Advantages of “Soft Steroids” in the Treatment of Inflammatory Eye Diseases. Оverview

The purpose to assess the benefits of using soft steroids in the treatment of inflammatory eye disorders according to literature data.Methods. The literature review concerning the administration of the gluco-corticosteroids and combination drugs based on gluco-corticosteroid for the treatment of inflammatory eye disorders. Both Russian and foreign sources for the 1980–2021 period were analyzed.The results. The combination drugs containing anti-infective drugs and gluco-corticosteroids are actively applied for the treatment of inflammatory eye disorders. That exerts joint ethiopathogenetic effect on the disorder. However, gluco-corticosteroid being a part of such drugs (predominantly dexamethasone) as often as not leads to ocular hypertension. In order to deal with this problem the so-called soft steroids (also classified as gluco-corticosteroids) were introduced. They lessen the possibility of the ocular hypertension and are marked by high efficiency and increased safety profile. One of the representatives of soft steroids is fluorometholone. There is a large evidential base in the modern literature that confirms much lesser influence of fluorometholone on ocular pressure if compared to dexamethasone. At the same time, dexamethasone has a higher anti-inflammatory activity, while on the other hand, its systemic immunosuppressive activity is lower. What is more, in terms of influence on the ocular surfaces, dexamethasone has an additional advantage which is causing mucin expression in conjuctival and corneal epithelium. The above mentioned merits of dexamethasone served as basis for its inclusion into the combination drug called Floas-T which is essentially the combination of tobramycin 0.3 % and fluorometholone 0.1 %. It is used in the treatment of inflammatory eye diseases and diseases of eye appendages, as well as for profylaxis of the diseases in the postoperative period.Conclusion. Combination drugs containing anti-infective components and gluco-corticosteroids seem to be highly promising for the treatment of inflammatory eye diseases. One of them worth highlighting is Floas-T classified as soft steroids containing tobramycin and fluorometholone. It compares to dexamethasone favourably in terms of efficiency, while contributing less to ocular hypertension.

Ingested Engineered Nanomaterials Affect the Expression of Mucin Genes—An In Vitro-In Vivo Comparison

The increasing use of engineered nanomaterials (ENM) in food has fueled the development of intestinal in vitro models for toxicity testing. However, ENM effects on intestinal mucus have barely been addressed, although its crucial role for intestinal health is evident. We investigated the effects of ENM on mucin expression and aimed to evaluate the suitability of four in vitro models of increasing complexity compared to a mouse model exposed through feed pellets. We assessed the gene expression of the mucins MUC1, MUC2, MUC5AC, MUC13 and MUC20 and the chemokine interleukin-8 in pre-confluent and confluent HT29-MTX-E12 cells, in stable and inflamed triple cultures of Caco-2, HT29-MTX-E12 and THP-1 cells, and in the ileum of mice following exposure to TiO2, Ag, CeO2 or SiO2. All ENM had shared and specific effects. CeO2 downregulated MUC1 in confluent E12 cells and in mice. Ag induced downregulation of Muc2 in mice. Overall, the in vivo data were consistent with the findings in the stable triple cultures and the confluent HT29-MTX-E12 cells but not in pre-confluent cells, indicating the higher relevance of advanced models for hazard assessment. The effects on MUC1 and MUC2 suggest that specific ENM may lead to an elevated susceptibility towards intestinal infections and inflammations.

Whole genome sequencing identifies multiple loci for critical illness caused by COVID-19

Critical illness in COVID-19 is caused by inflammatory lung injury, mediated by the host immune system. We and others have shown that host genetic variation influences the development of illness requiring critical care or hospitalisation following SARS-Co-V2 infection. The GenOMICC (Genetics of Mortality in Critical Care) study is designed to compare genetic variants in critically-ill cases with population controls in order to find underlying disease mechanisms. Here, we use whole genome sequencing and statistical fine mapping in 7,491 critically-ill cases compared with 48,400 population controls to discover and replicate 22 independent variants that significantly predispose to life-threatening COVID-19. We identified 15 new independent associations with severe COVID-19, including variants within genes involved in interferon signalling (IL10RB, PLSCR1), leucocyte differentiation (BCL11A), and blood type secretor status (FUT2). Using transcriptome-wide association and colocalisation to infer the effect of gene expression on disease severity, we find evidence implicating expression of multiple genes, including reduced expression of a membrane flippase (ATP11A), and increased mucin expression (MUC1), in severe disease. We show that comparison between critically-ill cases and population controls is highly efficient for genetic association analysis and enables detection of therapeutically-relevant mechanisms of disease. Therapeutic predictions arising from these findings require testing in clinical trials.

Neutrophil Elastase and Chronic Lung Disease

Neutrophil elastase (NE) is a major inflammatory protease released by neutrophils and is present in the airways of patients with cystic fibrosis (CF), chronic obstructive pulmonary disease, non-CF bronchiectasis, and bronchopulmonary dysplasia. Although NE facilitates leukocyte transmigration to the site of infection and is required for clearance of Gram-negative bacteria, it also activates inflammation when released into the airway milieu in chronic inflammatory airway diseases. NE exposure induces airway remodeling with increased mucin expression and secretion and impaired ciliary motility. NE interrupts epithelial repair by promoting cellular apoptosis and senescence and it activates inflammation directly by increasing cytokine expression and release, and indirectly by triggering extracellular trap release and exosome release, which magnify protease activity and inflammation in the airway. NE inhibits innate immune function by digesting opsonins and opsonin receptors, degrading innate immune proteins such as lactoferrin, and inhibiting macrophage phagocytosis. Importantly, NE-directed therapies have not yet been effective in preventing the pathologic sequelae of NE exposure, but new therapies are being developed that offer both direct antiprotease activity and multifunctional anti-inflammatory properties.

