα-7 were identified as positive regulators that increased FOXP3 and/or CTLA4 expression. PAP is a phosphatase. A catalytic-dead version of the protein did not induce an increase in FOXP3 expression. Ten interferon proteins were identified as negative regulators that reduced the expression of both CTLA4 and FOXP3, without affecting cell viability. A transcriptomics analysis supported the differential effect on Tregs of IFNα-7 versus other IFNα proteins, indicating differences in JAK/STAT signaling. A conformational model experiment confirmed a tenfold reduction in IFNAR-mediated ISG transcription for IFNα-7 compared to IFNα-10. This further strengthened the theory of a shift in downstream messaging upon external stimulation. As a summary, we have identified four positive regulators of FOXP3 and/or CTLA4 expression. Further exploration of these Treg modulators and their method of action has the potential to aid the discovery of novel therapies for both autoimmune and infectious diseases as well as for cancer., (© 2021. The Author(s).)

Objectives: This review article describes the role of neutrophils in mucosal injury and the resulting crypt abscesses characteristic of ulcerative colitis. We also review selected biomarkers for monitoring neutrophil presence and activity in the mucosa as well as their potential as therapeutic targets., Material: We have collated and selectively reviewed data on the most prominent well-established and emerging neutrophil-related biomarkers and potential therapeutic targets (calprotectin, lactoferrin, CXCR1, CXCR2, MMP-9, NGAL, elafin, HNE, pANCAs, MPO, CD16, CD177, CD64, HNPs, SLPI and PTX3) in ulcerative colitis., Results: Systemic and intestinal neutrophil activity increases substantially in active ulcerative colitis, driving tissue damage and extra-intestinal manifestations. Calprotectin is a robust neutrophil and disease biomarker, and a few neutrophil-related targets are being clinically explored as therapeutic targets., Conclusion: We propose that targeting neutrophils and their inflammatory mediators per se is an opportunity that should be explored to identify new effective medical therapies. The overall clinical goal for neutrophil-targeted therapy will be to modulate, but not completely silence, neutrophil activity, thereby abolishing the destructive inflammation with associated acute and chronic tissue damage without compromising host-defense.

Objective: Neutrophil elastase (NE) concentration is associated with progression of acute pancreatitis (AP), but measuring total NE concentration includes biologically inactive NE. This study aims to investigate the relationship between NE activity and the aetiology and severity of AP and associated organ failure., Methods: Seventy-five patients admitted to our surgery department with a first episode of AP during 2004-2005 were age- and sex-matched to 20 healthy volunteers (controls). NE activity was assessed using venous blood samples obtained on patient admission and after 1, 2 and 14 days. One sample was also taken from each control. ANOVA was used for statistical comparison between groups., Results: Baseline NE activity (geometric mean; 95% confidence intervals) differed between patients (58.6 nM of substrate 7-amino-4-methylcoumarin [AMC]/hour; 48.52-70.72) and controls (31.5 nM AMC/hour; 25.5-39.0) (p = 0.0003), and did not correlate with time between symptom onset and admission. Patients with alcohol-induced AP demonstrated higher mean activity (59.1 nM AMC/h; 44.7-78.2) than those with gallstone-induced AP (41.7 nM AMC/h; 33.9-51.4) (p = 0.0496). NE activity was higher overall in patients with predicted severe AP (60.9 nM AMC/h; 48.0-77.2) than in those with predicted mild AP (42.1 nM AMC/h; 34.9-50.8) (p = 0.027). Patients with respiratory failure had higher NE activity (82.5 nM AMC/h; 57.5-118.4) than those without (43.9 nM AMC/h; 37.6-51.3) (p = 0.0024)., Conclusions: NE activity was associated with predicted severity of AP and AP-associated respiratory failure. Specific NE inhibitors may have therapeutic potential in acute pancreatitis.

In general, most women are familiar with the need to stop smoking when they are pregnant. In spite of this, many women find it difficult to stop. Using a phenomenographic approach, this study explored Swedish pregnant and post-pregnant women's ways of making sense of smoking during pregnancy. A total of 17 women who either smoked throughout pregnancy or stopped smoking during pregnancy were interviewed. Five different story types of how they are making sense of smoking during pregnancy were identified: smoking can be justified; will stop later; my smoking might hurt the baby; smoking is just given up; smoking must be taken charge of. Based on the study it is argued that the approach used in health education in relation to smoking cessation in antenatal care needs to move from information transfer and advice-giving to the creation of a dialogue. The starting point should be the woman's knowledge, concerns, rationalizations and prejudices. A model is suggested in which a woman may move in a space on three axes depending on life encounters, dialogue and reflections on meaning. The goal in health education would be to encourage movement along three axes: 'increase of self-efficacy towards control', 'increase awareness by reflection on meaning of the smoking issue' and 'avoidance of defense of the smoking behavior'.

Conditions which permit the dissociation of IgG-staphylococcal protein A interactions without resort to low pH buffers or the use of chaotropic ions are discussed in relation to: (a) the mechanism of the binding reaction; (b) the use of immobilised protein A for purification of cells or removal of immune complexes from serum. Glycyl-tyrosine, glycyl-histidine, glycyl-phenylalanine and tryptophan, representing the class of competing ligand desorbents, and ethylene glycol, an agent which disrupts hydrophobic interactions, were found to be the best desorbents.