Psoriatic inflammation enhances allergic airway inflammation through IL-23/STAT3 signaling in a murine model.

PubMed

Nadeem, Ahmed; Al-Harbi, Naif O; Ansari, Mushtaq A; Al-Harbi, Mohammed M; El-Sherbeeny, Ahmed M; Zoheir, Khairy M A; Attia, Sabry M; Hafez, Mohamed M; Al-Shabanah, Othman A; Ahmad, Sheikh F

2017-01-15

Psoriasis is an autoimmune inflammatory skin disease characterized by activated IL-23/STAT3/Th17 axis. Recently psoriatic inflammation has been shown to be associated with asthma. However, no study has previously explored how psoriatic inflammation affects airway inflammation. Therefore, this study investigated the effect of imiquimod (IMQ)-induced psoriatic inflammation on cockroach extract (CE)-induced airway inflammation in murine models. Mice were subjected to topical and intranasal administration of IMQ and CE to develop psoriatic and airway inflammation respectively. Various analyses in lung/spleen related to inflammation, Th17/Th2/Th1 cell immune responses, and their signature cytokines/transcription factors were carried out. Psoriatic inflammation in allergic mice was associated with increased airway inflammation with concurrent increase in Th2/Th17 cells/signature cytokines/transcription factors. Splenic CD4+ T and CD11c+ dendritic cells in psoriatic mice had increased STAT3/RORC and IL-23 mRNA expression respectively. This led us to explore the effect of systemic IL-23/STAT3 signaling on airway inflammation. Topical application of STA-21, a small molecule STAT3 inhibitor significantly reduced airway inflammation in allergic mice having psoriatic inflammation. On the other hand, adoptive transfer of IL-23-treated splenic CD4+ T cells from allergic mice into naive recipient mice produced mixed neutrophilic/eosinophilic airway inflammation similar to allergic mice with psoriatic inflammation. Our data suggest that systemic IL-23/STAT3 axis is responsible for enhanced airway inflammation during psoriasis. The current study also suggests that only anti-asthma therapy may not be sufficient to alleviate airway inflammatory burden in asthmatics with psoriasis. Copyright © 2016 Elsevier Inc. All rights reserved.

Emerging mechanisms and novel targets in allergic inflammation and asthma.

PubMed

Weiss, Scott T

2017-12-04

Airway inflammation is key to the severity and persistence of asthma. Recent studies have revealed novel immune mechanisms that target dendritic cells, T helper 2 cytokines, regulatory T cells, and type 2 innate lymphoid cells in allergic inflammation, as well as novel approaches that target airway smooth muscle in asthma. These advances inform the development of new targeted treatments for allergic inflammation and asthma with the potential to provide therapeutic benefit.

A pathophysiological role of PDE3 in allergic airway inflammation

PubMed Central

Beute, Jan; Lukkes, Melanie; Koekoek, Ewout P.; Nastiti, Hedwika; Ganesh, Keerthana; de Bruijn, Marjolein J.W.; Hockman, Steve; van Nimwegen, Menno; Braunstahl, Gert-Jan; Boon, Louis; Lambrecht, Bart N.; Manganiello, Vince C.; Hendriks, Rudi W.

2018-01-01

Phosphodiesterase 3 (PDE3) and PDE4 regulate levels of cyclic AMP, which are critical in various cell types involved in allergic airway inflammation. Although PDE4 inhibition attenuates allergic airway inflammation, reported side effects preclude its application as an antiasthma drug in humans. Case reports showed that enoximone, which is a smooth muscle relaxant that inhibits PDE3, is beneficial and lifesaving in status asthmaticus and is well tolerated. However, clinical observations also showed antiinflammatory effects of PDE3 inhibition. In this study, we investigated the role of PDE3 in a house dust mite–driven (HDM-driven) allergic airway inflammation (AAI) model that is characterized by T helper 2 cell activation, eosinophilia, and reduced mucosal barrier function. Compared with wild-type (WT) littermates, mice with a targeted deletion of the PDE3A or PDE3B gene showed significantly reduced HDM-driven AAI. Therapeutic intervention in WT mice showed that all hallmarks of HDM-driven AAI were abrogated by the PDE3 inhibitors enoximone and milrinone. Importantly, we found that enoximone also reduced the upregulation of the CD11b integrin on mouse and human eosinophils in vitro, which is crucial for their recruitment during allergic inflammation. This study provides evidence for a hitherto unknown antiinflammatory role of PDE3 inhibition in allergic airway inflammation and offers a potentially novel treatment approach. PMID:29367458

Ovalbumin-induced allergic inflammation lead to structural alterations in mouse model and protective effects of intranasal curcumin: A comparative study.

PubMed

Subhashini; Chauhan, P S; Singh, R

2016-01-01

Antigen exposure and persistent inflammation leads to structural changes in the asthmatic airways which are collectively termed as "airway remodelling". Presently available asthma medications ameliorate inflammations but are unable to prevent or reverse the airway remodelling process as most of the treatment strategies are only focused on inflammation instead of remodelling. Curcumin, a phytochemical present in the rhizome of Curcuma longa is well known for its anti-inflammatory activity; however, the main drawback is its poor bioavailability which limits its therapeutic approval. So, the effect of nasal curcumin on acute and chronic asthma has been studied where short exposure to ovalbumin (4 days) represents acute phase whereas repeated exposures for longer (twice per week till 5 weeks) represents chronic asthma. Disodium cromoglycate (DSCG, 50mg/kg, i.p.) and dexamethasone (1mg/kg, i.p.) were used as standard drugs in acute and chronic model of asthma respectively. OVA-induced airway inflammation initiated in acute stage led to remodelling due to persistent inflammation, epithelial and sub epithelial thickening (smooth muscle thickening), extracellular matrix (ECM) deposition, goblet cell hyperplasia and mucus plug formation. Intranasal curcumin is effective in inhibiting airway inflammation and remodelling both by maintaining the structural integrity of lungs in terms of inflammation, airway wall thickening and mucus production. Our findings suggest that curcumin administered through nasal route might prove therapeutically efficient in inhibiting allergic airway inflammations and maintaining structural integrity in the mouse model of allergic asthma. This may lead to the development of curcumin aerosol in near future. Copyright © 2016 SEICAP. Published by Elsevier Espana. All rights reserved.

Silibinin attenuates allergic airway inflammation in mice

DOE Office of Scientific and Technical Information (OSTI.GOV)

Choi, Yun Ho; Jin, Guang Yu; Guo, Hui Shu

Highlights: Black-Right-Pointing-Pointer Silibinin diminishes ovalbumin-induced inflammatory reactions in the mouse lung. Black-Right-Pointing-Pointer Silibinin reduces the levels of various cytokines into the lung of allergic mice. Black-Right-Pointing-Pointer Silibinin prevents the development of airway hyperresponsiveness in allergic mice. Black-Right-Pointing-Pointer Silibinin suppresses NF-{kappa}B transcriptional activity. -- Abstract: Allergic asthma is a chronic inflammatory disease regulated by coordination of T-helper2 (Th2) type cytokines and inflammatory signal molecules. Silibinin is one of the main flavonoids produced by milk thistle, which is reported to inhibit the inflammatory response by suppressing the nuclear factor-kappa B (NF-{kappa}B) pathway. Because NF-{kappa}B activation plays a pivotal role in the pathogenesismore » of allergic inflammation, we have investigated the effect of silibinin on a mouse ovalbumin (OVA)-induced asthma model. Airway hyperresponsiveness, cytokines levels, and eosinophilic infiltration were analyzed in bronchoalveolar lavage fluid and lung tissue. Pretreatment of silibinin significantly inhibited airway inflammatory cell recruitment and peribronchiolar inflammation and reduced the production of various cytokines in bronchoalveolar fluid. In addition, silibinin prevented the development of airway hyperresponsiveness and attenuated the OVA challenge-induced NF-{kappa}B activation. These findings indicate that silibinin protects against OVA-induced airway inflammation, at least in part via downregulation of NF-{kappa}B activity. Our data support the utility of silibinin as a potential medicine for the treatment of asthma.« less

Coumarins from the roots of Angelica dahurica cause anti-allergic inflammation

PubMed Central

Li, Dong; Wu, Li

2017-01-01

Allergic inflammation is induced by allergens and leads to various allergic diseases, including rhinitis, asthma and conjunctivitis. Histamine is important in the pathogenesis of an immunoglobulin E-dependent allergic reaction and results in the secretion of cytokines associated with inflammation. Angelica dahurica (A. dahurica) is a medicinal plant widely used in China for the treatment of symptoms related to allergic inflammation. The present study investigated the chemical constituents from A. dahurica and evaluated their reductive effect on allergic inflammation. As a result, 15 compounds including 13 coumarins have been identified as isoimperatorin (1), imperatorin (2), oxypeucedanin (3), oxypeucedanin hydrate (4), bergapten (5), byakangelicin (6), phellopterin (7), byakangelicol (8), isopimpinellin (9), xanthotoxol (10), xanthotoxin (11), pimpinellin (12), scopoletin (13), β-sitosterol (14) and daucosterol (15). Compounds 1–13 were able to reduce the release of histamine, with compounds 4–6 exhibiting the most potent activity. Furthermore, compounds 1–12 were able to inhibit the secretion of tumor necrosis factor-α, interleukin (IL)-1β and IL-4, with compounds 5 and 7 exhibiting the strongest inhibitory effects. These compounds implemented the inhibitory effects on the expression of inflammatory cytokine genes through the inhibition of nuclear factor-κB activation. Virtual screening by a docking program indicated that compound 3 is a potent histamine H1 receptor antagonist. Additionally, the calculated physicochemical properties of these compounds support most furanocoumarins to be delivered to binding sites and permeate the cell membrane. The present findings contribute to understanding how A. dahurica attenuates allergic inflammation. PMID:28673013

Local Effect of Neurotrophin-3 in Neuronal Inflammation of Allergic Rhinitis: Preliminary Report.

PubMed

İsmi, Onur; Özcan, Cengiz; Karabacak, Tuba; Polat, Gürbüz; Vayisoğlu, Yusuf; Güçlütürk, Taylan; Görür, Kemal

2015-10-01

Allergic rhinitis is a common inflammatory nasal mucosal disease characterized by sneezing, watery nasal discharge, nasal obstruction and itching. Although allergen-specific antibodies play a main role in the allergic airway inflammation, neuronal inflammation may also contribute to the symptoms of allergic rhinitis. Neuronal inflammation is primarily caused by the stimulation of sensory nerve endings with histamine. It has been shown that neurotrophins may also have a role in allergic reactions and neuronal inflammation. Nerve growth factor, neurotrophin 3 (NT-3), neurotrophin 4/5 and brain-derived neurotrophic factor are members of the neurotrophin family. Although nerve growth factor and brain-derived neurotrophic factor are well studied in allergic rhinitis patients, the exact role of Neurotrophin-3 is not known. To investigate the possible roles of neurotrophin-3 in allergic rhinitis patients. Case-control study. Neurotrophin-3 levels were studied in the inferior turbinate and serum samples of 20 allergic rhinitis and 13 control patients. Neurotrophin-3 staining of nasal tissues was evaluated by immunohistochemistry and ELISA was used for the determination of serum Neurotrophin-3 levels. Neurotrophin-3 staining scores were statistically higher in the study group than in the control patients (p=0.001). Regarding serum Neurotrophin-3 levels, no statistically significant difference could be determined between allergic rhinitis and control patients (p=0.156). When comparing the serum NT-3 levels with tissue staining scores, there were no statistically significant differences in the allergic rhinitis and control groups (p=0.254 for allergic rhinitis and p=0.624 for control groups). We suggest that Neurotrophin-3 might affect the nasal mucosa locally without being released into the systemic circulation in allergic rhinitis patients.

Limonene and its ozone-initiated reaction products attenuate allergic lung inflammation in mice.

PubMed

Hansen, Jitka S; Nørgaard, Asger W; Koponen, Ismo K; Sørli, Jorid B; Paidi, Maya D; Hansen, Søren W K; Clausen, Per Axel; Nielsen, Gunnar D; Wolkoff, Peder; Larsen, Søren Thor

2016-11-01

Inhalation of indoor air pollutants may cause airway irritation and inflammation and is suspected to worsen allergic reactions. Inflammation may be due to mucosal damage, upper (sensory) and lower (pulmonary) airway irritation due to activation of the trigeminal and vagal nerves, respectively, and to neurogenic inflammation. The terpene, d-limonene, is used as a fragrance in numerous consumer products. When limonene reacts with the pulmonary irritant ozone, a complex mixture of gas and particle phase products is formed, which causes sensory irritation. This study investigated whether limonene, ozone or the reaction mixture can exacerbate allergic lung inflammation and whether airway irritation is enhanced in allergic BALB/cJ mice. Naïve and allergic (ovalbumin sensitized) mice were exposed via inhalation for three consecutive days to clean air, ozone, limonene or an ozone-limonene reaction mixture. Sensory and pulmonary irritation was investigated in addition to ovalbumin-specific antibodies, inflammatory cells, total protein and surfactant protein D in bronchoalveolar lavage fluid and hemeoxygenase-1 and cytokines in lung tissue. Overall, airway allergy was not exacerbated by any of the exposures. In contrast, it was found that limonene and the ozone-limonene reaction mixture reduced allergic inflammation possibly due to antioxidant properties. Ozone induced sensory irritation in both naïve and allergic mice. However, allergic but not naïve mice were protected from pulmonary irritation induced by ozone. This study showed that irritation responses might be modulated by airway allergy. However, aggravation of allergic symptoms was observed by neither exposure to ozone nor exposure to ozone-initiated limonene reaction products. In contrast, anti-inflammatory properties of the tested limonene-containing pollutants might attenuate airway allergy.

