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1.  S-Nitrosoglutathione Reductase Inhibition Regulates Allergen-Induced Lung Inflammation and Airway Hyperreactivity 
PLoS ONE  2013;8(7):e70351.
Allergic asthma is characterized by Th2 type inflammation, leading to airway hyperresponsivenes, mucus hypersecretion and tissue remodeling. S-Nitrosoglutathione reductase (GSNOR) is an alcohol dehydrogenase involved in the regulation of intracellular levels of S-nitrosothiols. GSNOR activity has been shown to be elevated in human asthmatic lungs, resulting in diminished S-nitrosothiols and thus contributing to increased airway hyperreactivity. Using a mouse model of allergic airway inflammation, we report that intranasal administration of a new selective inhibitor of GSNOR, SPL-334, caused a marked reduction in airway hyperreactivity, allergen-specific T cells and eosinophil accumulation, and mucus production in the lungs in response to allergen inhalation. Moreover, SPL-334 treatment resulted in a significant decrease in the production of the Th2 cytokines IL-5 and IL-13 and the level of the chemokine CCL11 (eotaxin-1) in the airways. Collectively, these observations reveal that GSNOR inhibitors are effective not only in reducing airway hyperresponsiveness but also in limiting lung inflammatory responses mediated by CD4+ Th2 cells. These findings suggest that the inhibition of GSNOR may provide a novel therapeutic approach for the treatment of allergic airway inflammation.
PMCID: PMC3723687  PMID: 23936192
2.  Prostaglandin I2 promotes the development of IL-17-producing γδ T cells that associate with the epithelium during allergic lung inflammation 
γδ T cells rapidly produce cytokines and represent a first line of defence against microbes and other environmental insults at mucosal tissues and are thus thought to play a local immunoregulatory role. We show that allergic airway inflammation was associated with an increase in innate IL-17-producing γδ T (γδ-17) cells that expressed the αEβ7 integrin and were closely associated with the airway epithelium. Importantly, prostaglandin (PG)I2 and its receptor IP, which downregulated airway eosinophilic inflammation, promoted the emergence of these intraepithelial γδ-17 cells into the airways by enhancing IL-6 production by lung eosinophils and dendritic cells. Accordingly, a pronounced reduction of γδ-17 cells was observed in the thymus of naïve mice lacking the PGI2 receptor IP, as well as in the lungs during allergic inflammation, implying a critical role for PGI2 in the programming of “natural” γδ-17 cells. Conversely, iloprost, a stable analog of PGI2, augmented IL-17 production by γδ T cells but significantly reduced the airway inflammation. Together, these findings suggest that PGI2 plays a key immunoregulatory role by promoting the development of innate intraepithelial γδ-17 cells through an IL-6-dependent mechanism. By enhancing γδ-17 cell responses, stable analogs of PGI2 may be exploited in the development of new immunotherapeutic approaches.
PMCID: PMC3208053  PMID: 21976777
Lung; inflammation; Th2 cells; γδ T cells; IL-17
3.  Design and Evaluation of a novel Fluorescent CB2 Ligand as Probe for Receptor Visualization in Immune Cells 
Cannabinoid CB2 receptor has emerged as a very promising target over the last decades. We have synthesized and evaluated a new fluorescent probe designated NMP6 based on 6-methoxyisatin scaffold, which exhibited selectivity and Ki value at hCB2 of 387 nM. We have demonstrated its ability to be an effective probe for visualization of CB2 receptor binding using confocal microscopy and a flow cytometry probe for the analysis of CB2 protein expression. Furthermore, NMP6 was easily obtained in two chemical steps from commercially available building blocks.
PMCID: PMC3171627  PMID: 21855337
4.  Crocidolite Induces Prostaglandin I2 Release Mediated by Vitronectin Receptor and Cyclooxygenase-2 in Lung Cells 
Lung  2010;188(2):133-141.
Interstitial lung disease (ILD) produces disruption of alveolar walls with loss of functionality and scar tissue accumulation. Asbestosis is the ILD produced by the inhalation of asbestos fibers. This study attempts to elucidate the role of lung epithelial cells in the generation of asbestos-induced ILD. When exposed to crocidolite LA-4 cells had a decrease in viability and an increase in the release of lactate dehydrogenase (LDH) and 6-keto PGF1α, a PGI2 metabolite. PGI2 release was mediated by cyclo-oxygenase-2 (COX-2) and vitronectin receptor (VNR). When LA-4 cells were treated with VNR inhibitors, either RGD (Arg-Gly-Asp) peptide or VNR blocking antibody, a statistically significant decrease in PGI2 metabolite production was observed, but crocidolite-induced cytotoxicity was not prevented. These findings propose that crocidolite is coated by an RGD protein and binds VNR-inducing COX-2 expression and PGI2 release. Moreover, when LA-4 cells were exposed to crocidolite in the presence of reduced serum culture media, PGI2 production was prevented, and when bronchoalveolar lavage fluid (BALF) was added, PGI2 production was rescued. Cytotoxicity did not occur, either in reduced serum culture media or when BALF was added. In conclusion, crocidolite requires the presence of an RGD protein coating the fibers to induce inflammation (PGI2 production) and crocidolite alone cannot induce cytotoxicity in lung cells.