Human Neutrophil Elastase Mediates MUC5AC Hypersecretion via the Tumour Necrosis Factor-α Converting Enzyme-Epidermal Growth Factor Receptor Signalling Pathway in vivo

<b><i>Objectives:</i></b> The objective of this study is to examine the role of the tumour necrosis factor-α converting enzyme-epidermal growth factor receptor (TACE-EGFR) pathway in human neutrophil elastase (HNE)-induced MUC5AC mucin expression in mice. <b><i>Method:</i></b> Four groups of mice, treated with HNE alone (HNE group), HNE plus TACE inhibitor (HNE + TAPI-2 group), HNE plus EGFR inhibitor (HNE + AG1478 group), and untreated (control group), were used in the experiment. Histopathological changes were monitored by haematoxylin-eosin (HE) and periodic acid-Schiff (PAS) staining. TACE, EGFR, and MUC5AC expression in the nasal mucosa were determined using immunohistochemistry. The expression of p-EGFR, EGFR, and TACE protein was analysed on Western blots, and MUC5AC protein levels were assessed via ELISA. TACE, EGFR, and MUC5AC expression in the nasal mucosa were determined using real-time quantitative PCR. <b><i>Results:</i></b> Compared to the control group, HE-stained tissues from the HNE group showed an irregular epithelium as well as goblet cell and submucosal glandular hyperplasia. In the nasal mucosa, strongly positive fuchsia granules were seen in PAS staining and significant increases in TACE, EGFR, MUC5AC mRNA, and protein expression were detected (<i>p</i> &#x3c; 0.01). The HNE + TAPI-2 and HNE + AG1478 groups had significantly less goblet cell and submucosal gland hyperplasia as well as weaker PAS staining. Compared to mice treated with HNE alone, in HNE + TAPI-2-treated mice, the levels of TACE, EGFR, and MUC5AC mRNA and protein as well as p-EGFR protein were significantly reduced (<i>p</i> &#x3c; 0.01). In HNE + AG1478-treated mice, EGFR and MUC5AC mRNA and protein levels and p-EGFR protein expression were reduced significantly (<i>p</i> &#x3c; 0.01), but the difference in TACE mRNA and protein expression between the HNE + AG1478 and HNE groups was not significant (<i>p</i> &#x3e; 0.05). <b><i>Conclusion:</i></b> Using a newly developed, stable experimental model of nasal hypersecretion in mice, we showed that TAPI-2 or AG1478 inhibited HNE-induced MUC5AC production. This suggests that MUC5AC mucin expression in vivo is mediated by a cascade involving the HNE-TACE-EGFR signalling pathway.

IL-17 Is a Key Regulator of Mucin-Galectin-3 Interactions in Asthma

Mucus hypersecretion and chronic airway inflammation are standard characteristics of several airway diseases, such as chronic obstructive pulmonary disease and asthma. Increased mucus secretion from increased mucin gene expression in the airway epithelium is associated with poor prognosis and mortality. We previously showed that the absence of tissue inhibitor of metalloproteinase 1 (TIMP-1) enhances lung inflammation, airway hyperreactivity, and lung remodeling in asthma in an ovalbumin (OVA) asthma model of TIMP-1 knockout (TIMPKO) mice as compared to wild-type (WT) controls and mediated by increased galectin-3 (Gal-3) levels. Additionally, we have shown that in the lung epithelial cell line A549, Gal-3 inhibition increases interleukin-17 (IL-17) levels, leading to increased mucin expression in the airway epithelium. Therefore, in the current study, we further examined the relationship between Gal-3 and the production of IL-17-axis cytokines and critical members of the mucin family in the murine TIMPKO asthma model and the lung epithelium cell line A549. While Gal-3 may regulate a Th1/Th2 response, IL-17 could stimulate the mucin genes, MUC5B and MUC5AC. Gal-3 and IL-17 interactions induce mucus expression in OVA-sensitized mice. We conclude that Gal-3 may play an essential role in the pathogenesis of asthma, and modulation of Gal-3 may prove helpful in the treatment of this disease.

Congenital Deletion of Nedd4-2 in Lung Epithelial Cells Causes Progressive Alveolitis and Pulmonary Fibrosis in Neonatal Mice

Recent studies found that expression of Nedd4‑2 is reduced in lung tissue from patients with idiopathic pulmonary fibrosis (IPF) and that the conditional deletion of Nedd4‑2 in lung epithelial cells causes IPF-like disease in adult mice via multiple defects, including dysregulation of the epithelial Na+ channel (ENaC), TGFβ signaling and the biosynthesis of surfactant protein-C proprotein (proSP-C). However, knowledge of the impact of congenital deletion of Nedd4‑2 on the lung phenotype remains limited. In this study, we therefore determined the effects of congenital deletion of Nedd4‑2 in the lung epithelial cells of neonatal doxycycline-induced triple transgenic Nedd4‑2fl/fl/CCSP‑rtTA2S‑M2/LC1 mice, with a focus on clinical phenotype, survival, lung morphology, inflammation markers in BAL, mucin expression, ENaC function and proSP‑C trafficking. We found that the congenital deletion of Nedd4‑2 caused a rapidly progressive lung disease in neonatal mice that shares key features with interstitial lung diseases in children (chILD), including hypoxemia, growth failure, sterile pneumonitis, fibrotic lung remodeling and high mortality. The congenital deletion of Nedd4‑2 in lung epithelial cells caused increased expression of Muc5b and mucus plugging of distal airways, increased ENaC activity and proSP-C mistrafficking. This model of congenital deletion of Nedd4‑2 may support studies of the pathogenesis and preclinical development of therapies for chILD.