Commensal bacterial–derived signals regulate basophil hematopoiesis and allergic inflammation

PubMed Central

Hill, David A.; Siracusa, Mark C.; Abt, Michael C.; Kim, Brian S.; Kobuley, Dmytro; Kubo, Masato; Kambayashi, Taku; LaRosa, David F.; Renner, Ellen D.; Orange, Jordan S.; Bushman, Frederic D.; Artis, David

2012-01-01

Commensal bacteria that colonize mammalian barrier surfaces are reported to influence T helper type 2 (TH2) cytokine–dependent inflammation and susceptibility to allergic disease, although the mechanisms that underlie these observations are poorly understood. In this report, we identify that deliberate alteration of commensal bacterial populations via oral antibiotic treatment resulted in elevated serum immunoglobulin E (IgE) levels, increased steady–state circulating basophil populations, and exaggerated basophil–mediated TH2 cell responses and allergic inflammation. Elevated serum IgE levels correlated with increased circulating basophil populations in mice and subjects with hyperimmunoglobulinemia E syndrome. Furthermore, B cell–intrinsic expression of MyD88 was required to limit serum IgE levels and circulating basophil populations in mice. Commensal–derived signals were found to influence basophil development by limiting proliferation of bone marrow–resident precursor populations. Collectively, these results identify a previously unrecognized pathway through which commensal–derived signals influence basophil hematopoiesis and susceptibility to TH2 cytokine–dependent inflammation and allergic disease. PMID:22447074

Innate Immune Responses to Engineered Nanomaterials During Allergic Airway Inflammation

NASA Astrophysics Data System (ADS)

Shipkowski, Kelly Anne

The field of nanotechnology is continually advancing, and increasing amounts of consumer goods are being produced using engineered nanomaterials (ENMs). The health risks of occupational and/or consumer exposure to ENMs are not completely understood, although significant research indicates that pulmonary exposure to nanomaterials induces toxic effects in the lungs of exposed animals. Multi-walled carbon nanotubes (MWCNTs) are a specific category of ENMs and consist of sheets of graphene rolled into cylinders that are multiple layers thick in order to strengthen their rigidity. MWCNTs have a fiber-like shape, similar to that of asbestos, which allows for a high aspect ratio and makes them difficult to clear from the lung. Studies with rodent models have demonstrated that pulmonary exposure to ENMs, in particular MWCNTs, results in acute lung inflammation and the subsequent development of chronic fibrosis, suggesting a potential human health risk to individuals involved in the manufacturing of products utilizing these nanomaterials. Induction of IL-1beta secretion via activation of the inflammasome is a prime mechanism of MWCNT-induced inflammation. The inflammasome is a multi-protein scaffold found in a variety of cell types that forms in response to a variety of immune signals, including particulates. Sensitization with allergens, such as house dust mite (HDM), increases levels of the T helper 2 (Th2) cytokines IL-4 and IL-13 in mice and in humans, and there is particular cause for concern in cases of MWCNT exposure in individuals with pre-existing allergic airway disease, such as asthma. MWCNT exposure exacerbates airway inflammation and fibrosis in animal models of pre-existing allergic asthma, suggesting that individuals suffering from asthma are more susceptible to the toxic pulmonary effects of MWCNT exposure. Asthma is an exceptionally prominent human disease, and therefore the goal of this research was to better understand how pre-existing allergic airway

RhoA orchestrates glycolysis for Th2 cell differentiation and allergic airway inflammation

PubMed Central

Yang, Jun-Qi; Kalim, Khalid W.; Li, Yuan; Zhang, Shuangmin; Hinge, Ashwini; Filippi, Marie-Dominique; Zheng, Yi; Guo, Fukun

2015-01-01

Background Mitochondrial metabolism is known to be important for T cell activation. However, its involvement in effector T cell differentiation has just begun to gain attention. Importantly, how metabolic pathways are integrated with T cell activation and effector cell differentiation and function remains largely unknown. Objective We sought to test our hypothesis that RhoA GTPase orchestrates glycolysis for Th2 cell differentiation and Th2-mediated allergic airway inflammation. Methods Conditional RhoA-deficient mice were generated by crossing RhoAflox/flox mice with CD2-Cre transgenic mice. Effects of RhoA on Th2 differentiation were evaluated by in vitro Th2-polarized culture conditions, and in vivo in ovalbumin (OVA)-induced allergic airway inflammation. Cytokines were measured by intracellular staining and ELISA. T cell metabolism was measured by Seahorse XF24 Analyzer and flow cytometry. Results Disruption of RhoA inhibited T cell activation and Th2 differentiation in vitro and prevented the development of allergic airway inflammation in vivo, with no effect on Th1 cells. RhoA deficiency in activated T cells led to multiple defects in metabolic pathways such as glycolysis and oxidative phosphorylation. Importantly, RhoA couples glycolysis to Th2 cell differentiation and allergic airway inflammation via regulating IL-4 receptor mRNA expression and Th2-specific signaling events. Finally, inhibition of Rho-associated protein kinase (ROCK), an immediate downstream effector of RhoA, blocked Th2 differentiation and allergic airway inflammation. Conclusion RhoA is a key component of the signaling cascades leading to Th2-differentiation and allergic airway inflammation, at least in part, through the control of T cell metabolism and via ROCK pathway. PMID:26100081

Endocrine disruptors found in food contaminants enhance allergic sensitization through an oxidative stress that promotes the development of allergic airway inflammation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kato, Takuma, E-mail: katotaku@doc.medic.mie-u.ac.jp; Tada-Oikawa, Saeko; Wang, Linan

In the past few decades, there has been a significant increase in incidence of allergic diseases. The hygiene hypothesis may provide some clues to explain this rising trend, but it may also be attributable to other environmental factors that exert a proallergic adjuvant effects. However, there is limited information on the risks of developing allergic asthma and related diseases through the ingestion of environmental chemicals found in food contaminants. In the present study, we have shown that oral administration of tributyltin, used as a model environmental chemical, induced oxidative-stress status in the bronchial lymph node, mesenteric lymph node and spleen,more » but not in the lung, where the initial step of allergic asthma pathogenesis takes place. Mice exposed to tributyltin exhibited heightened Th2 immunity to the allergen with more severe airway inflammation. Tributyltin also induced Treg cells apoptosis preferentially over non-Treg cells. All these effects of tributyltin exposure were canceled by the administration of glutathione monoethyl ester. Meanwhile, tributyltin did not affect airway inflammation of mice transferred with allergen-specific Th2 cells. Collectively, these results suggest that tributyltin exerts its pathological effect during the sensitization phase through oxidative stress that enhances the development of allergic diseases. The current study dissects the pathogenic role of oxidative stress induced by oral exposure to an environmental chemical during the sensitization phase of allergic airway inflammation and would be important for developing therapeutics for prevention of allergic diseases. - Highlights: • Oral exposure to TBT exacerbates airway inflammation. • TBT induces oxidative stress in secondary lymphoid organs, but not in the lung. • TBT preferentially induces regulatory T cell apoptosis over non-Treg cells. • TBT does not enhance pre-existing airway inflammation in sensitized mice. • Chemicals in food

Cockroach protease allergen induces allergic airway inflammation via epithelial cell activation

PubMed Central

Kale, Sagar L.; Agrawal, Komal; Gaur, Shailendra Nath; Arora, Naveen

2017-01-01

Protease allergens are known to enhance allergic inflammation but their exact role in initiation of allergic reactions at mucosal surfaces still remains elusive. This study was aimed at deciphering the role of serine protease activity of Per a 10, a major cockroach allergen in initiation of allergic inflammation at mucosal surfaces. We demonstrate that Per a 10 increases epithelial permeability by disruption of tight junction proteins, ZO-1 and occludin, and enhances the migration of Monocyte derived dendritic cell precursors towards epithelial layer as exhibited by trans-well studies. Per a 10 exposure also leads to secretion of IL-33, TSLP and intracellular Ca2+ dependent increase in ATP levels. Further, in vivo experiments revealed that Per a 10 administration in mice elevated allergic inflammatory parameters along with high levels of IL-33, TSLP, IL-1α and uric acid in the mice lungs. We next demonstrated that Per a 10 cleaves CD23 (low affinity IgE receptor) from the surface of PBMCs and purified B cells and CD25 (IL-2 receptor) from the surface of PBMCs and purified T cells in an activity dependent manner, which might favour Th2 responses. In conclusion, protease activity of Per a 10 plays a significant role in initiation of allergic airway inflammation at the mucosal surfaces. PMID:28198394

Toxoplasma gondii infection induces suppression in a mouse model of allergic airway inflammation.

PubMed

Fenoy, Ignacio M; Chiurazzi, Romina; Sánchez, Vanesa R; Argenziano, Mariana A; Soto, Ariadna; Picchio, Mariano S; Martin, Valentina; Goldman, Alejandra

2012-01-01

Allergic asthma is an inflammatory disorder characterized by infiltration of the airway wall with inflammatory cells driven mostly by activation of Th2-lymphocytes, eosinophils and mast cells. There is a link between increased allergy and a reduction of some infections in Western countries. Epidemiological data also show that respiratory allergy is less frequent in people exposed to orofecal and foodborne microbes such as Toxoplasma gondii. We previously showed that both acute and chronic parasite T. gondii infection substantially blocked development of airway inflammation in adult BALB/c mice. Based on the high levels of IFN-γ along with the reduction of Th2 phenotype, we hypothesized that the protective effect might be related to the strong Th1 immune response elicited against the parasite. However, other mechanisms could also be implicated. The possibility that regulatory T cells inhibit allergic diseases has received growing support from both animal and human studies. Here we investigated the cellular mechanisms involved in T. gondii induced protection against allergy. Our results show for the first time that thoracic lymph node cells from mice sensitized during chronic T. gondii infection have suppressor activity. Suppression was detected both in vitro, on allergen specific T cell proliferation and in vivo, on allergic lung inflammation after adoptive transference from infected/sensitized mice to previously sensitized animals. This ability was found to be contact-independent and correlated with high levels of TGF-β and CD4(+)FoxP3(+) cells.

Maternal immune response to helminth infection during pregnancy determines offspring susceptibility to allergic airway inflammation.

PubMed

Straubinger, Kathrin; Paul, Sabine; Prazeres da Costa, Olivia; Ritter, Manuel; Buch, Thorsten; Busch, Dirk H; Layland, Laura E; Prazeres da Costa, Clarissa U

2014-12-01

Schistosomiasis, a chronic helminth infection, elicits distinct immune responses within the host, ranging from an initial TH1 and subsequent TH2 phase to a regulatory state, and is associated with dampened allergic reactions within the host. We sought to evaluate whether non-transplacental helminth infection during pregnancy alters the offspring's susceptibility to allergy. Ovalbumin-induced allergic airway inflammation was analyzed in offspring from Schistosoma mansoni-infected mothers mated during the TH1, TH2, or regulatory phase of infection. Embryos derived from in vitro fertilized oocytes of acutely infected females were transferred into uninfected foster mice to determine the role of placental environment. The fetomaternal unit was further characterized by helminth-specific immune responses and microarray analyses. Eventually, IFN-γ-deficient mice were infected to evaluate the role of this predominant cytokine on the offspring's allergy phenotype. We demonstrate that offspring from schistosome-infected mothers that were mated in the TH1 and regulatory phases, but not the TH2 immune phase, are protected against the onset of allergic airway inflammation. Interestingly, these effects were associated with distinctly altered schistosome-specific cytokine and gene expression profiles within the fetomaternal interface. Furthermore, we identified that it is not the transfer of helminth antigens but rather maternally derived IFN-γ during the acute phase of infection that is essential for the progeny's protective immune phenotype. Overall, we present a novel immune phase-dependent coherency between the maternal immune responses during schistosomiasis and the progeny's predisposition to allergy. Therefore, we propose to include helminth-mediated transmaternal immune modulation into the expanded hygiene hypothesis. Copyright © 2014 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

FABP4 regulates eosinophil recruitment and activation in allergic airway inflammation.

PubMed

Ge, Xiao Na; Bastan, Idil; Dileepan, Mythili; Greenberg, Yana; Ha, Sung Gil; Steen, Kaylee A; Bernlohr, David A; Rao, Savita P; Sriramarao, P

2018-04-26

Fatty acid binding protein 4 (FABP4), a member of a family of lipid-binding proteins, is known to play a role in inflammation by virtue of its ability to regulate intracellular events such as lipid fluxes and signaling. Studies have indicated a pro-inflammatory role for FABP4 in allergic asthma, although its expression and function in eosinophils, the predominant inflammatory cells recruited to allergic airways, was not investigated. We examined expression of FABP4 in murine eosinophils and its role in regulating cell recruitment in vitro as well as in cockroach antigen (CRA)-induced allergic airway inflammation. CRA exposure led to airway recruitment of FABP4-expressing inflammatory cells, specifically eosinophils, in wild type (WT) mice. FABP4 expression in eosinophils was induced by TNF-α as well as IL-4 and IL-13. FABP4-deficient eosinophils exhibited markedly decreased cell spreading/formation of leading edges on vascular cell adhesion molecule-1 and significantly decreased adhesion to intercellular adhesion molecule-1 associated with reduced β2 integrin expression relative to WT cells. Further, FABP4-deficient eosinophils exhibited decreased migration, F-actin polymerization, calcium flux and ERK (1/2) phosphorylation in response to eotaxin-1. In vivo, CRA-challenged FABP4-deficient mice exhibited attenuated eosinophilia and significantly reduced airway inflammation (improved airway reactivity, lower IL-5, IL-13, TNFα and LTC4 levels, decreased airway structural changes) compared to WT mice. In conclusion, expression of FABP4 in eosinophils is induced during conditions of inflammation and plays a pro-inflammatory role in the development of allergic asthma by promoting eosinophil adhesion and migration and contributing to the development of various aspects of airway inflammation.

Vehicular exhaust particles promote allergic airway inflammation through an aryl hydrocarbon receptor-notch signaling cascade.

PubMed

Xia, Mingcan; Viera-Hutchins, Loida; Garcia-Lloret, Maria; Noval Rivas, Magali; Wise, Petra; McGhee, Sean A; Chatila, Zena K; Daher, Nancy; Sioutas, Constantinos; Chatila, Talal A

2015-08-01

Traffic-related particulate matter (PM) has been linked to a heightened incidence of asthma and allergic diseases. However, the molecular mechanisms by which PM exposure promotes allergic diseases remain elusive. We sought to determine the expression, function, and regulation of pathways involved in promotion of allergic airway inflammation by PM. We used gene expression transcriptional profiling, in vitro culture assays, and in vivo murine models of allergic airway inflammation. We identified components of the Notch pathway, most notably Jagged 1 (Jag1), as targets of PM induction in human monocytes and murine dendritic cells. PM, especially ultrafine particles, upregulated TH cytokine levels, IgE production, and allergic airway inflammation in mice in a Jag1- and Notch-dependent manner, especially in the context of the proasthmatic IL-4 receptor allele Il4raR576. PM-induced Jag1 expression was mediated by the aryl hydrocarbon receptor (AhR), which bound to and activated AhR response elements in the Jag1 promoter. Pharmacologic antagonism of AhR or its lineage-specific deletion in CD11c(+) cells abrogated the augmentation of airway inflammation by PM. PM activates an AhR-Jag1-Notch cascade to promote allergic airway inflammation in concert with proasthmatic alleles. Copyright © 2015 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Real-time assessment of inflammation and treatment response in a mouse model of allergic airway inflammation

PubMed Central

Cortez-Retamozo, Virna; Swirski, Filip K.; Waterman, Peter; Yuan, Hushan; Figueiredo, Jose Luiz; Newton, Andita P.; Upadhyay, Rabi; Vinegoni, Claudio; Kohler, Rainer; Blois, Joseph; Smith, Adam; Nahrendorf, Matthias; Josephson, Lee; Weissleder, Ralph; Pittet, Mikael J.

