Aspirin-exacerbated respiratory disease (AERD) is associated with overproduction of proinflammatory cysteinyl leukotrienes (CysLTs), defective generation of anti-inflammatory prostaglandin E2 (PGE2), ...and reduced expression of the EP2 receptor for PGE2. Reduced PGE2 synthesis results from the downregulation of inducible COX-2. Because PGE2 signaling via EP2 inhibits the 5-lipoxygenase/leukotriene C4 synthase–dependent pathway, the deficient levels of both PGE2 and EP2 likely contribute to the excessive baseline production of cysteinyl leukotrienes in patients with AERD compared with in patients with aspirin-tolerant asthma. The COX-2 pathway is regulated by an autocrine metabolic loop involving IL-1β, IL-1 receptor type I, EP2, COX-2, membrane-bound PGE2 prostaglandin E2 synthase-1, and PGE2. Previous studies reported that this metabolic loop is dysregulated in patients with AERD. When the downexpressed EP2 receptor is normalized, the entire loop returns to its normal function. Cotreatment of airway cells from healthy subjects with IL-4 and IFN-γ induces alterations in the metabolic loop similar to those seen in patients with AERD. In these patients, IL-4, which is produced in excess in airways of patients with AERD, likely contributes to the alteration of normal functioning of the autocrine metabolic loop involving IL-1β, IL-1 receptor type I, EP2, COX-2, membrane-bound PGE2 prostaglandin E2 synthase-1, and PGE2. We hypothesized that by blocking IL-4 action, dupilumab normalizes EP2 expression and restores the normal functioning of the COX-2 pathway autocrine metabolic loop, thereby normalizing the synthesis of PGE2 and restoring aspirin tolerance.
Asthma and obesity are two epidemics affecting the developed world. The relationship between obesity and both asthma and severe asthma appears to be weight-dependent, causal, partly genetic, and ...probably bidirectional. There are two distinct phenotypes: 1. Allergic asthma in children with obesity, which worsens a pre-existing asthma, and 2. An often non allergic, late-onset asthma developing as a consequence of obesity. In obesity, infiltration of adipose tissue by macrophages M1, together with an increased expression of multiple mediators that amplify and propagate inflammation, is considered as the culprit of obesity-related inflammation. Adipose tissue is an important source of adipokines, such as pro-inflammatory leptin, produced in excess in obesity, and adiponectin with anti-inflammatory effects with reduced synthesis. The inflammatory process also involves the synthesis of pro-inflammatory cytokines such as IL-1β, IL-6, TNFα, and TGFβ, which also contribute to asthma pathogenesis. In contrast, asthma pro-inflammatory cytokines such as IL-4, IL-5, IL-13, and IL-33 contribute to maintain the lean state. The resulting regulatory effects of the immunomodulatory pathways underlying both diseases have been hypothesized to be one of the mechanisms by which obesity increases asthma risk and severity. Reduction of weight by diet, exercise, or bariatric surgery reduces inflammatory activity and improves asthma and lung function.
Analytical and functional comparison is key for substantiating the level of convergence (essential sameness) or divergence between versions or variants of a given biological medicine. Accordingly, an ...overlapping biological activity between products meant to be equal probably reflects a highly similar structure and anticipates a comparable pharmacodynamic behavior. We developed an orthogonal approach to compare the human IgE binding features of different lots and versions of Xolair® (omalizumab), an anti-human IgE monoclonal antibody. The IgE binding affinity and kinetics were measured by surface plasmon resonance. Ability to prevent mast cell activity was assessed in vitro and in vivo in mast cell-based models. The variability of monoclonal antibodies with identical amino acid sequences produced either in Chinese hamster ovarian cells or in human HEK293 cells, was compared. Monoclonal antibodies from the two sources exhibited slightly different human IgE binding and neutralizing features. A known variant exhibiting a three amino acid replacement in the Fab region had lower IgE binding affinity than the original omalizumab. The lower binding affinity translated into reduced IgE neutralizing capacity and, in turn, a difference in the ability to prevent mast cell activation in vitro and in vivo. The proposed set of analytical and functional assays was sensitive enough to detect Fab-linked differences between anti-IgE antibody versions exhibiting an identical aminoacid sequence. In addition to add value to the comparative assessment of biosimilar candidates bearing omalizumab, these methods can aid pre-assessments of new anti-IgE agents that aim to improve therapeutic performance.
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•Omalizumab and omalizumab-like agents are compared for functional properties.•An innovative approach to assess binding features to human IgE has been developed.•A refined SPR protocol is suitable to determine IgE binding affinity and kinetics.•Proposed in vitro and in vivo assays are sensitive for anti-IgE function assessment.•The combined techniques are key in the context of biosimilar-to-original comparison.
