Introduction: Asthma and chronic obstructive pulmonary disease (COPD) display features of overlap in airway physiology and airway inflammation. The relationship between mediator expression and airway inflammation was explored within these airway diseases. Methods: Patients with asthma (54 patients: 21 men) and COPD (49 patients: 36 men) were studied. Clinical characteristics and sputum was collected at entry into the study. A two-step sputum processing method was performed for supernatant and cytospin preparation. The Meso Scale Discovery and Luminex platforms were used to measure cytokines, chemokines and matrix metalloproteinase levels. Results: Analytes sensitive to dithiothreitol (DTT) that had increased recovery in the two step sputum process were IL-1b, 4, 5, 10, 13, IFN-g, TNFRI, GM-CSF, CCL2, 3, 4, 5, 13 and 17. There was a differential expression in IL-8, TNFRI and TNFRII between asthma and COPD (mean fold difference (95% confidence interval) IL-8, 2.6 (1.3 to 5.4), p=0.01; TNFRI, 2.1 (1.3 to 5.4), p=0.03; and TNFRII, 2.6 (1.2 to 5.6), p=0.02). In neutrophilic and eosinophilic airway inflammation, TNFα, TNFRI, TNFRII, IL-6, IL-8 and IL-5 could differentiate between these phenotypes. However, these phenotypes were unrelated to the diagnosis of asthma or COPD. Conclusion: Recovery of sputum mediators sensitive to DTT can be improved using a new sputum processing technique. Within airway inflammatory sub-phenotypes there is a differential pattern of mediator expression that is independent of disease. Whether these inflammatory phenotypes in asthma and COPD confer distinct pathogenesis, therapeutic responses and clinical phenotypes needs to be further evaluated.

Profiling of sputum inflammatory mediators in asthma and chronic obstructive pulmonary disease

IL-33/ST2 Pathway as a Rational Therapeutic Target for CNS Diseases.

The effective approach to discover innovative drugs will ask natural products for answers because of their complex and changeable structures and multiple biological activities. Inhibitory kappa B kinase beta (IKKβ), known as IKK2, is a key regulatory kinase responsible for the activation of NF-κB through its phosphorylation at Ser177 and Ser181 to promote the phosphorylation of inhibitors of kappa B (IκBs), triggering their ubiquitination and degradation to active the nuclear factor kappa-B (NF-κB) cascade. Chemical inhibition of IKKβ or its genetic knockout has become an effective method to block NF-κB-mediated proliferation and migration of tumor cells and inflammatory response. In this review, we summarized the structural feature and transduction mechanism of IKKβ and the discovery of inhibitors from natural resources (e.g. sesquiterpenoids, diterpenoids, triterpenoids, flavonoids, and alkaloids) and chemical synthesis (e.g. pyrimidines, pyridines, pyrazines, quinoxalines, thiophenes, and thiazolidines). In addition, the biosynthetic pathway of novel natural IKKβ inhibitors and their biological potentials were discussed. This review will provide inspiration for the structural modification of IKKβ inhibitors based on the skeleton of natural products or chemical synthesis and further phytochemistry investigations.

IκB kinase β (IKKβ): Structure, transduction mechanism, biological function, and discovery of its inhibitors.

Recombinant IL-33 prolongs leflunomide-mediated graft survival by reducing IFN- γ and expanding CD4 + Foxp3 + T cells in concordant heart transplantation