2008-01-01

Eosinophils are multifunctional leukocytes that degrade and remodel tissue extracellular matrix through production of proteolytic enzymes, release of proinflammatory factors to initiate and propagate inflammatory responses, and direct activation of mucus secretion and smooth muscle cell constriction. Thus, eosinophils are central effector cells during allergic airway inflammation and an important clinical therapeutic target. Here we describe the use of an injectable MMP-targeted optical sensor that specifically and quantitatively resolves eosinophil activity in the lungs of mice with experimental allergic airway inflammation. Through the use of real-time molecular imaging methods, we report the visualization of eosinophil responses in vivo and at different scales. Eosinophil responses were seen at single-cell resolution in conducting airways using near-infrared fluorescence fiberoptic bronchoscopy, in lung parenchyma using intravital microscopy, and in the whole body using fluorescence-mediated molecular tomography. Using these real-time imaging methods, we confirmed the immunosuppressive effects of the glucocorticoid drug dexamethasone in the mouse model of allergic airway inflammation and identified a viridin-derived prodrug that potently inhibited the accumulation and enzyme activity of eosinophils in the lungs. The combination of sensitive enzyme-targeted sensors with noninvasive molecular imaging approaches permitted evaluation of airway inflammation severity and was used as a model to rapidly screen for new drug effects. Both fluorescence-mediated tomography and fiberoptic bronchoscopy techniques have the potential to be translated into the clinic. PMID:19033674

The active contribution of Toll-like receptors to allergic airway inflammation.

PubMed

Chen, Keqiang; Xiang, Yi; Yao, Xiaohong; Liu, Ying; Gong, Wanghua; Yoshimura, Teizo; Wang, Ji Ming

2011-10-01

Epithelia lining the respiratory tract represent a major portal of entry for microorganisms and allergens and are equipped with innate and adaptive immune signaling receptors for host protection. These include Toll-like receptors (TLRs) that recognize microbial components and evoke diverse responses in cells of the respiratory system. TLR stimulation by microorganism-derived molecules activates antigen presenting cells, control T helper (Th) 1, Th2, and Th17 immune cell differentiation, cytokine production by mast cells, and activation of eosinophils. It is clear that TLR are involved in the pathophysiology of allergic airway diseases such as asthma. Dendritic cells (DCs), a kind of antigen presenting cells, which play a key role in the induction of allergic airway inflammation, are privileged targets for pathogen associated molecular patterns (PAMPs). During the allergic responses, engagement of TLRs on DCs determines the Th2 polarization of the T cells. TLR signaling in mast cells increases the release of IL-5, and TLR activation of airway epithelial cells forces the generation of proallergic Th2 type of cytokines. Although these responses aim to protect the host, they may also result in inflammatory tissue damage in the airway. Under certain conditions, stimulation of TLRs, in particular, TLR9, may reduce Th2-dependent allergic inflammation by induction of Th1 responses. Therefore, understanding the complex regulatory roles of TLRs in the pathogenesis of allergic airway inflammation should facilitate the development of preventive and therapeutic measures for asthmatic patients. Copyright © 2011 Elsevier B.V. All rights reserved.

The Effects of Maternal Exposure to Bisphenol A on Allergic Lung Inflammation into Adulthood

PubMed Central

Lawrence, B. Paige

2012-01-01

Bisphenol A (BPA) is a high–production volume chemical classified as an environmental estrogen and used primarily in the plastics industry. BPA’s increased usage correlates with rising BPA levels in people and a corresponding increase in the incidence of asthma. Due to limited studies, the contribution of maternal BPA exposure to allergic asthma pathogenesis is unclear. Using two established mouse models of allergic asthma, we examined whether developmental exposure to BPA alters hallmarks of allergic lung inflammation in adult offspring. Pregnant C57BL/6 dams were gavaged with 0, 0.5, 5, 50, or 500 μg BPA/kg/day from gestational day 6 until postnatal day 21. To induce allergic inflammation, adult offspring were mucosally sensitized with inhaled ovalbumin containing low-dose lipopolysaccharide or ip sensitized using ovalbumin with alum followed by ovalbumin aerosol challenge. In the mucosal sensitization model, female offspring that were maternally exposed to ≥ 50 μg BPA/kg/day displayed enhanced airway lymphocytic and lung inflammation, compared with offspring of control dams. Peritoneally sensitized, female offspring exposed to ≤ 50 μg BPA/kg/day presented dampened lung eosinophilia, compared with vehicle controls. Male offspring did not exhibit these differences in either sensitization model. Our data demonstrate that maternal exposure to BPA has subtle and qualitatively different effects on allergic inflammation, which are critically dependent upon route of allergen sensitization and sex. However, these subtle, yet persistent changes due to developmental exposure to BPA did not lead to significant differences in overall airway responsiveness, suggesting that early life exposure to BPA does not exacerbate allergic inflammation into adulthood. PMID:22821851

Effects of local nasal immunotherapy in allergic airway inflammation: Using urea denatured Dermatophagoides pteronyssinus

PubMed Central

Yu, Sheng-Jie; Liao, En-Chih; Tsai, Jaw-Ji

2015-01-01

Despite improvements in anti-allergy medication, the prevalence of allergic airway inflammation remains high, affecting up to 40% of the population worldwide. Allergen immunotherapy is effective for inducing tolerance but has the adverse effect of severe allergic reaction. This can be avoided by denaturing with urea. In this study, we demonstrated that the serum level of allergen-specific IgE in mice sensitized with native Dermatophagoides pteronyssinus (Der p) crude extract after receiving local nasal immunotherapy (LNIT) with urea-denatured Der p crude extract (DN-Dp) significantly decreased compared to that in the normal saline (NS) treatment group. Expressions of IL-4 were significantly reduced in lung tissues after treatment. Inflammation around the bronchial epithelium improved and airway hypersensitivity was down-regulated. LNIT with DN-Dp can down-regulate IL-1b, IL-6 and TNF-a expression and then decrease Der p-induced allergic airway inflammation. This therapeutic modality may be used as an alternative treatment for airway allergic diseases. PMID:25933184

Endocrine disruptors found in food contaminants enhance allergic sensitization through an oxidative stress that promotes the development of allergic airway inflammation.

PubMed

Kato, Takuma; Tada-Oikawa, Saeko; Wang, Linan; Murata, Mariko; Kuribayashi, Kagemasa

2013-11-15

In the past few decades, there has been a significant increase in incidence of allergic diseases. The hygiene hypothesis may provide some clues to explain this rising trend, but it may also be attributable to other environmental factors that exert a proallergic adjuvant effects. However, there is limited information on the risks of developing allergic asthma and related diseases through the ingestion of environmental chemicals found in food contaminants. In the present study, we have shown that oral administration of tributyltin, used as a model environmental chemical, induced oxidative-stress status in the bronchial lymph node, mesenteric lymph node and spleen, but not in the lung, where the initial step of allergic asthma pathogenesis takes place. Mice exposed to tributyltin exhibited heightened Th2 immunity to the allergen with more severe airway inflammation. Tributyltin also induced Treg cells apoptosis preferentially over non-Treg cells. All these effects of tributyltin exposure were canceled by the administration of glutathione monoethyl ester. Meanwhile, tributyltin did not affect airway inflammation of mice transferred with allergen-specific Th2 cells. Collectively, these results suggest that tributyltin exerts its pathological effect during the sensitization phase through oxidative stress that enhances the development of allergic diseases. The current study dissects the pathogenic role of oxidative stress induced by oral exposure to an environmental chemical during the sensitization phase of allergic airway inflammation and would be important for developing therapeutics for prevention of allergic diseases. © 2013.

Adoptive transfer of induced-Treg cells effectively attenuates murine airway allergic inflammation.

PubMed

Xu, Wei; Lan, Qin; Chen, Maogen; Chen, Hui; Zhu, Ning; Zhou, Xiaohui; Wang, Julie; Fan, Huimin; Yan, Chun-Song; Kuang, Jiu-Long; Warburton, David; Togbe, Dieudonnée; Ryffel, Bernhard; Zheng, Song-Guo; Shi, Wei

2012-01-01

Both nature and induced regulatory T (Treg) lymphocytes are potent regulators of autoimmune and allergic disorders. Defects in endogenous Treg cells have been reported in patients with allergic asthma, suggesting that disrupted Treg cell-mediated immunological regulation may play an important role in airway allergic inflammation. In order to determine whether adoptive transfer of induced Treg cells generated in vitro can be used as an effective therapeutic approach to suppress airway allergic inflammation, exogenously induced Treg cells were infused into ovalbumin-sensitized mice prior to or during intranasal ovalbumin challenge. The results showed that adoptive transfer of induced Treg cells prior to allergen challenge markedly reduced airway hyperresponsiveness, eosinophil recruitment, mucus hyper-production, airway remodeling, and IgE levels. This effect was associated with increase of Treg cells (CD4(+)FoxP3(+)) and decrease of dendritic cells in the draining lymph nodes, and with reduction of Th1, Th2, and Th17 cell response as compared to the controls. Moreover, adoptive transfer of induced Treg cells during allergen challenge also effectively attenuate airway inflammation and improve airway function, which are comparable to those by natural Treg cell infusion. Therefore, adoptive transfer of in vitro induced Treg cells may be a promising therapeutic approach to prevent and treat severe asthma.

Adoptive Transfer of Induced-Treg Cells Effectively Attenuates Murine Airway Allergic Inflammation

PubMed Central

Chen, Maogen; Chen, Hui; Zhu, Ning; Zhou, Xiaohui; Wang, Julie; Fan, Huimin; Yan, Chun-Song; Kuang, Jiu-Long; Warburton, David; Togbe, Dieudonnée; Ryffel, Bernhard; Zheng, Song-Guo; Shi, Wei

2012-01-01

Both nature and induced regulatory T (Treg) lymphocytes are potent regulators of autoimmune and allergic disorders. Defects in endogenous Treg cells have been reported in patients with allergic asthma, suggesting that disrupted Treg cell-mediated immunological regulation may play an important role in airway allergic inflammation. In order to determine whether adoptive transfer of induced Treg cells generated in vitro can be used as an effective therapeutic approach to suppress airway allergic inflammation, exogenously induced Treg cells were infused into ovalbumin-sensitized mice prior to or during intranasal ovalbumin challenge. The results showed that adoptive transfer of induced Treg cells prior to allergen challenge markedly reduced airway hyperresponsiveness, eosinophil recruitment, mucus hyper-production, airway remodeling, and IgE levels. This effect was associated with increase of Treg cells (CD4+FoxP3+) and decrease of dendritic cells in the draining lymph nodes, and with reduction of Th1, Th2, and Th17 cell response as compared to the controls. Moreover, adoptive transfer of induced Treg cells during allergen challenge also effectively attenuate airway inflammation and improve airway function, which are comparable to those by natural Treg cell infusion. Therefore, adoptive transfer of in vitro induced Treg cells may be a promising therapeutic approach to prevent and treat severe asthma. PMID:22792275

Semaphorin 4C Protects against Allergic Inflammation: Requirement of Regulatory CD138+ Plasma Cells.

PubMed

Xue, Di; Kaufman, Gabriel N; Dembele, Marieme; Beland, Marianne; Massoud, Amir H; Mindt, Barbara C; Fiter, Ryan; Fixman, Elizabeth D; Martin, James G; Friedel, Roland H; Divangahi, Maziar; Fritz, Jörg H; Mazer, Bruce D

2017-01-01

The regulatory properties of B cells have been studied in autoimmune diseases; however, their role in allergic diseases is poorly understood. We demonstrate that Semaphorin 4C (Sema4C), an axonal guidance molecule, plays a crucial role in B cell regulatory function. Mice deficient in Sema4C exhibited increased airway inflammation after allergen exposure, with massive eosinophilic lung infiltrates and increased Th2 cytokines. This phenotype was reproduced by mixed bone marrow chimeric mice with Sema4C deficient only in B cells, indicating that B lymphocytes were the key cells affected by the absence of Sema4C expression in allergic inflammation. We determined that Sema4C-deficient CD19 + CD138 + cells exhibited decreased IL-10 and increased IL-4 expression in vivo and in vitro. Adoptive transfer of Sema4c -/- CD19 + CD138 + cells induced marked pulmonary inflammation, eosinophilia, and increased bronchoalveolar lavage fluid IL-4 and IL-5, whereas adoptive transfer of wild-type CD19 + CD138 + IL-10 + cells dramatically decreased allergic airway inflammation in wild-type and Sema4c -/- mice. This study identifies a novel pathway by which Th2-mediated immune responses are regulated. It highlights the importance of plasma cells as regulatory cells in allergic inflammation and suggests that CD138 + B cells contribute to cytokine balance and are important for maintenance of immune homeostasis in allergic airways disease. Furthermore, we demonstrate that Sema4C is critical for optimal regulatory cytokine production in CD138 + B cells. Copyright © 2016 by The American Association of Immunologists, Inc.

Hyperoside attenuates OVA-induced allergic airway inflammation by activating Nrf2.

PubMed

Ye, Peng; Yang, Xi-Liang; Chen, Xing; Shi, Cai

2017-03-01

Allergic airways disease (AAD) is one of the most common medical illnesses that is associated with an increased allergic airway inflammation. Hyperoside, an active compound isolated from Rhododendron brachycarpum G. Don, has been reported to have anti-inflammatory effect. The aim of this study was to analyze the protective effect of hyperoside on OVA-induced allergic airway inflammation in mice. In the present study, the mouse asthma model was induced by given OVA and hyperoside was administrated 1h before OVA challenge. The levels of IL-4, IL-5, IL-13, and IgE were detected by ELISA. H&E staining was used to assess lung histopathological changes. The expression of NF-κB p65, IκB, HO-1, and Nf-E2 related factor 2 (Nrf2) were measured by western blot analysis. The results showed that hyperoside significantly reduced the inflammatory cells infiltration and the levels of IL-4, IL-5, IL-13, and IgE. Hyperoside significantly inhibited OVA-induced oxidative stress as demonstrated by decreased MDA, and increased GSH and SOD levels. Treatment of hyperoside also inhibited OVA-induced airway hyperresponsiveness (AHR). Furthermore, the results showed that treatment of hyperoside significantly inhibited LPS-induced NF-κB activation. In addition, hyperoside was found to activate Nrf2/HO-1 signaling pathway. In conclusion, these results suggest that hyperoside ameliorates OVA-induced allergic airway inflammation by activating Nrf2 signaling pathway. Copyright © 2017 Elsevier B.V. All rights reserved.

GARP inhibits allergic airway inflammation in a humanized mouse model.