Obese Asthma Syndrome: Much Work to Do Arismendi, Ebymar; Bantulà, Marina; Picado, César
Archivos de bronconeumología (English ed.),
08/2023, Volume:
59, Issue:
8
Journal Article
We hypothesized that the peculiar mixed interleukin-4 (IL-4/Th2) and interferon gamma INF-γ (INF-γ/Th1) inflammatory milieu found in the airways of patients with aspirin-exacerbated respiratory ...disease (AERD) is responsible for the altered regulation of the IL-1β/IL-1RI-/EP2/COX-2 autocrine loop also found in these patients. The objective of the study is to demonstrate that IL-4 and INF-γ cytokines, are capable of inducing in healthy nasal mucosa (NM) the dysregulation of the autocrine loop of COX reported in AERD.
Fibroblasts were obtained from NM (n = 8). To evaluate the role of IL-4 and IFN-γ on the autocrine loop, fibroblasts were incubated with or without IL-1β, in the presence or absence of IL-4 and/or IFN-γ for 48 h. After this period, the expression of EP2, EP3, EP4, IL-1RI, COX-2 and mPGES-1 was measured by Western blot.
Stimulation of fibroblasts with IL-1β significantly increased the expression of EP2, but had no effects on EP3 and EP4 expression Incubation with IL-4 or IFN-γ alone was not able to modify the expression of any of the components of the autocrine loop. In contrast, co-treatment with IL-4 and IFN-γ was able to significantly inhibit IL-1β-induced EP2, IL-1RI, COX-2 and mPGES-1.
These results suggest that the mixed Th1/Th2 inflammatory pattern found in the airways of AERD patients might be responsible for the altered regulation of the COX pathway also reported in these asthma patients.
•Cyclooxygenase 2 is down-expressed in aspirin exacerbated respiratory disease (AERD).•Low expression of EP2 is involved in the altered regulation of COX-2 in AERD.•AERD is characterized by a peculiar mixed interleukin-4(Th2)/INF-γ (Th1) inflammation.•We hypothesized that this inflammation is involved in EP2 and COX-2 alteration in AERD.•The study shows that IL-4/INF-γ down-regulate EP2/COX-2 in nasal mucosa mimicking AERD.
•Clinical studies showed that PGE2 may exert a protective effect in asthmatics.•EP receptors and available agonists are of therapeutic interest.•PGE2 attenuates mast cell activity in vitro and in ...vivo through EP2 agonism.•EP2-mediated mast cell restraining explains the PGE2-driven reduced airway damage.•Understanding the PGE2–EP2–mast cell axis may uncover antiasthma targets.
Despite the fact that cyclooxygenase and its products, prostaglandins, have been traditionally associated with the development of inflammation, PGE2 was implicated early on as potentially beneficial in asthma. During the 1970s and 1980s, several studies reported the bronchodilator effect of PGE2 in asthma patients. In parallel, it was being shown to exert an inhibitory effect on mast cells in vitro. In spite of this, data supporting the beneficial role for PGE2 in asthma were scarce and sometimes controversial.
Many years later, in vitro and in vivo studies suggested a range of biological activities attributable to PGE2, others than the ability to relax smooth muscle, that potentially explained some of the observed positive effects in asthma. The identification and cloning of the four PGE2 receptors made available new tools with which to fine-tune investigation of the anti-inflammatory, pro-inflammatory, immunoregulatory, and bronchodilation mechanisms of PGE2. Among these, several suggested involvement of mast cells, a cell population known to play a fundamental role in acute and chronic asthma. Indeed, it has been shown that PGE2 prevents human and murine MC activity in vitro through activation of the EP2 receptor, and also that both exogenously administered and endogenous PGE2 inhibit airway MC activity in vivo in mouse models of asthma (likely through an EP2-mediated mechanism as well). In the last few years, we have furthered into the functional connection between PGE2-induced mast cells inhibition and attenuated damage, in asthma and allergy models. The validity of the findings supporting a beneficial effect of PGE2 in different asthma phases, the direct effect of PGE2 on mast cells populations, and the functional implications of the PGE2–MC interaction on airway function are some of the topics addressed in this review, under the assumption that increased understanding of the PGE2–EP2–mast cell axis will likely lead to the discovery of novel antiasthma targets.
Purpose of the Review
The classic treatment of non-steroidal anti-inflammatory drug (NSAID) exacerbated respiratory disease (NERD) includes aspirin desensitization (AD). Introduction of biologics in ...the treatment of asthma and chronic rhinosinusitis with nasal polyps (CRSwNP) has raised the question: which of the two options may be the most suitable for NERD?