Interleukin (IL)-33 plays important roles in pulmonary immune responses and lung diseases including asthma and chronic obstructive pulmonary disease (COPD). There is substantial interest in identifying and characterizing cellular sources vs. targets of IL-33, and downstream signaling pathways involved in disease pathophysiology. While epithelial and immune cells have largely been the focus, in this review, we summarize current knowledge of expression, induction, and function of IL-33 and its receptor ST2 in non-hematopoietic lung cells in the context of health and disease. Under basal conditions, epithelial cells and endothelial cells are thought to be the primary resident cell types that express high levels of IL-33 and serve as ligand sources compared to mesenchymal cells (smooth muscle cells and fibroblasts). Under inflammatory conditions, IL-33 expression is increased in most non-hematopoietic lung cells, including epithelial, endothelial, and mesenchymal cells. In comparison to its ligand, the receptor ST2 shows low expression levels at baseline but similar to IL-33, ST2 expression is upregulated by inflammation in these non-hematopoietic lung cells which may then participate in chronic inflammation both as sources and autocrine/paracrine targets of IL-33. Downstream effects of IL-33 may occur via direct receptor activation or indirect interactions with the immune system, overall contributing to lung inflammation, airway hyper-responsiveness and remodeling (proliferation and fibrosis). Accordingly from a therapeutic perspective, targeting IL-33 and/or its receptor in non-hematopoietic lung cells becomes relevant.

/pdf/contributions-of-il-33-in-non-hematopoietic-lung-cells-to-28wqtt1cvg.pdf

Contributions of IL-33 in Non-hematopoietic Lung Cells to Obstructive Lung Disease.

Dach1 Deficiency Drives Alveolar Epithelium Apoptosis in Pulmonary Fibrosis via Modulating C-Jun/Bim Activity.

Background: Although it is recognized that IL-33 plays a key role in the onset of asthma, it is currently unclear whether IL-33 acts on any other target cells besides mast cells and Th2 cells in asthma. We investigated that whether airway smooth muscle cells (ASMCs) could contribute to asthma via stimulation with IL-33 . Methods: To create a mouse model of acute asthma , murine ASMCs were isolated and cultured in vitro with IL-33. The ASMCs were divided into two groups, ASMCs from normal mice and ASMCs from ovalbumin-se n sitized mice. The release of mouse KC was analyzed by PCR and ELISA. I mmuno cy tochemical Staining of murine ASMCs for ST2 and IL-1RAcP was performed. Results: IL-33 promote d KC expression, both in terms of mRNA and protien levels,  in ASMCs from ovalbumin-se n sitized mice . ST2 and IL-1RAcP were expressed in the membrane of ASMCs in ovalbumin-se n sitized mice . Conclusion: IL-33 may contribute to the inflammation in the airways by acting on airway smooth muscle cells. IL-33 and ST2 may play important roles in allergic bronchial asthma.

IL-33 promotes mouse KC, an IL-8 homologue, expression in airway smooth muscle cells in ovalbumin-sensitized mice

Abstract 
 Objective:
 Club cell 10-kDa protein (CC10) is a documented biomarker for airway obstructive diseases. Primarily produced by nonciliated club cells in the distal airway and in nasal epithelial cells, CC10 suppresses Th2 cell differentiation and Th2 cytokine production. In this study, we aimed to determine whether CC10 can also be used as an alternative biomarker for identifying Type 2 (T2) asthma. 
 Methods:
 74 patients with asthma, and 24 healthy controls were enrolled in the study. T2-high asthma was defined as elevation in two or more biomarkers, such as sputum eosinophilia ≥ 3%, high blood eosinophils ≥ 300/µL, or high FeNO ≥ 30 ppb. T2-low asthma was defined as no elevation in biomarkers. Enzyme-linked immunosorbent assay (ELISA) was used to assess the CC10 levels in plasma. 
 Results:
 The plasma CC10 level in patients with T2-high asthma was lower than that of patients with T2-low asthma and healthy controls (P < 0.05). To distinguish between T2-high and T2-low phenotype in patients with asthma, a receiver-operating characteristic (ROC) analysis was performed. It showed a sensitivity of 58.1% and specificity of 78.0% when using 22.74 ng/ml of plasma CC10. Correlation analysis indicated that the plasma CC10 level was inversely correlated with sputum eosinophil, blood eosinophil, and FeNO, and positively correlated with log PD20. However, no correlation with sputum neutrophil percentages, macrophage percentages, IgE, or lung function was found. 
 Conclusions:
 Plasma CC10 is potentially useful in predicting T2-high and T2-low asthma. Lower plasma CC10 was associated with enhanced airway hyperresponsiveness, and Type 2 inflammation.