PubMed

Meyer-Martin, H; Hahn, S A; Beckert, H; Belz, C; Heinz, A; Jonuleit, H; Becker, C; Taube, C; Korn, S; Buhl, R; Reuter, S; Tuettenberg, A

2016-09-01

Regulatory T cells (Treg) represent a promising target for novel treatment strategies in patients with inflammatory/allergic diseases. A soluble derivate of the Treg surface molecule glycoprotein A repetitions predominant (sGARP) has strong anti-inflammatory and regulatory effects on human cells in vitro as well as in vivo through de novo induction of peripheral Treg. The aim of this study was to investigate the immunomodulatory function of sGARP and its possible role as a new therapeutic option in allergic diseases using a humanized mouse model. To analyze the therapeutic effects of sGARP, adult NOD/Scidγc(-/-) (NSG) mice received peripheral blood mononuclear cells (PBMC) derived from allergic patients with sensitization against birch allergen. Subsequently, allergic inflammation was induced in the presence of Treg alone or in combination with sGARP. In comparison with mice that received Treg alone, additional treatment with sGARP reduced airway hyperresponsiveness (AHR), influx of neutrophils and macrophages into the bronchoalveolar lavage (BAL), and human CD45(+) cells in the lungs. Furthermore, the numbers of mucus-producing goblet cells and inflammatory cell infiltrates were reduced. To elucidate whether the mechanism of action of sGARP involves the TGF-β receptor pathway, mice additionally received anti-TGF-β receptor II (TGF-βRII) antibodies. Blocking the signaling of TGF-β through TGF-βRII abrogated the anti-inflammatory effects of sGARP, confirming its essential role in inhibiting the allergic inflammation. Induction of peripheral tolerance via sGARP is a promising potential approach to treat allergic airway diseases. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Purified aged garlic extract modulates allergic airway inflammation in BALB/c mice.

PubMed

Zare, Ahad; Farzaneh, Parvaneh; Pourpak, Zahra; Zahedi, Fatemeh; Moin, Mostafa; Shahabi, Shahram; Hassan, Zuhair M

2008-09-01

Garlic is known as a potent spice and a medicinal herb with broad therapeutic properties ranging from antibacterial to anticancer and anticoagulant. Our previous studies have shown some immunoregulatory effects for aged garlic extract, suggesting a key role for 14-kD glycoprotein of garlic in shifting the cytokine pattern to T helper-1. In present study, we investigated the effect of 1, 2, and 3 times intraperitoneal injections of aged garlic extract on an established allergic airway inflammation in murine model (BALB/c mice). The garlic extract, isolated by biochemical method, includes proteins precipitation by ammonium sulfate. After injection of the aged garlic extract, IFN-, anti allergen specific IgE and IgG1 were measured in lavage and serum by ELISA and histological assessment was performed on the lung tissues. The results indicated that three-time intra peritoneal injections of the aged garlic extract caused a significant decrease in the hallmark criteria of allergic airway inflammation levels which included eosinophil percentage in lavage, peribronchial lung eosinophils, IgG1 level in lavage and serum, mucous producing goblet cells grade and peribronchial and perivascular inflammation. Our findings in the present research suggested that aged garlic extract has the potential of attenuation of inflammatory features of allergic airway inflammation in murine model.

Murine lung eosinophil activation and chemokine production in allergic airway inflammation

PubMed Central

Rose, C Edward; Lannigan, Joanne A; Kim, Paul; Lee, James J; Fu, Shu Man; Sung, Sun-sang J

2010-01-01

Eosinophils play important roles in asthma and lung infections. Murine models are widely used for assessing the functional significance and mechanistic basis for eosinophil involvements in these diseases. However, little is known about tissue eosinophils in homeostasis. In addition, little data on eosinophil chemokine production during allergic airway inflammation are available. In this study, the properties and functions of homeostatic and activated eosinophils were compared. Eosinophils from normal tissues expressed costimulation and adhesion molecules B7-1, B7-2 and ICAM-1 for Ag presentation but little major histocompatibility complex (MHC) class II, and were found to be poor stimulators of T-cell proliferation. However, these eosinophils expressed high levels of chemokine mRNA including C10, macrophage inflammatory protein (MIP)-1α, MIP-1γ, MIP-2, eotaxin and monocyte chemoattractant protein-5 (MCP-5), and produced chemokine proteins. Eosinophil intracellular chemokines decreased rapidly with concomitant surface marker downregulation upon in vitro culturing consistent with piecemeal degranulation. Lung eosinophils from mice with induced allergic airway inflammation exhibited increased chemokines mRNA expression and chemokines protein production and upregulated MHC class II and CD11c expression. They were also found to be the predominant producers of the CCR1 ligands CCL6/C10 and CCL9/MIP-1γ in inflamed lungs. Eosinophil production of C10 and MIP-1γ correlated with the marked influx of CD11bhigh lung dendritic cells during allergic airway inflammation and the high expression of CCR1 on these dendritic cells (DCs). The study provided baseline information on tissue eosinophils, documented the upregulation of activation markers and chemokine production in activated eosinophils, and indicated that eosinophils were a key chemokine-producing cell type in allergic lung inflammation. PMID:20622891

G-CSF suppresses allergic pulmonary inflammation, downmodulating cytokine, chemokine and eosinophil production.

PubMed

Queto, Túlio; Vasconcelos, Zilton F M; Luz, Ricardo Alves; Anselmo, Carina; Guiné, Ana Amélia A; e Silva, Patricia Machado R; Farache, Júlia; Cunha, José Marcos T; Bonomo, Adriana C; Gaspar-Elsas, Maria Ignez C; Xavier-Elsas, Pedro

2011-05-09

Granulocyte Colony-Stimulating Factor (G-CSF), which mobilizes hemopoietic stem cells (HSC), is believed to protect HSC graft recipients from graft-versus-host disease by enhancing Th2 cytokine secretion. Accordingly, G-CSF should aggravate Th2-dependent allergic pulmonary inflammation and the associated eosinophilia. We evaluated the effects of G-CSF in a model of allergic pulmonary inflammation. Allergic pulmonary inflammation was induced by repeated aerosol allergen challenge in ovalbumin-sensitized C57BL/6J mice. The effects of allergen challenge and of G-CSF pretreatment were evaluated by monitoring: a) eosinophilia and cytokine/chemokine content of bronchoalveolar lavage fluid, pulmonary interstitium, and blood; b) changes in airway resistance; and c) changes in bone-marrow eosinophil production. Contrary to expectations, G-CSF pretreatment neither induced nor enhanced allergic pulmonary inflammation. Instead, G-CSF: a) suppressed accumulation of infiltrating eosinophils in bronchoalveolar, peribronchial and perivascular spaces of challenged lungs; and b) prevented ovalbumin challenge-induced rises in airway resistance. G-CSF had multiple regulatory effects on cytokine and chemokine production: in bronchoalveolar lavage fluid, levels of IL-1 and IL-12 (p40), eotaxin and MIP-1a were decreased; in plasma, KC, a neutrophil chemoattractant, was increased, while IL-5 was decreased and eotaxin was unaffected. In bone-marrow, G-CSF: a) prevented the increase in bone-marrow eosinophil production induced by ovalbumin challenge of sensitized mice; and b) selectively stimulated neutrophil colony formation. These observations challenge the view that G-CSF deviates cytokine production towards a Th2 profile in vivo, and suggest that this neutrophil-selective hemopoietin affects eosinophilic inflammation by a combination of effects on lung cytokine production and bone-marrow hemopoiesis. Copyright © 2011 Elsevier Inc. All rights reserved.

Effects of ZCR-2060 on allergic airway inflammation and cell activation in guinea-pigs.

PubMed

Abe, T; Yoshida, K; Omata, T; Segawa, Y; Matsuda, K; Nagai, H

1994-11-01

The effects of 2-(2-(4-(diphenylmethyl)-1-piperadinyl) ethoxy) benzoic acid malate (ZCR-2060) on allergic airway inflammation and inflammatory cell activation in guinea-pigs were studied. Allergic airway inflammation was induced by inhalation of antigen into actively-sensitized animals and the increase in inflammatory cells into bronchoalveolar lavage fluid (BALF) was measured. Aeroantigen-induced infiltration of inflammatory cells, especially eosinophils and neutrophils, in BALF gradually increased, and reached a peak at 6 or 9 h after the challenge. ZCR-2060 (1 mg kg-1 p.o.) clearly inhibited the increase of eosinophil numbers in BALF. Moreover, the effect of ZCR-2060 on inflammatory cell activation in terms of chemotaxis and superoxide generation in-vitro was studied. ZCR-2060 (10(-6)-10(-4) M) inhibited the platelet-activating factor (PAF)-induced chemotaxis of eosinophils and neutrophils, but did not inhibit the leukotriene B4-induced chemotaxis of eosinophils and the formyl-Met-Leu-Phe-induced chemotaxis of neutrophils. PAF-induced superoxide anion generation by eosinophils, neutrophils and alveolar macrophages was inhibited by ZCR-2060 (10(-6)-10(-4) M). However, ZCR-2060 did not affect phorbol myristate acetate-induced superoxide anion generation by eosinophils, neutrophils and alveolar macrophages. These results indicate that ZCR-2060 inhibits allergic airway inflammation, and PAF-induced inflammatory cell activation in guinea-pigs. ZCR-2060 may prove useful for the treatment of allergic airway inflammation or allergic disorders, especially inflammatory cell infiltration and activation.

Iron Supplementation Decreases Severity of Allergic Inflammation in Murine Lung

PubMed Central

Hale, Laura P.; Kant, Erin Potts; Greer, Paula K.; Foster, W. Michael

2012-01-01

The incidence and severity of allergic asthma have increased over the last century, particularly in the United States and other developed countries. This time frame was characterized by marked environmental changes, including enhanced hygiene, decreased pathogen exposure, increased exposure to inhaled pollutants, and changes in diet. Although iron is well-known to participate in critical biologic processes such as oxygen transport, energy generation, and host defense, iron deficiency remains common in the United States and world-wide. The purpose of these studies was to determine how dietary iron supplementation affected the severity of allergic inflammation in the lungs, using a classic model of IgE-mediated allergy in mice. Results showed that mice fed an iron-supplemented diet had markedly decreased allergen-induced airway hyperreactivity, eosinophil infiltration, and production of pro-inflammatory cytokines, compared with control mice on an unsupplemented diet that generated mild iron deficiency but not anemia. In vitro, iron supplementation decreased mast cell granule content, IgE-triggered degranulation, and production of pro-inflammatory cytokines post-degranulation. Taken together, these studies show that iron supplementation can decrease the severity of allergic inflammation in the lung, potentially via multiple mechanisms that affect mast cell activity. Further studies are indicated to determine the potential of iron supplementation to modulate the clinical severity of allergic diseases in humans. PMID:23029172

The adipocyte fatty acid–binding protein aP2 is required in allergic airway inflammation

PubMed Central

Shum, Bennett O.V.; Mackay, Charles R.; Gorgun, Cem Z.; Frost, Melinda J.; Kumar, Rakesh K.; Hotamisligil, Gökhan S.; Rolph, Michael S.

2006-01-01

The adipocyte fatty acid–binding protein aP2 regulates systemic glucose and lipid metabolism. We report that aP2, in addition to being abundantly expressed by adipocytes, is also expressed by human airway epithelial cells and shows a striking upregulation following stimulation of epithelial cells with the Th2 cytokines IL-4 and IL-13. Regulation of aP2 mRNA expression by Th2 cytokines was highly dependent on STAT6, a transcription factor with a major regulatory role in allergic inflammation. We examined aP2-deficient mice in a model of allergic airway inflammation and found that infiltration of leukocytes, especially eosinophils, into the airways was highly dependent on aP2 function. T cell priming was unaffected by aP2 deficiency, suggesting that aP2 was acting locally within the lung, and analysis of bone marrow chimeras implicated non-hematopoietic cells, most likely bronchial epithelial cells, as the site of action of aP2 in allergic airway inflammation. Thus, aP2 regulates allergic airway inflammation and may provide a link between fatty acid metabolism and asthma. PMID:16841093

Secretoglobin Superfamily Protein SCGB3A2 Alleviates House Dust Mite-Induced Allergic Airway Inflammation in Mice.

PubMed

Yoneda, Mitsuhiro; Xu, Lei; Kajiyama, Hiroaki; Kawabe, Shuko; Paiz, Jorge; Ward, Jerrold M; Kimura, Shioko

2016-01-01

Secretoglobin (SCGB) 3A2, a novel, lung-enriched, cytokine-like, secreted protein of small molecular weight, was demonstrated to exhibit various biological functions including anti-inflammatory, antifibrotic and growth-factor activities. Anti-inflammatory activity was uncovered using the ovalbumin-induced allergic airway inflammation model. However, further validation of this activity using knockout mice in a different allergic inflammation model is necessary in order to establish the antiallergic inflammatory role for this protein. Scgb3a2-null (Scgb3a2-/-) mice were subjected to nasal inhalation of Dermatophagoides pteronyssinus extract for 5 days/week for 5 consecutive weeks; control mice received nasal inhalation of saline as a comparator. Airway inflammation was assessed by histological analysis, the number of inflammatory cells and various Th2-type cytokine levels in the lungs and bronchoalveolar lavage fluids by qRT-PCR and ELISA, respectively. Exacerbated inflammation was found in the airway of Scgb3a2-/- mice subjected to house dust mite (HDM)-induced allergic airway inflammation compared with saline-treated control groups. All the inflammation end points were increased in the Scgb3a2-/- mice. The Ccr4 and Ccl17 mRNA levels were higher in HDM-treated lungs of Scgb3a2-/- mice than wild-type mice or saline-treated Scgb3a2-/- mice, whereas no changes were observed for Ccr3 and Ccl11 mRNA levels. These results demonstrate that SCGB3A2 has an anti-inflammatory activity in the HDM-induced allergic airway inflammation model, in which SCGB3A2 may modulate the CCR4-CCL17 pathway. SCGB3A2 may provide a useful tool to treat allergic airway inflammation, and further studies on the levels and function of SCGB3A2 in asthmatic patients are warranted. © 2016 S. Karger AG, Basel.

Bakery flour dust exposure causes non-allergic inflammation and enhances allergic airway inflammation in mice

PubMed Central

Marraccini, Paolo; Brass, David M.; Hollingsworth, John W.; Maruoka, Shuichiro; Garantziotis, Stavros; Schwartz, David A.

2014-01-01

Background Baker’s asthma is one of the most commonly reported occupational lung diseases in countries where fresh bread is baked daily in large quantities, and is characterized by rhinitis, bronchial hyperresponsiveness, and reversible airflow obstruction. Epidemiological studies have identified pre-existing atopy as an important risk factor for developing baker’s asthma, yet the etiology and pathogenesis of baker’s asthma remain poorly understood. Objective We sought to develop a mouse model of baker’s asthma that could be used to characterize the development and progression of baker’s asthma. Methods We were unable to sensitize mice to bakery flour dust or flour dust extract. We assessed total inflammatory cells, cellular differential, total serum IgE and the pro-inflammatory cytokine response to oropharyngeally instilled bakery flour dust or flour dust extract by itself or in the context of OVA sensitization and challenge. Results Both bakery flour dust and flour dust extract consistently elicited a neutrophilic inflammation in a tlr4-independent manner; suggesting that endotoxin is not playing a role in the inflammatory response to flour dust. Moreover, bakery flour dust and dust extract significantly enhance the inflammatory response in OVA sensitized and challenged mice. Conclusions Bakery flour dust and flour dust extract are strongly pro-inflammatory and can cause non-allergic airway inflammation and can enhance allergen-mediated airway inflammation. PMID:18564331

Multi-Walled Carbon Nanotubes Augment Allergic Airway Eosinophilic Inflammation by Promoting Cysteinyl Leukotriene Production.