PMCID: PMC2862624  PMID: 20155273
Crocidolite; Pulmonary fibrosis; Cyclooxygenase 2; Prostaglandin I2; Vitronectin receptor
5.  Antigen-specific Treg regulate Th17-mediated lung neutrophilic inflammation, B cell recruitment and polymeric IgA and IgM levels in the airways 
European journal of immunology  2009;39(12):3307-3314.
Th17 cells play key roles in mediating autoimmunity, inflammation and mucosal host defense against pathogens. To determine whether naturally occurring Treg (nTreg) limit Th17-mediated pulmonary inflammation, OVA-specific CD4+ Th17 cells and expanded CD4+CD25+Foxp3+ nTreg were cotransferred into BALB/c mice that were then exposed to OVA aerosols. Th17 cells, when transferred alone, accumulated in the lungs and posterior mediastinal LN and evoked a pronounced airway hyperreactivity (AHR) and neutrophilic inflammation, characterized by B cell recruitment and elevated IgA and IgM levels. Cotransfer of antigen-specific nTreg markedly reduced the Th17-induced pulmonary inflammation and associated neutrophilia, B cell influx and polymeric Ig levels in the airways, but did not inhibit AHR. Moreover, the regulation appeared restricted to the site of mucosal inflammation, since transfer of nTreg did not affect the Th17 response developing in the lung draining LN, as evidenced by unaltered levels of IL-17 production and low numbers of Foxp3+ Treg. Our findings suggest a crucial role for Th17 cells in mediating airway B cell influx and IgA response and demonstrate that antigen-specific nTreg suppress Th17-mediated lung inflammation. These results provide new insights into how Th17 responses are limited and may facilitate development of novel approaches for controlling Th17-induced inflammation.
PMCID: PMC2849980  PMID: 19830731
Th17 cells; regulatory T cells; B cells; lung inflammation; regulation
6.  Cutting Edge: Lung mucosal Th17-mediated responses induce polymeric immunoglobulin receptor expression by the airway epithelium and elevate secretory IgA levels1 
Polymeric immunoglobulin receptor (pIgR) is a central player in mucosal immunity that mediates delivery of polymeric IgA and IgM to the apical surface of epithelial cells via transcytosis. Emerging evidence suggests that Th17 cells, not only mediate autoimmunity, but also play key roles in mucosal host defense against pathogens. We demonstrate that OVA-specific CD4+ Th17 cells, in addition to causing neutrophilic inflammation in mice, mediated a pronounced influx of CD19+ B cells into the lungs following antigen inhalation. Coincident with this recruitment, was a striking induction in pIgR expression by the bronchial epithelium and subsequent increase in airway IgM and secretory IgA levels. Intranasal administration of IL-17 revealed a crucial role for this cytokine in inducing pIgR expression by the epithelium. These findings support a key role for Th17 cells in pulmonary immune defense against respiratory pathogens by promoting pIgR-mediated transport of secretory IgA and IgM into the airway.
PMCID: PMC2740792  PMID: 19342622
T cells; inflammation; lung; mucosa; rodent
7.  IL-4 increases type 2, but not type 1, cytokine production in CD8+ T cells from mild atopic asthmatics 
Respiratory Research  2005;6(1):67.
Virus infections are the major cause of asthma exacerbations. CD8+ T cells have an important role in antiviral immune responses and animal studies suggest a role for CD8+ T cells in the pathogenesis of virus-induced asthma exacerbations. We have previously shown that the presence of IL-4 during stimulation increases the frequency of IL-5-positive cells and CD30 surface staining in CD8+ T cells from healthy, normal subjects. In this study, we investigated whether excess IL-4 during repeated TCR/CD3 stimulation of CD8+ T cells from atopic asthmatic subjects alters the balance of type 1/type 2 cytokine production in favour of the latter.
Peripheral blood CD8+ T cells from mild atopic asthmatic subjects were stimulated in vitro with anti-CD3 and IL-2 ± excess IL-4 and the expression of activation and adhesion molecules and type 1 and type 2 cytokine production were assessed.
Surface expression of very late antigen-4 [VLA-4] and LFA-1 was decreased and the production of the type 2 cytokines IL-5 and IL-13 was augmented by the presence of IL-4 during stimulation of CD8+ T cells from mild atopic asthmatics.
These data suggest that during a respiratory virus infection activated CD8+ T cells from asthmatic subjects may produce excess type 2 cytokines and may contribute to asthma exacerbation by augmenting allergic inflammation.
PMCID: PMC1198257  PMID: 16001979

Results 1-7 (7)