Club cell 10-kDa protein (CC10) as a surrogate for identifying type 2 asthma phenotypes

BACKGROUND Allergic asthma is a chronic airway inflammatory disease partly characterised by high concentration of T help 2 (Th2) cytokines in bronchoalveolar lavage fluid (BALF). There is no report on the relation of peripherally circulating blood lymphocytes and asthma. We explored the balance of Th2/Th1 cytokines in asthmatic mice. Exogenous recombinant interleukin (IL) 33 acted on murine peripheral circulating blood lymphocytes, IL-5 cytokine was selected for assessing Th2 cytokines and interferon-gamma (IFN-γ) for Th1 cytokines. METHODS Female specific pathogen free BABL/c mice were sensitised by intraperitoneal injection of 20 µg of ovalbumin emulsified in 1 mg of aluminium hydroxide gel in a total volume of 200 µl, and challenged for 30 minutes in 7 consecutive days with an aerosol of 2 g ovalbumin in 100 ml of PBS. Then we collected BALF and isolated lymphocytes from the peripheral blood. The lymphocytes were divided into two groups: asthmatic group and normal group. Th1/Th2 cytokines was detected by enzyme-linked immunosorbent assay (ELISA) kits. RESULTS In the asthma group, we found numerous eosinophils and lymphocytes on the glass slides. We then confirmed that the optimal concentration of IL-33 was 10 ng/ml and time of IL-33 stimulating lymphocytes was 24 hours. In the asthma group, the production of IL-5 was significantly increased over normal group after stimulation with IL-33 (P < 0.05) and the production of IFNγ was supressed from IL-33 stimulated lymphocytes (P < 0.05). CONCLUSION IL-33 acts on lymphocytes of peripheral blood increasing secretion of Th2 cytokines and inhibiting secretion of Th1 cytokines.

Effect of interleukin-33 on Th1/Th2 cytokine ratio in peripheral lymphocytes in asthmatic mice.

Patients with eosinophilic asthma react well to conventional treatment of asthma while individualized therapy for non-eosinophilic endotypes have yet to be developed. Dysregulated sphingosine metabolites are associated with the pathophysiology of different asthma endotypes with their receptors involved. However, whether the sphingosine-1-phosphate receptor 4 (S1PR4) contributes to disease progression of asthma remains underappreciated. In this study, we demonstrated that sphingosine metabolism was disturbed in asthma while it could not be used to distinguish between different endotypes of asthma. S1PR4, a vital receptor of bioactive sphingosine metabolites and mainly expressed in macrophages, exhibited lower expression both in patients and experimental mice with neutrophilic airway inflammation. Additionally, S1pr4 deficiency aggravated the OVA/LPS-induced pulmonary inflammation in mice along with a significant up-regulation in M1 macrophage activation. Mechanistic studies showed that S1PR4 was strongly connected to bioactive oxylipins concurrent with bounding to formyl peptide receptor 2 to influence the phosphorylation of JNK and contributed to the macrophage M1 program, which in turn secreted amounts of inflammatory cytokines associated to the inflammatory response of neutrophilic asthma. Furthermore, treating mice with S1PR4 agonist CYM50308 was characterized by less pulmonary inflammatory infiltration. Our research indicates S1PR4 a promising therapeutic target for non-eosinophilic phenotypes of asthma.

/pdf/sphingosine-1-phosphate-receptor-4-attenuates-neutrophilic-2gv44qlh.pdf

Sphingosine-1-Phosphate Receptor 4 Attenuates Neutrophilic Airway Inflammation in Experimental Asthma via Repressing Proinflammatory Macrophage Activation

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