PubMed

Carvalho, Sophia; Ferrini, Maria; Herritt, Lou; Holian, Andrij; Jaffar, Zeina; Roberts, Kevan

2018-01-01

Multi-walled carbon nanotubes (MWCNT) have been reported to promote lung inflammation and fibrosis. The commercial demand for nanoparticle-based materials has expanded rapidly and as demand for nanomaterials grows, so does the urgency of establishing an appreciation of the degree of health risk associated with their increased production and exposure. In this study, we examined whether MWCNT inhalation elicited pulmonary eosinophilic inflammation and influenced the development of allergic airway inflammatory responses. Our data revealed that instillation of FA21 MWCNT into the airways of mice resulted in a rapid increase, within 24 h, in the number of eosinophils present in the lungs. The inflammatory response elicited was also associated with an increase in the level of cysteinyl leukotrienes (cysLTs) present in the bronchoalveolar lavage fluid. CysLTs were implicated in the airway inflammatory response since pharmacological inhibition of their biosynthesis using the 5-lipoxygenase inhibitor Zileuton resulted in a marked reduction in the severity of inflammation observed. Moreover, FA21 MWCNT entering the airways of mice suffering from house dust mite (HDM)-elicited allergic lung inflammation markedly exacerbated the intensity of the airway inflammation. This response was characterized by a pulmonary eosinophilia, lymphocyte infiltration, and raised cysLT levels. The severity of pulmonary inflammation caused by either inhalation of MWCNT alone or in conjunction with HDM allergen correlated with the level of nickel present in the material, since preparations that contained higher levels of nickel (FA21, 5.54% Ni by weight) were extremely effective at eliciting or exacerbating inflammatory or allergic responses while preparations containing lower amounts of nickel (FA04, 2.54% Ni by weight) failed to initiate or exacerbate pulmonary inflammation. In summary, instillation of high nickel MWCNT into the lungs promoted eosinophilic inflammation and caused an intense

Parasitic Nematode-Induced CD4+Foxp3+T Cells Can Ameliorate Allergic Airway Inflammation

PubMed Central

Kang, Shin Ae; Park, Mi-Kyung; Cho, Min Kyoung; Park, Sang Kyun; Jang, Min Seong; Yang, Bo-Gie; Jang, Myoung Ho; Kim, Dong-Hee; Yu, Hak Sun

2014-01-01

Background The recruitment of CD4+CD25+Foxp3+T (Treg) cells is one of the most important mechanisms by which parasites down-regulate the immune system. Methodology/Principal Findings We compared the effects of Treg cells from Trichinella spiralis-infected mice and uninfected mice on experimental allergic airway inflammation in order to understand the functions of parasite-induced Treg cells. After four weeks of T. spiralis infection, we isolated Foxp3-GFP-expressing cells from transgenic mice using a cell sorter. We injected CD4+Foxp3+ cells from T. spiralis-infected [Inf(+)Foxp3+] or uninfected [Inf(-)Foxp3+] mice into the tail veins of C57BL/6 mice before the induction of inflammation or during inflammation. Inflammation was induced by ovalbumin (OVA)-alum sensitization and OVA challenge. The concentrations of the Th2-related cytokines IL-4, IL-5, and IL-13 in the bronchial alveolar lavage fluid and the levels of OVA-specific IgE and IgG1 in the serum were lower in mice that received intravenous application of Inf(+)Foxp3+ cells [IV(inf):+(+) group] than in control mice. Some features of allergic airway inflammation were ameliorated by the intravenous application of Inf(-)Foxp3+ cells [IV(inf):+(-) group], but the effects were less distinct than those observed in the IV(inf):+(+) group. We found that Inf(+)Foxp3+ cells migrated to inflammation sites in the lung and expressed higher levels of Treg-cell homing receptors (CCR5 and CCR9) and activation markers (Klrg1, Capg, GARP, Gzmb, OX40) than did Inf(-)Foxp3+ cells. Conclusion/Significance T. spiralis infection promotes the proliferation and functional activation of Treg cells. Parasite-induced Treg cells migrate to the inflammation site and suppress immune responses more effectively than non-parasite-induced Treg cells. The adoptive transfer of Inf(+)Foxp3+ cells is an effective method for the treatment and prevention of allergic airway diseases in mice and is a promising therapeutic approach for the treatment

Measuring T cell cytokines in allergic upper and lower airway inflammation: can we move to the clinic?

PubMed

Bullens, Dominique M A

2007-06-01

Recent insights regarding the development of allergic diseases such as allergic rhinitis, asthma and atopic eczema are based on the functional diversity of T helper (Th)1 and Th2 lymphocytes. Th2 cells (secreting Interleukin (IL)-4, IL-5, IL-9 and IL-13) are considered to be responsible for the induction and for many of the manifestations of atopic diseases. Local overproduction of Th2 cytokines at the site of allergic inflammation, and an intrinsic defect in the production of IFN-gamma by Th1 cells in atopic individuals, have now been reported by several authors. Both IFN-gamma and IL-10 have been suggested to play a modulatory role in the induction and maintenance of allergen-specific tolerance in healthy individuals. However, recent studies indicate that Th1 cells, secreting IFN-gamma might cause severe airway inflammation. On the other hand, 'inflammatory T cells' or Th17 cells, producing IL-17, could represent a link between T cell inflammation and granulocytic influx as observed in allergic airway inflammation. We focus in this review on local (at the side of inflammation) T cell cytokine production and cytokine production by circulating T cells (after in vitro restimulation) from individuals with allergic airway disease, rhinitis and/or asthma. We furthermore review the changes in local T cell cytokine production and/or cytokine production by circulating T cells (after restimulation in vitro) from allergic/asthmatic individuals after treatment with anti-inflammatory agents or immunotherapy. Finally, we discuss whether measuring these T cell cytokines in the airways might be of diagnostic importance or could help to follow-up patients with allergy/asthma.

Bronchial inflammation in seasonal allergic rhinitis with or without asthma in relation to natural exposure to pollen allergens.

PubMed

Panzner, P; Malkusová, I; Vachová, M; Liška, M; Brodská, P; Růžičková, O; Malý, M

2015-01-01

Nasal inflammation in allergic rhinitis enhances bronchial Th2 driven inflammation and development of asthma. We assessed bronchial inflammation induced by natural allergen exposure during pollen season in patients with pollinosis with or without asthma to show the intensity of inflammation in asthma and rhinitis and possible persistence of inflammation in periods without allergen exposure. Sputum was induced in 52 patients with seasonal allergic rhinitis without asthma, 38 patients with seasonal allergic rhinitis and seasonal asthma and 23 healthy volunteers. Sampling was performed 6-8 weeks before the expected beginning of symptoms, during symptomatic period and 6-8 weeks after the end of symptoms. Sputum ECP was measured by means of chemi-luminiscent immunometric assay and sputum cell counts were assessed by classical staining and immunocytochemistry. Sputum eosinophils were on the whole higher in both asthma and rhinitis compared to controls (p<0.001, p=0.003). The rise of eosinophils during pollen season compared with values out of pollen season was significant in asthma (classical staining) (p=0.014) and slightly apparent in rhinitis (immunocytochemistry) (p=0.073). The seasonal rise of sputum ECP was observed only in rhinitis (p=0.006). Inflammation of the lower airway in patients with allergic rhinitis with and without asthma has been confirmed by means of both sputum eosinophil count and sputum ECP level. Persistent inflammation of lower airway in periods without allergen exposure was proven in seasonal asthma. This may have implications for the therapy of seasonal allergic rhinitis with and without asthma in terms of promoting long-term anti-inflammatory treatment. Copyright © 2013 SEICAP. Published by Elsevier Espana. All rights reserved.

Expression of the protein serum amyloid A in response to Aspergillus fumigatus in murine models of allergic airway inflammation.

PubMed

Moran, Gabriel; Carcamo, Carolina; Concha, Margarita; Folch, Hugo

2015-01-01

Serum amyloid A (SAA) is an acute phase protein that is elevated in blood during inflammation. The role of this protein in allergic diseases of airways remains unclear. The objective of this study was to evaluate the SAA in blood, lung and bronchial cells in a murine model of bronchial hypersensitivity to Aspergillus fumigatus. To achieve this purpose, different groups of 5-month-old mice were housed in cages containing hay bedding that was contaminated with A. fumigatus and were kept in an isolation room for 16 days to allow for the induction of allergic airway inflammation. Subsequently, the mice were then exposed once again to Aspergillus spores at 0, 2, 8, 24 and 72 h, and they were bled to acquire serum and sacrificed to obtain bronchoalveolar lavage fluid (BALF) or lung tissues for analysis. SAA levels were measured in lung, serum and BALF by dot blot assay and RT-PCR (reverse transcription polymerase chain reaction). The results indicated that SAA protein levels increased in both serum and lung within 2-24h after mice were exposed to Aspergillus spores. Moreover, the SAA mRNA expression levels in the lungs and BALF cells demonstrated the same trend that was observed for the protein levels through the dot blot assay; in particular, SAA mRNA levels increased within the first hour after mice were exposed to A. fumigatus. In this allergic airway model, we conclude that A. fumigatus can induce an acute inflammatory response in the airways through the stimulation of the SAA protein, increasing its levels in serum, lung tissue and BALF samples during the early hours of exposure of mice that have been sensitised for this fungus. Copyright © 2012 Revista Iberoamericana de Micología. Published by Elsevier Espana. All rights reserved.

Formononetin ameliorates mast cell-mediated allergic inflammation via inhibition of histamine release and production of pro-inflammatory cytokines

PubMed Central

Xu, Ning; An, Jun

2017-01-01

Various allergic diseases cause allergic inflammation, which is mediated by mast cells. The current study investigated the anti-allergic inflammatory effects of formononetin and its mechanism of action in vitro using mast cells. Levels of histamine and pro-inflammatory cytokines, including tumor necrosis factor-α (TNF-α), interleukin (IL)-1β and IL-6, were measured to assess the effects of formononetin on allergic inflammation. The activation of intracellular calcium and nuclear factor (NF)-κB, as well as the activity of caspase-1, were assessed to determine the mechanism of action. It was determined that difference concentrations of formononetin (0.1, 1 and 10 µM) suppressed histamine release and secretion of TNF-α, IL-1β and IL-6. Further investigations indicated that the effects of formononetin were associated with a reduction of intracellular calcium, suppression of NF-κB activation and upstream IκKα phosphorylation and inhibition of caspase-1 activity. Therefore, the results of the current study demonstrated that formononetin ameliorated mast cell-mediated allergic inflammation. PMID:29250144

Formononetin ameliorates mast cell-mediated allergic inflammation via inhibition of histamine release and production of pro-inflammatory cytokines.

PubMed

Xu, Ning; An, Jun

2017-12-01

Various allergic diseases cause allergic inflammation, which is mediated by mast cells. The current study investigated the anti-allergic inflammatory effects of formononetin and its mechanism of action in vitro using mast cells. Levels of histamine and pro-inflammatory cytokines, including tumor necrosis factor-α (TNF-α), interleukin (IL)-1β and IL-6, were measured to assess the effects of formononetin on allergic inflammation. The activation of intracellular calcium and nuclear factor (NF)-κB, as well as the activity of caspase-1, were assessed to determine the mechanism of action. It was determined that difference concentrations of formononetin (0.1, 1 and 10 µM) suppressed histamine release and secretion of TNF-α, IL-1β and IL-6. Further investigations indicated that the effects of formononetin were associated with a reduction of intracellular calcium, suppression of NF-κB activation and upstream IκKα phosphorylation and inhibition of caspase-1 activity. Therefore, the results of the current study demonstrated that formononetin ameliorated mast cell-mediated allergic inflammation.

CARMA3 Is Critical for the Initiation of Allergic Airway Inflammation

PubMed Central

Causton, Benjamin; Ramadas, Ravisankar A.; Cho, Josalyn L.; Jones, Khristianna; Pardo-Saganta, Ana; Rajagopal, Jayaraj; Xavier, Ramnik J.

2015-01-01

Innate immune responses to allergens by airway epithelial cells (AECs) help initiate and propagate the adaptive immune response associated with allergic airway inflammation in asthma. Activation of the transcription factor NF-κB in AECs by allergens or secondary mediators via G protein–coupled receptors (GPCRs) is an important component of this multifaceted inflammatory cascade. Members of the caspase recruitment domain family of proteins display tissue-specific expression and help mediate NF-κB activity in response to numerous stimuli. We have previously shown that caspase recruitment domain–containing membrane-associated guanylate kinase protein (CARMA)3 is specifically expressed in AECs and mediates NF-κB activation in these cells in response to stimulation with the GPCR agonist lysophosphatidic acid. In this study, we demonstrate that reduced levels of CARMA3 in normal human bronchial epithelial cells decreases the production of proasthmatic mediators in response to a panel of asthma-relevant GPCR ligands such as lysophosphatidic acid, adenosine triphosphate, and allergens that activate GPCRs such as Alternaria alternata and house dust mite. We then show that genetically modified mice with CARMA3-deficient AECs have reduced airway eosinophilia and proinflammatory cytokine production in a murine model of allergic airway inflammation. Additionally, we demonstrate that these mice have impaired dendritic cell maturation in the lung and that dendritic cells from mice with CARMA3-deficient AECs have impaired Ag processing. In conclusion, we show that AEC CARMA3 helps mediate allergic airway inflammation, and that CARMA3 is a critical signaling molecule bridging the innate and adaptive immune responses in the lung. PMID:26041536

TNF is required for TLR ligand-mediated but not protease-mediated allergic airway inflammation.

PubMed

Whitehead, Gregory S; Thomas, Seddon Y; Shalaby, Karim H; Nakano, Keiko; Moran, Timothy P; Ward, James M; Flake, Gordon P; Nakano, Hideki; Cook, Donald N

2017-09-01

Asthma is associated with exposure to a wide variety of allergens and adjuvants. The extent to which overlap exists between the cellular and molecular mechanisms triggered by these various agents is poorly understood, but it might explain the differential responsiveness of patients to specific therapies. In particular, it is unclear why some, but not all, patients benefit from blockade of TNF. Here, we characterized signaling pathways triggered by distinct types of adjuvants during allergic sensitization. Mice sensitized to an innocuous protein using TLR ligands or house dust extracts as adjuvants developed mixed eosinophilic and neutrophilic airway inflammation and airway hyperresponsiveness (AHR) following allergen challenge, whereas mice sensitized using proteases as adjuvants developed predominantly eosinophilic inflammation and AHR. TLR ligands, but not proteases, induced TNF during allergic sensitization. TNF signaled through airway epithelial cells to reprogram them and promote Th2, but not Th17, development in lymph nodes. TNF was also required during the allergen challenge phase for neutrophilic and eosinophilic inflammation. In contrast, TNF was dispensable for allergic airway disease in a protease-mediated model of asthma. These findings might help to explain why TNF blockade improves lung function in only some patients with asthma.