Recent Findings
NERD is a highly eosinophilic disease. Monoclonal antibodies targeting IL-5 or the IL-5 receptor, involved in eosinophil recruitment, have been shown to be effective in asthma and CRSwNP. However, no difference in clinical efficacy was observed between NERD and aspirin-tolerant patients. Dupilumab, an IL-4 alpha receptor antagonist, demonstrated greater efficacy in NERD than in aspirin-tolerant patients for some clinical symptoms in a sub-analysis. Patients with NERD respond very rapidly to omalizumab with improvement in asthma and CRSwNP symptoms associated with reductions in prostaglandin D2 and cysteinyl leukotrienes release. Furthermore, omalizumab and dupilumab partially or totally restored tolerance to aspirin in NERD patients.
Summary
The decision to treat a NERD patient with AD or a biologic depends on many variables, such as differences between countries in the use of AD treatment in specialized units, limitations in accessing very expensive treatment in low-income countries and in countries where insurance systems do not cover or partially cover the cost of treatment. Patients who live in countries with public health systems that fully fund biologic treatments are more likely to benefit from biologic treatment. The limited data available so far suggest that, among current biologics, dupilumab ranks best for the treatment of CRSwNP associated with NERD.
The presence of aspirin-exacerbated respiratory disease (AERD) in a patient with chronic rhinosinusitis with nasal polyps and asthma is associated with severe eosinophilic upper and lower airway ...disease. This article deals with the inflammatory disease of the respiratory tract as it relates to the sinuses. Involvement of the sinuses in AERD is almost universal, depending on the stage of onset of the disease and evaluation by computed tomography. This article explores the clinical aspects, physiopathology, and treatment of rhinosinusitis as it relates to AERD.
An adverse role for obstructive sleep apnea (OSA) in cancer epidemiology and outcomes has recently emerged from clinical and animal studies. In animals, intermittent hypoxia (IH) mimicking OSA ...promotes tumor malignancy both directly and via host immune alterations. We hypothesized that IH could potentiate cancer aggressiveness through activation of the cyclooxygenase-2 (COX-2) pathway and the concomitant increases in prostaglandin E2 (PGE
). The contribution of the COX-2 in IH-induced enhanced tumor malignancy was assessed using celecoxib as a COX-2 specific inhibitor in a murine model of OSA bearing Lewis lung carcinoma (LLC1) tumors. Exposures to IH accelerated tumor progression with a tumor associated macrophages (TAMs) shift towards a pro-tumoral M2 phenotype. Treatment with celecoxib prevented IH-induced adverse tumor outcomes by inhibiting IH-induced M2 polarization of TAMs. Furthermore, TAMs isolated from IH-exposed mice treated with celecoxib reduced the proliferation of LLC1 naïve cells, while the opposite occurred with placebo-treated IH-exposed mice. Finally, in vitro IH exposures of murine macrophages and LLC1 cells showed that both cell types increased PGE
release in response to IH. These results suggest a crucial role for the COX-2 signaling pathway in the IH-exacerbated malignant processes, and designate macrophages and lung adenocarcinoma cells, as potential sources of PGE
.
Primary human airway epithelial cells cultured in an air-liquid interface (ALI) develop a well-differentiated epithelium. However, neither characterization of mucociliar differentiation overtime nor ...the inflammatory function of reconstituted nasal polyp (NP) epithelia have been described.
1st) To develop and characterize the mucociliar differentiation overtime of human epithelial cells of chronic rhinosinusitis with nasal polyps (CRSwNP) in ALI culture system; 2nd) To corroborate that 3D in vitro model of NP reconstituted epithelium maintains, compared to control nasal mucosa (NM), an inflammatory function.
Epithelial cells were obtained from 9 NP and 7 control NM, and differentiated in ALI culture for 28 days. Mucociliary differentiation was characterized at different times (0, 7, 14, 21, and 28 days) using ultrastructure analysis by electron microscopy; ΔNp63 (basal stem/progenitor cell), β-tubulin IV (cilia), and MUC5AC (goblet cell) expression by immunocytochemistry; and mucous (MUC5AC, MUC5B) and serous (Lactoferrin) secretion by ELISA. Inflammatory function of ALI cultures (at days 0, 14, and 28) through cytokine (IL-8, IL-1β, IL-6, IL-10, TNF-α, and IL-12p70) and chemokine (RANTES, MIG, MCP-1, IP-10, eotaxin-1, and GM-CSF) production was analysed by CBA (Cytometric Bead Array).
In both NP and control NM ALI cultures, pseudostratified epithelium with ciliated, mucus-secreting, and basal cells were observed by electron microscopy at days 14 and 28. Displaying epithelial cell re-differentation, β-tubulin IV and MUC5AC positive cells increased, while ΔNp63 positive cells decreased overtime. No significant differences were found overtime in MUC5AC, MUC5B, and lactoferrin secretions between both ALI cultures. IL-8 and GM-CSF were significantly increased in NP compared to control NM regenerated epithelia.
Reconstituted epithelia from human NP epithelial cells cultured in ALI system provides a 3D in vitro model that could be useful both for studying the role of epithelium in CRSwNP while developing new therapeutic strategies, including cell therapy, for CRSwNP.
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