TNF is required for TLR ligand–mediated but not protease-mediated allergic airway inflammation

PubMed Central

Whitehead, Gregory S.; Thomas, Seddon Y.; Shalaby, Karim H.; Nakano, Keiko; Moran, Timothy P.; Ward, James M.; Flake, Gordon P.; Cook, Donald N.

2017-01-01

Asthma is associated with exposure to a wide variety of allergens and adjuvants. The extent to which overlap exists between the cellular and molecular mechanisms triggered by these various agents is poorly understood, but it might explain the differential responsiveness of patients to specific therapies. In particular, it is unclear why some, but not all, patients benefit from blockade of TNF. Here, we characterized signaling pathways triggered by distinct types of adjuvants during allergic sensitization. Mice sensitized to an innocuous protein using TLR ligands or house dust extracts as adjuvants developed mixed eosinophilic and neutrophilic airway inflammation and airway hyperresponsiveness (AHR) following allergen challenge, whereas mice sensitized using proteases as adjuvants developed predominantly eosinophilic inflammation and AHR. TLR ligands, but not proteases, induced TNF during allergic sensitization. TNF signaled through airway epithelial cells to reprogram them and promote Th2, but not Th17, development in lymph nodes. TNF was also required during the allergen challenge phase for neutrophilic and eosinophilic inflammation. In contrast, TNF was dispensable for allergic airway disease in a protease-mediated model of asthma. These findings might help to explain why TNF blockade improves lung function in only some patients with asthma. PMID:28758900

A 4-Week Model of House Dust Mite (HDM) Induced Allergic Airways Inflammation with Airway Remodeling.

PubMed

Woo, L N; Guo, W Y; Wang, X; Young, A; Salehi, S; Hin, A; Zhang, Y; Scott, J A; Chow, C W

2018-05-02

Animal models of allergic airways inflammation are useful tools in studying the pathogenesis of asthma and potential therapeutic interventions. The different allergic airways inflammation models available to date employ varying doses, frequency, duration and types of allergen, which lead to the development of different features of asthma; showing varying degrees of airways inflammation and hyper-responsiveness (AHR) and airways remodeling. Models that also exhibit airway remodeling, a key feature of asthma, in addition to AHR and airway inflammation typically require 5-12 weeks to develop. In this report, we describe a 4-week mouse model of house dust mite (HDM)-induced allergic airways inflammation, and compare the phenotypic features of two different doses of HDM exposures (10 µg and 25 µg) for 5 days/week with a well-characterized 8-week chronic HDM model. We found that 4 weeks of intranasal HDM (25 µg in 35 µl saline; 5 days/week) resulted in AHR, airway inflammation and airway remodeling that were comparable to the 8-week model. We conclude that this new 4-week HDM model is another useful tool in studies of human asthma that offers advantages of shorter duration for development and decreased costs when compared to other models that require longer durations of exposure (5-12 weeks) to develop.

Preventive Intra Oral Treatment of Sea Cucumber Ameliorate OVA-Induced Allergic Airway Inflammation.

PubMed

Lee, Da-In; Park, Mi-Kyung; Kang, Shin Ae; Choi, Jun-Ho; Kang, Seok-Jung; Lee, Jeong-Yeol; Yu, Hak Sun

2016-01-01

Sea cucumber extracts have potent biological effects, including anti-viral, anti-cancer, antibacterial, anti-oxidant, and anti-inflammation effects. To understand their anti-asthma effects, we induced allergic airway inflammation in mice after 7 oral administrations of the extract. The hyper-responsiveness value in mice with ovalbumin (OVA)-alum-induced asthma after oral injection of sea cucumber extracts was significantly lower than that in the OVA-alum-induced asthma group. In addition, the number of eosinophils in the lungs of asthma-induced mice pre-treated with sea cucumber extract was significantly decreased compared to that of PBS pre-treated mice. Additionally, CD4[Formula: see text]CD25[Formula: see text]Foxp3[Formula: see text]T (regulatory T; Treg) cells significantly increased in mesenteric lymph nodes after 7 administrations of the extract. These results suggest that sea cucumber extract can ameliorate allergic airway inflammation via Treg cell activation and recruitment to the lung.

CARMA3 Is Critical for the Initiation of Allergic Airway Inflammation.

PubMed

Causton, Benjamin; Ramadas, Ravisankar A; Cho, Josalyn L; Jones, Khristianna; Pardo-Saganta, Ana; Rajagopal, Jayaraj; Xavier, Ramnik J; Medoff, Benjamin D

2015-07-15

Innate immune responses to allergens by airway epithelial cells (AECs) help initiate and propagate the adaptive immune response associated with allergic airway inflammation in asthma. Activation of the transcription factor NF-κB in AECs by allergens or secondary mediators via G protein-coupled receptors (GPCRs) is an important component of this multifaceted inflammatory cascade. Members of the caspase recruitment domain family of proteins display tissue-specific expression and help mediate NF-κB activity in response to numerous stimuli. We have previously shown that caspase recruitment domain-containing membrane-associated guanylate kinase protein (CARMA)3 is specifically expressed in AECs and mediates NF-κB activation in these cells in response to stimulation with the GPCR agonist lysophosphatidic acid. In this study, we demonstrate that reduced levels of CARMA3 in normal human bronchial epithelial cells decreases the production of proasthmatic mediators in response to a panel of asthma-relevant GPCR ligands such as lysophosphatidic acid, adenosine triphosphate, and allergens that activate GPCRs such as Alternaria alternata and house dust mite. We then show that genetically modified mice with CARMA3-deficient AECs have reduced airway eosinophilia and proinflammatory cytokine production in a murine model of allergic airway inflammation. Additionally, we demonstrate that these mice have impaired dendritic cell maturation in the lung and that dendritic cells from mice with CARMA3-deficient AECs have impaired Ag processing. In conclusion, we show that AEC CARMA3 helps mediate allergic airway inflammation, and that CARMA3 is a critical signaling molecule bridging the innate and adaptive immune responses in the lung. Copyright © 2015 by The American Association of Immunologists, Inc.

Exacerbation of allergic inflammation in mice exposed to diesel exhaust particles prior to viral infection

PubMed Central

Jaspers, Ilona; Sheridan, Patricia A; Zhang, Wenli; Brighton, Luisa E; Chason, Kelly D; Hua, Xiaoyang; Tilley, Stephen L

2009-01-01

Background Viral infections and exposure to oxidant air pollutants are two of the most important inducers of asthma exacerbation. Our previous studies have demonstrated that exposure to diesel exhaust increases the susceptibility to influenza virus infections both in epithelial cells in vitro and in mice in vivo. Therefore, we examined whether in the setting of allergic asthma, exposure to oxidant air pollutants enhances the susceptibility to respiratory virus infections, which in turn leads to increased virus-induced exacerbation of asthma. Ovalbumin-sensitized (OVA) male C57BL/6 mice were instilled with diesel exhaust particles (DEP) or saline and 24 hours later infected with influenza A/PR/8. Animals were sacrificed 24 hours post-infection and analyzed for markers of lung injury, allergic inflammation, and pro-inflammatory cytokine production. Results Exposure to DEP or infection with influenza alone had no significant effects on markers of injury or allergic inflammation. However, OVA-sensitized mice that were exposed to DEP and subsequently infected with influenza showed increased levels of eosinophils in lung lavage and tissue. In addition Th2-type cytokines, such as IL-4 and IL-13, and markers of eosinophil chemotaxis, such as CCL11 and CCR3, were increased in OVA-sensitized mice exposed to DEP prior to infection with influenza. These mice also showed increased levels of IL-1α, but not IL-10, RANTES, and MCP-1 in lung homogenates. Conclusion These data suggest that in the setting of allergic asthma, exposure to diesel exhaust could enhance virus-induced exacerbation of allergic inflammation. PMID:19682371

CDIP-2, a synthetic peptide derived from chemokine (C-C motif) ligand 13 (CCL13), ameliorates allergic airway inflammation

PubMed Central

Mendez-Enriquez, E; Melendez, Y; Martinez, F; Baay, G; Huerta-Yepez, S; Gonzalez-Bonilla, C; Fortoul, T I; Soldevila, G; García-Zepeda, E A

2008-01-01

Airway inflammation is characterized by selective recruitment of mononuclear and granulocytic cells. This recruitment is mediated by the action of chemotactic cytokines, such as chemokines. A number of chemokines and their receptors have been identified and proposed as potential therapeutic agents in allergic airway inflammation. One of these chemokines is chemokine (C-C motif) ligand 13 (CCL13), a CC chemokine that has been associated with allergic inflammatory diseases such as asthma and allergic rhinitis. To investigate alternative therapeutic agents to alleviate allergic inflammatory diseases, a number of chemokine-derived synthetic peptides were designed and tested for their ability to modulate in vitro and in vivo chemokine-mediated functions. Our results show that one of these peptides, CDIP-2, displayed antagonist functions in in vitro chemotaxis assays using monocytic cell lines. In addition, we found that CDIP-2 significantly reduced peribronchial, perivascular infiltrate and mucus overproduction in an ovalbumin-induced allergic lung inflammation murine model. Thus, CDIP-2 may be considered as part of a novel group of anti-inflammatory agents based on chemokine-derived synthetic peptides. PMID:18336592

CDIP-2, a synthetic peptide derived from chemokine (C-C motif) ligand 13 (CCL13), ameliorates allergic airway inflammation.

PubMed

Mendez-Enriquez, E; Melendez, Y; Martinez, F; Baay, G; Huerta-Yepez, S; Gonzalez-Bonilla, C; Fortoul, T I; Soldevila, G; García-Zepeda, E A

2008-05-01

Airway inflammation is characterized by selective recruitment of mononuclear and granulocytic cells. This recruitment is mediated by the action of chemotactic cytokines, such as chemokines. A number of chemokines and their receptors have been identified and proposed as potential therapeutic agents in allergic airway inflammation. One of these chemokines is chemokine (C-C motif) ligand 13 (CCL13), a CC chemokine that has been associated with allergic inflammatory diseases such as asthma and allergic rhinitis. To investigate alternative therapeutic agents to alleviate allergic inflammatory diseases, a number of chemokine-derived synthetic peptides were designed and tested for their ability to modulate in vitro and in vivo chemokine-mediated functions. Our results show that one of these peptides, CDIP-2, displayed antagonist functions in in vitro chemotaxis assays using monocytic cell lines. In addition, we found that CDIP-2 significantly reduced peribronchial, perivascular infiltrate and mucus overproduction in an ovalbumin-induced allergic lung inflammation murine model. Thus, CDIP-2 may be considered as part of a novel group of anti-inflammatory agents based on chemokine-derived synthetic peptides.

Platelet–Eosinophil Interactions As a Potential Therapeutic Target in Allergic Inflammation and Asthma

PubMed Central

Shah, Sajeel A.; Page, Clive P.; Pitchford, Simon C.

2017-01-01

The importance of platelet activation during hemostasis is well understood. An understanding of these mechanisms has led to the use of several classes of anti-platelet drugs to inhibit aggregation for the prevention of thrombi during cardiovascular disease. It is now also recognized that platelets can function very differently during inflammation, as part of their role in the innate immune response against pathogens. This dichotomy in platelet function occurs through distinct physiological processes and alternative signaling pathways compared to that of hemostasis (leading to platelet aggregation) and is manifested as increased rheological interactions with leukocytes, the ability to undergo chemotaxis, communication with antigen-presenting cells, and direct anti-pathogen responses. Mounting evidence suggests platelets are also critical in the pathogenesis of allergic diseases such as asthma, where they have been associated with antigen presentation, bronchoconstriction, bronchial hyperresponsiveness, airway inflammation, and airway remodeling in both clinical and experimental studies. In particular, platelets have been reported bound to eosinophils in the blood of patients with asthma and the incidence of these events increases after both spontaneous asthma attacks in a biphasic manner, or after allergen challenge in the clinic. Platelet depletion in animal models of allergic airway inflammation causes a profound reduction in eosinophil recruitment to the lung, suggesting that the association of platelets with eosinophils is indeed an important event during eosinophil activation. Furthermore, in cases of severe asthma, and in animal models of allergic airways inflammation, platelet–eosinophil complexes move into the lung through a platelet P-selectin-mediated, eosinophil β1-integrin activation-dependent process, while platelets increase adherence of eosinophils to the vascular endothelium in vitro, demonstrating a clear interaction between these cell types in

Insulin Receptor Substrate (IRS)-2 negatively regulates alternative macrophage activation and allergic lung inflammation

PubMed Central

Dasgupta, Preeta; Dorsey, Nicolas J.; Li, Jiaqi; Qi, Xiulan; Smith, Elizabeth P.; Yamaji-Kegan, Kazuyo; Keegan, Achsah D.

2017-01-01

Insulin Receptor Substrate (IRS)-2 is an adaptor protein that becomes tyrosine phosphorylated in response to IL-4 and IL-13 resulting in activation of the PI-3′ kinase/Akt pathway. While the contribution of IL-4 and IL-13 to allergic lung inflammation has been studied extensively, the functional significance of the IRS2 pathway is unclear. To examine the role of IRS2 in allergic disease, we evaluated responses in IRS2-deficient mice. Deficiency of IRS2 resulted in a substantial increase in expression of a subset of genes associated with alternatively activated macrophages (AAM) in response to IL-4 or IL-13 in vitro. Moreover, IRS2+/− and IRS2−/− mice developed enhanced pulmonary inflammation, accumulation of eosinophils and AAM, and airway and vascular remodeling upon allergen stimulation in comparison to IRS2+/+ mice; this enhanced response was in part macrophage intrinsic. Loss of IRS2 led to greater phosphorylation of Akt and ribosomal S6 protein in the basal state and upon IL-4 stimulation. Thus, we identify a critical negative regulatory loop downstream of IRS2, demonstrating a previously unrecognized role for IRS2 in suppressing allergic lung inflammation and remodeling. PMID:27330190

Immunomodulation: the future cure for allergic diseases.

PubMed

Tsitoura, Daphne C; Tassios, Yannis

2006-11-01

Allergies are the result of aberrant immune reactivity against common innocuous environmental proteins (allergens). A pivotal component of allergic pathogenesis is the generation of allergen-specific Th cells with an effector phenotype. These Th cells activate a complex immune cascade that triggers the release of potent mediators and enhances the mobilization of several inflammatory cells types, which in turn elicit the acute allergic reactions and promote the development of chronic inflammation. The current therapies for allergic diseases focus primarily on pharmacological control of symptoms and suppression of inflammation. This approach is beneficial, but not curative, since the underlying immune pathology is not inhibited. In an attempt to develop more effective therapeutic strategies, the scientific interest has been directed toward methods down-modulating the immune mechanisms that initiate and maintain the allergic cascade. Today, the only widely used disease-modifying form of allergy treatment is the specific immunotherapy with allergen extracts. More recently the use of anti-IgE has been approved for patients with allergic asthma. Other immunomodulatory methods being currently explored are the administration of microbial adjuvants that inhibit Th2 reactivity and the design of molecules that interrupt the activity of key allergic cytokines, chemokines, or other Th2 effector mediators.

Effects of multi-walled carbon nanotubes on a murine allergic airway inflammation model

DOE Office of Scientific and Technical Information (OSTI.GOV)

Inoue, Ken-ichiro; Koike, Eiko; Yanagisawa, Rie

The development of nanotechnology has increased the risk of exposure to types of particles other than combustion-derived particles in the environment, namely, industrial nanomaterials. On the other hand, patients with bronchial asthma are sensitive to inhaled substances including particulate matters. This study examined the effects of pulmonary exposure to a type of nano-sized carbon nanotube (multi-walled nanotubes: MWCNT) on allergic airway inflammation in vivo and their cellular mechanisms in vitro. In vivo, ICR mice were divided into 4 experimental groups. Vehicle, MWCNT (50 {mu}g/animal), ovalbumin (OVA), and OVA + MWCNT were repeatedly administered intratracheally. Bronchoalveolar lavage (BAL) cellularity, lung histology,more » levels of cytokines related to allergic inflammation in lung homogenates/BAL fluids (BALFs), and serum immunoglobulin levels were studied. Also, we evaluated the impact of MWCNT (0.1-1 {mu}g/ml) on the phenotype and function of bone marrow-derived dendritic cells (DC) in vitro. MWCNT aggravated allergen-induced airway inflammation characterized by the infiltration of eosinophils, neutrophils, and mononuclear cells in the lung, and an increase in the number of goblet cells in the bronchial epithelium. MWCNT with allergen amplified lung protein levels of Th cytokines and chemokines compared with allergen alone. MWCNT exhibited adjuvant activity for allergen-specific IgG{sub 1} and IgE. MWCNT significantly increased allergen (OVA)-specific syngeneic T-cell proliferation, particularly at a lower concentration in vitro. Taken together, MWCNT can exacerbate murine allergic airway inflammation, at least partly, via the promotion of a Th-dominant milieu. In addition, the exacerbation may be partly through the inappropriate activation of antigen-presenting cells including DC.« less

PKCλ/ι regulates Th17 differentiation and house dust mite-induced allergic airway inflammation.

PubMed

Yang, Yingying; Dong, Panpan; Zhao, Jing; Zhou, Wei; Zhou, Yonghua; Xu, Yongliang; Mei, Congjin; Guo, Fukun; Zheng, Yi; Yang, Jun-Qi

2018-03-01

Asthma is a chronic airway inflammation in which Th2 and Th17 cells play critical roles in its pathogenesis. We have reported that atypical protein kinase (PKC) λ/ι is a new regulator for Th2 differentiation and function. However, the role of PKCλ/ι for Th17 cells remains elusive. In this study, we explored the effect of PKCλ/ι on Th17 cells in the context of ex vivo cell culture systems and an in vivo murine model of allergic airway inflammation with the use of activated T cell-specific conditional PKCλ/ι-deficient mice. Our findings indicate that PKCλ/ι regulates Th17 cells. The secretion of Th17 effector cytokines, including IL-17, IL-21 and IL-22, were inhibited from PKCλ/ι-deficient T cells under non-skewing or Th17-skewing culture conditions. Moreover, the impaired Th17 differentiation and function by the PKCλ/ι-deficiency was associated with the downregulation of Stat3 and Rorγt, key Th17 transcription factors. We developed a model of Th17 and neutrophil-involved allergic airway inflammation by intratracheal inoculation of house dust mites. PKCλ/ι-deficiency significantly inhibited airway inflammations. The infiltrating cells in the lungs and bronchoalveolar lavage fluids were significantly reduced in conditional PKCλ/ι-deficient mice. Th17 effector cytokines were reduced in the bronchoalveolar lavage fluids and lungs at protein and mRNA levels. Thus, PKCλ/ι emerges as a critical regulator of Th17 differentiation and allergic airway hyperresponsiveness. Copyright © 2018 Elsevier B.V. All rights reserved.

Protease-activated receptor 2 activation of myeloid dendritic cells regulates allergic airway inflammation

PubMed Central

2011-01-01

Background A common characteristic of allergens is that they contain proteases that can activate protease-activated receptor (PAR-2); however the mechanism by which PAR-2 regulates allergic airway inflammation is unclear. Methods Mice (wild type and PAR-2-deficient) were sensitized using German cockroach (GC) feces (frass), the isolated protease from GC frass, or through adoptive transfer of GC frass-treated bone marrow-derived dendritic cells (BMDC) and measurements of airway inflammation (cellular infiltration, cytokine expression, and mucin production), serum IgE levels and airway hyperresponsiveness (AHR) were assessed. BMDC were cultured, treated with GC frass and assessed for cytokine production. PAR-2 expression on pulmonary mDCs was determined by flow cytometry. Results Exposure to GC frass induced AHR and airway inflammation in wild type mice; however PAR-2-deficient mice had significantly attenuated responses. To directly investigate the role of the protease, we isolated the protease from GC frass and administered the endotoxin-free protease into the airways of mice in the presence of OVA. GC frass proteases were sufficient to promote the development of AHR, serum IgE, and Th2 cytokine production. PAR-2 expression on mDC was upregulated following GC frass exposure, but the presence of a functional PAR-2 did not alter antigen uptake. To determine if PAR-2 activation led to differential cytokine production, we cultured BMDC in the presence of GM-CSF and treated these cells ex vivo with GC frass. PAR-2-deficient BMDC released significantly less IL-6, IL-23 and TNFα compared to BMDC from wild type mice, suggesting PAR-2 activation was important in Th2/Th17 skewing cytokine production. To determine the role for PAR-2 on mDCs on the initiation of allergic airway inflammation, BMDCs from wild type and PAR-2-deficient mice were treated in the presence or absence of GC frass and then adoptively transferred into the airway of wild type mice. Importantly, GC frass

Black seed oil ameliorates allergic airway inflammation by inhibiting T-cell proliferation in rats.

PubMed

Shahzad, Muhammad; Yang, Xudong; Raza Asim, M B; Sun, Qingzhu; Han, Yan; Zhang, Fujun; Cao, Yongxiao; Lu, Shemin

2009-02-01

The black seeds, from the Ranunculaceae family, have been traditionally used by various cultures as a natural remedy for several ailments. In this study, we examined the effect of black seed oil as an immunomodulator in a rat model of allergic airway inflammation. Rats sensitized to ovalbumin and challenged intranasally with ovalbumin to induce an allergic inflammatory response were compared to ovalbumin-sensitized, intranasally ovalbumin-exposed rats pretreated with intraperitoneally administered black seed oil and to control rats. The levels of IgE, IgG1 and ova-specific T-cell proliferation in spleen were measured by ELISA. The pro-inflammatory cytokine IL-4, IL-5, IL-6 and TGF-beta1 mRNA expression levels were measured by reverse transcription polymerase chain reaction. The intraperitoneal administration of black seed oil inhibited the Th2 type immune response in rats by preventing inflammatory cell infiltration and pathological lesions in the lungs. It significantly decreased the nitric oxide production in BALF, total serum IgE, IgG1 and OVA-specific IgG1 along with IL-4, IL-5, IL-6 and TGF-beta1 mRNA expression. Black seed oil treatment resulted in decreased T-cell response evident by lesser delayed type hypersensitivity and lower T-cell proliferation in spleen. In conclusion, black seed oil exhibited a significant reduction in all the markers of allergic inflammation mainly by inhibiting the delayed type hypersensitivity and T-cell proliferation. The data suggests that inhibition of T-cell response may be responsible for immunomodulatory effect of black seed oil in the rat model of allergic airway inflammation.

MAG-EPA resolves lung inflammation in an allergic model of asthma.

PubMed

Morin, C; Fortin, S; Cantin, A M; Rousseau, É

2013-09-01

Asthma is a chronic disease characterized by airways hyperresponsiveness, inflammation and airways remodelling involving reversible bronchial obstruction. Omega-3 fatty acids and their derivatives are known to reduce inflammation in several tissues including lung. The effects of eicosapentaenoic acid monoacylglyceride (MAG-EPA), a newly synthesized EPA derivative, were determined on the resolution of lung inflammation and airway hyperresponsiveness in an in vivo model of allergic asthma. Ovalbumin (OVA)-sensitized guinea-pigs were treated or not with MAG-EPA administered per os. Isometric tension measurements, histological analyses, homogenate preparation for Western blot experiments or total RNA extraction for RT-PCR were performed to assess the effect of MAG-EPA treatments. Mechanical tension measurements revealed that oral MAG-EPA treatments reduced methacholine (MCh)-induced bronchial hyperresponsiveness in OVA-sensitized guinea-pigs. Moreover, MAG-EPA treatments also decreased Ca(2+) hypersensitivity of bronchial smooth muscle. Histological analyses and leucocyte counts in bronchoalveolar lavages revealed that oral MAG-EPA treatments led to less inflammatory cell recruitment in the lung of OVA-sensitized guinea-pigs when compared with lungs from control animals. Results also revealed a reduction in mucin production and MUC5AC expression level in OVA-sensitized animals treated with MAG-EPA. Following MAG-EPA treatments, the transcript levels of pro-inflammatory markers such as IL-5, eotaxin, IL-13 and IL-4 were markedly reduced. Moreover, per os MAG-EPA administrations reduced COX2 over-expression in OVA-sensitized animals. We demonstrate that MAG-EPA reduces airway hyperresponsiveness and lung inflammation in OVA-sensitized animals, a finding consistent with a decrease in IL-4, IL-5, IL-13, COX-2 and MUC5AC expression levels in the lung. The present data suggest that MAG-EPA represents a new potential therapeutic strategy for resolving inflammation in allergic

8-oxoguanine DNA glycosylase 1-deficiency modifies allergic airway inflammation by regulating STAT6 and IL-4 in cells and in mice

USDA-ARS?s Scientific Manuscript database

Background: 8-oxoguanine-DNA glycosylase (OGG-1) is an enzyme involved in DNA repair. OGG-1 has a potential role in regulating inflammation but its function in modulating allergic diseases remains undefined. Objectives: To investigate the role of OGG-1 in mediating allergic inflammation, we used OGG...

Evaluation of eicosanoids in nasal lavage as biomarkers of inflammation in patients with allergic rhinitis

PubMed Central

Górski, Paweł; Antczak, Adam

2014-01-01

Introduction Cysteinyl leukotrienes (cys-LTs), 8-isoprostane and prostaglandin E2 (PGE2) constitute fundamental mediators in allergic inflammation; therefore we wanted to determine the utility of PGE2, 8-isoprostane and cys-LT levels in nasal lavage as biomarkers of allergic inflammation. Material and methods Twenty-one patients with allergic rhinitis (AR) were included on the basis of a positive history of AR symptoms and positive results of skin prick tests to grass pollen allergens. The main exclusion criteria were: uncontrolled asthma, nasal polyps, respiratory infection, tuberculosis, neoplastic and autoimmune diseases, current smoking and immunotherapy. Both outside the pollen season and at the height of the pollen season, total nasal symptom score (TNS-4) was evaluated and the levels of cys-LTs, 8-isoprostane and PGE2 were measured in nasal lavage fluid (NALF). Results Natural allergen stimulation resulted in a significant increase of TNS-4 (p < 0.001) and nasal eosinophilia (p < 0.001). The concentration of PGE2 dominated in the NALF outside the pollen season and decreased significantly at the height of natural exposure (p < 0.01). In contrast, lower baseline concentrations of cys-LTs and 8-isoprostane increased significantly upon allergen stimulation (p < 0.05). There was a significant correlation between mean concentration of PGE2 and eosinophil number in NALF (r = 0.67, p = 0.0439). Conclusions The NALF concentrations of cys-LTs and 8-isoprostane change simultaneously with TNS-4 and nasal eosinophilia. However, due to the lack of any significant correlation, their utility as markers of allergic rhinitis should be warily considered. The decrease of PGE2 concentration in NALF which correlated with nasal eosinophilia may participate in escalation of allergic inflammation and needs further evaluation. PMID:25624848

Eosinophils as a novel cell source of prostaglandin D2: autocrine role in allergic inflammation

PubMed Central

Luna-Gomes, Tatiana; Magalhães, Kelly G; Mesquita-Santos, Fabio P.; Bakker-Abreu, Ilka; Samico, Rafaela F.; Molinaro, Raphael; Calheiros, Andrea S.; Diaz, Bruno L.; Bozza, Patrícia T.

2011-01-01

Prostaglandin (PG)D2 is a key mediator of allergic inflammatory diseases that is mainly synthesized by mast cells, which constitutively express high levels of the terminal enzyme involved in PGD2 synthesis, the hematopoietic PGD synthase (H-PGDS). Here, we investigated whether eosinophils are also able to synthesize, and therefore, supply biologically active PGD2. PGD2 synthesis was evaluated within human blood eosinophils, in vitro-differentiated mouse eosinophils, and eosinophils infiltrating inflammatory site of mouse allergic reaction. Biological function of eosinophil-derived PGD2 was studied by employing inhibitors of synthesis and activity. Constitutive expression of H-PGDS was found within non-stimulated human circulating eosinophils. Acute stimulation of human eosinophils with A23187 (0.1 – 5 μM) evoked PGD2 synthesis, which was located at the nuclear envelope and was inhibited by pre-treatment with HQL-79 (10 μM), a specific H-PGDS inhibitor. Pre-stimulation of human eosinophils with arachidonic acid (AA; 10 μM) or human eotaxin (6 nM) also enhanced HQL-79-sensitive PGD2 synthesis, which, by acting on membrane-expressed specific receptors (DP1 and DP2), displayed an autocrine/paracrine ability to trigger leukotriene (LT)C4 synthesis and lipid body biogenesis, hallmark events of eosinophil activation. In vitro-differentiated mouse eosinophils also synthesized paracrine/autocrine active PGD2 in response to AA stimulation. In vivo, at late time point of the allergic reaction, infiltrating eosinophils found at the inflammatory site appeared as an auxiliary PGD2-synthesizing cell population. Our findings reveal that eosinophils are indeed able to synthesize and secrete PGD2, hence representing during allergic inflammation an extra cell source of PGD2, which functions as an autocrine signal for eosinophil activation. PMID:22102725

Propofol inhibits NF-κB activation to ameliorate airway inflammation in ovalbumin (OVA)-induced allergic asthma mice.

PubMed

Zhang, Qiong; Wang, Liangrong; Chen, Baihui; Zhuo, Qian; Bao, Caiying; Lin, Lina

2017-10-01

Propofol, one of the most commonly used intravenous anesthetic agents, has been reported to have anti-inflammatory property. However, the anti-allergic inflammation effect of propofol and its underlying molecular mechanisms have not been elucidated. In the present study, we aim to investigate the roles of NF-kB activation in propofol anti-asthma effect on OVA-induced allergic airway inflammation in mice. In a standard experimental asthma model, Balb/c mice were sensitized with ovalbumin, treated with propofol (50,100,150mg/kg) or a vehicle control 1h before OVA challenge. Blood samples, bronchoalveolar lavage fluid (BALF) and lung tissues were harvested after measurement of airway hyperresponsiveness. Results revealed that propofol not only significantly inhibit airway hyperresponsiveness, but also inhibited the production of Th2 cytokines, NO, Ova-specific IgE and eotaxin. Histological studies indicated that propofol significantly attenuated OVA-induced inflammatory cell infiltration in the peribronchial areas and mucus hypersecretion. Meanwhile, our results indicated that propofol was found to inhibit NF-kB activation in OVA-Induced mice. Furthermore, propofol significantly reduced the TNF-α-induced NF-kB activation in A549 cells. In conclusion, our study suggested that propofol effectively reduced allergic airway inflammation by inhibiting NF-kB activation and could thus be used as a therapy for allergic asthma. Copyright © 2017. Published by Elsevier B.V.

Diesel exhaust augments allergen-induced lower airway inflammation in allergic individuals: a controlled human exposure study.

PubMed

Carlsten, Chris; Blomberg, Anders; Pui, Mandy; Sandstrom, Thomas; Wong, Sze Wing; Alexis, Neil; Hirota, Jeremy

2016-01-01

Traffic-related air pollution has been shown to augment allergy and airway disease. However, the enhancement of allergenic effects by diesel exhaust in particular is unproven in vivo in the human lung, and underlying details of this apparent synergy are poorly understood. To test the hypothesis that a 2 h inhalation of diesel exhaust augments lower airway inflammation and immune cell activation following segmental allergen challenge in atopic subjects. 18 blinded atopic volunteers were exposed to filtered air or 300 µg PM(2.5)/m(3) of diesel exhaust in random fashion. 1 h post-exposure, diluent-controlled segmental allergen challenge was performed; 2 days later, samples from the challenged segments were obtained by bronchoscopic lavage. Samples were analysed for markers and modifiers of allergic inflammation (eosinophils, Th2 cytokines) and adaptive immune cell activation. Mixed effects models with ordinal contrasts compared effects of single and combined exposures on these end points. Diesel exhaust augmented the allergen-induced increase in airway eosinophils, interleukin 5 (IL-5) and eosinophil cationic protein (ECP) and the GSTT1 null genotype was significantly associated with the augmented IL-5 response. Diesel exhaust alone also augmented markers of non-allergic inflammation and monocyte chemotactic protein (MCP)-1 and suppressed activity of macrophages and myeloid dendritic cells. Inhalation of diesel exhaust at environmentally relevant concentrations augments allergen-induced allergic inflammation in the lower airways of atopic individuals and the GSTT1 genotype enhances this response. Allergic individuals are a susceptible population to the deleterious airway effects of diesel exhaust. NCT01792232. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

Chimeric Antigen Receptor-Redirected Regulatory T Cells Suppress Experimental Allergic Airway Inflammation, a Model of Asthma.

PubMed

Skuljec, Jelena; Chmielewski, Markus; Happle, Christine; Habener, Anika; Busse, Mandy; Abken, Hinrich; Hansen, Gesine

2017-01-01

Cellular therapy with chimeric antigen receptor (CAR)-redirected cytotoxic T cells has shown impressive efficacy in the treatment of hematologic malignancies. We explored a regulatory T cell (Treg)-based therapy in the treatment of allergic airway inflammation, a model for asthma, which is characterized by an airway hyper-reactivity (AHR) and a chronic, T helper-2 (Th2) cell-dominated immune response to allergen. To restore the immune balance in the lung, we redirected Tregs by a CAR toward lung epithelia in mice upon experimentally induced allergic asthma, closely mimicking the clinical situation. Adoptively transferred CAR Tregs accumulated in the lung and in tracheobronchial lymph nodes, reduced AHR and diminished eosinophilic airway inflammation, indicated by lower cell numbers in the bronchoalveolar lavage fluid and decreased cell infiltrates in the lung. CAR Treg cells furthermore prevented excessive pulmonary mucus production as well as increase in allergen-specific IgE and Th2 cytokine levels in exposed animals. CAR Tregs were more efficient in controlling asthma than non-modified Tregs, indicating the pivotal role of specific Treg cell activation in the affected organ. Data demonstrate that lung targeting CAR Treg cells ameliorate key features of experimental airway inflammation, paving the way for cell therapy of severe allergic asthma.

Induction of Thymic Stromal Lymphopoietin Production by Nonanoic Acid and Exacerbation of Allergic Inflammation in Mice

PubMed Central

Yamashita, Saori; Segawa, Ryosuke; Satou, Nozomi; Hiratsuka, Masahiro; Leonard, Warren J.; Hirasawa, Noriyasu

2013-01-01

Background Thymic stromal lymphopoietin (TSLP) plays critical roles in the induction and exacerbation of allergic diseases. We tested various chemicals in the environment and found that xylene and 1,2,4-trimethylbenzene induced the production of TSLP in vivo. These findings prompted us to search for additional chemicals that induce TSLP production. In this study, we examined whether fatty acids could induce the production of TSLP in vivo and exacerbate allergic inflammation. Methods Various fatty acids and related compounds were painted on the ear lobes of mice and the amount of TSLP in the homogenate of ear lobe tissue was determined. The effects of nonanoic acid on allergic inflammation were also examined. Results Octanoic acid, nonanoic acid, and decanoic acid markedly induced TSLP production, while a medium-chain aldehyde and alcohol showed only weak activity. Nonanoic acid induced the production of TSLP with a maximum at 24 h. TSLP production was even observed in nonanoic acid-treated C3H/HeJ mice that lacked functional toll-like receptor 4. The aryl hydrocarbon receptor agonist β-naphthoflavone did not induce TSLP production. Nonanoic acid promoted sensitization to ovalbumin, resulting in an enhancement in the cutaneous anaphylactic response. In addition, painting of nonanoic acid after the sensitization augmented picryl chloride-induced thickening of the ear, which was reversed in TSLP receptor-deficient mice. Conclusion Nonanoic acid and certain fatty acids induced TSLP production, resulting in the exacerbation of allergic inflammation. We propose that TSLP-inducing chemical compounds such as nonanoic acid be recognized as chemical allergo-accelerators. PMID:24060765

Allergic asthma is distinguished by sensitivity of allergen-specific CD4+ T cells and airway structural cells to type 2 inflammation.

PubMed

Cho, Josalyn L; Ling, Morris F; Adams, David C; Faustino, Lucas; Islam, Sabina A; Afshar, Roshi; Griffith, Jason W; Harris, Robert S; Ng, Aylwin; Radicioni, Giorgia; Ford, Amina A; Han, Andre K; Xavier, Ramnik; Kwok, William W; Boucher, Richard; Moon, James J; Hamilos, Daniel L; Kesimer, Mehmet; Suter, Melissa J; Medoff, Benjamin D; Luster, Andrew D

2016-10-05

Despite systemic sensitization, not all allergic individuals develop asthma symptoms upon airborne allergen exposure. Determination of the factors that lead to the asthma phenotype in allergic individuals could guide treatment and identify novel therapeutic targets. We used segmental allergen challenge of allergic asthmatics (AA) and allergic nonasthmatic controls (AC) to determine whether there are differences in the airway immune response or airway structural cells that could drive the development of asthma. Both groups developed prominent allergic airway inflammation in response to allergen. However, asthmatic subjects had markedly higher levels of innate type 2 receptors on allergen-specific CD4 + T cells recruited into the airway. There were also increased levels of type 2 cytokines, increased total mucin, and increased mucin MUC5AC in response to allergen in the airways of AA subjects. Furthermore, type 2 cytokine levels correlated with the mucin response in AA but not AC subjects, suggesting differences in the airway epithelial response to inflammation. Finally, AA subjects had increased airway smooth muscle mass at baseline measured in vivo using novel orientation-resolved optical coherence tomography. Our data demonstrate that the development of allergic asthma is dependent on the responsiveness of allergen-specific CD4 + T cells to innate type 2 mediators as well as increased sensitivity of airway epithelial cells and smooth muscle to type 2 inflammation. Copyright © 2016, American Association for the Advancement of Science.

Baicalin ameliorates isoproterenol-induced acute myocardial infarction through iNOS, inflammation and oxidative stress in rat

PubMed Central

Chen, Huaguo; Xu, Yongfu; Wang, Jianzhong; Zhao, Wei; Ruan, Huihui

2015-01-01

Baicalin belongs to glucuronic acid glycosides and after hydrolysisbaicalein and glucuronic acid come into being. It has such effects as clearing heat and removing toxicity, anti-inflammation, choleresis, bringing high blood pressure down, diuresis, anti-allergic reaction and so on. In this study, we investigated whether baicalin ameliorates isoproterenol-induced acute myocardial infarction and its mechanism. Rat model of acute myocardial infarction was induced by isoproterenol. Casein kinase (CK), the MB isoenzyme of creatine kinase (CK-MB), lactate dehydrogenase (LDH), cardiac troponin T (cTnT) and infarct size measurement were used to measure the protective effect of baicalin on isoproterenol-induced acute myocardial infarction. iNOS protein expression in rat was analyzed using western blot analysis. Tumor necrosis factor-alpha (TNF-α), interleukin 6 (IL-6), malondialdehyde (MDA) and superoxide dismutase (SOD) and caspase-3 activation levels were explored using commercial ELISA kits. In the acute myocardial infarction experiment, baicalin effectively ameliorates the level of CK, CK-MB, LDH and cTnT, reduced infarct size in acute myocardial infarction rat model. Meanwhile, treatment with baicalin effectively decreased the iNOS protein expression, inflammatory factors and oxidative stresses in a rat model of acute myocardial infarction. However, baicalin emerged that anti-apoptosis activity and suppressed the activation of caspase-3 in a rat model of acute myocardial infarction. The data suggest that the protective effect of baicalin ameliorates isoproterenol-induced acute myocardial infarction through iNOS, inflammation and oxidative stress in rat. PMID:26617721

Topical ivermectin improves allergic skin inflammation.

PubMed

Ventre, E; Rozières, A; Lenief, V; Albert, F; Rossio, P; Laoubi, L; Dombrowicz, D; Staels, B; Ulmann, L; Julia, V; Vial, E; Jomard, A; Hacini-Rachinel, F; Nicolas, J-F; Vocanson, M

2017-08-01

Ivermectin (IVM) is widely used in both human and veterinary medicine to treat parasitic infections. Recent reports have suggested that IVM could also have anti-inflammatory properties. Here, we investigated the activity of IVM in a murine model of atopic dermatitis (AD) induced by repeated exposure to the allergen Dermatophagoides farinae, and in standard cellular immunological assays. Our results show that topical IVM improved allergic skin inflammation by reducing the priming and activation of allergen-specific T cells, as well as the production of inflammatory cytokines. While IVM had no major impact on the functions of dendritic cells in vivo and in vitro, IVM impaired T-cell activation, proliferation, and cytokine production following polyclonal and antigen-specific stimulation. Altogether, our results show that IVM is endowed with topical anti-inflammatory properties that could have important applications for the treatment of T-cell-mediated skin inflammatory diseases. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Oroxylin A Inhibits Allergic Airway Inflammation in Ovalbumin (OVA)-Induced Asthma Murine Model.

PubMed

Zhou, De-Gang; Diao, Bao-Zhong; Zhou, Wen; Feng, Jia-Long

2016-04-01

Oroxylin A, a natural flavonoid isolated from the medicinal herb Scutellaria baicalensis Georgi, has been reported to have anti-inflammatory property. In this study, we aimed to investigate the protective effects and mechanism of oroxylin A on allergic inflammation in OVA-induced asthma murine model. BABL/c mice were sensitized and airway-challenged with OVA to induce asthma. Oroxylin A (15, 30, and 60 mg/kg) was administered by oral gavage 1 h before the OVA treatment on day 21 to 23. The results showed that oroxylin A attenuated OVA-induced lung histopathologic changes, airway hyperresponsiveness, and the number of inflammatory cells. Oroxylin A also inhibited the levels of IL-4, IL-5, IL-13, and OVA-specific IgE in BALF. Furthermore, oroxylin A significantly inhibited OVA-induced NF-κB activation. In conclusion, these results suggested that oroxylin A inhibited airway inflammation in OVA-induced asthma murine model by inhibiting NF-κB activation. These results suggested that oroxylin A was a potential therapeutic drug for treating allergic asthma.

The role of protease activation of inflammation in allergic respiratory diseases.

PubMed

Reed, Charles E; Kita, Hirohito

2004-11-01

Extracellular endogenous proteases, as well as exogenous proteases from mites and molds, react with cell-surface receptors in the airways to generate leukocyte infiltration and to amplify the response to allergens. Stimulation leads to increased intracellular Ca ++ and gene transcription. The most thoroughly investigated receptors, protease-activated receptors (PARs), are 7-transmembrane proteins coupled to G proteins. PARs are widely distributed on the cells of the airways, where they contribute to the inflammation characteristic of allergic diseases. PAR stimulation of epithelial cells opens tight junctions, causes desquamation, and produces cytokines, chemokines, and growth factors. They degranulate eosinophils and mast cells. Proteases contract bronchial smooth muscle and cause it to proliferate. PARs also promote maturation, proliferation, and collagen production of fibroblast precursors and mature fibroblasts. PAR-2, apparently the most important of the 4 PARs that have been characterized, is increased on the epithelium of patients with asthma. Trypsin, a product of injured epithelial cells, and mast cell tryptase are potent activators of PAR-2. Mast cell chymase activates PAR-1. Proteases from mites and molds appear to act through similar receptors. They amplify IgE production to allergens, degranulate eosinophils, and can generate inflammation, even in the absence of IgE. Proteases produced by Aspergillus species to support its growth are presumably responsible for the exuberant IgE, IgG, and granulomatous response of allergic bronchopulmonary aspergillosis. Similar proteases from molds germinating on the respiratory mucosa have been recently been implicated in the pathogenesis of chronic hyperplastic rhinitis and polyps and, by extension, of intrinsic asthma. Finally, proteases from mites and fungi growing in damp, water-damaged buildings might be the basis for the increased prevalence in these buildings of rhinitis, asthma, and other respiratory diseases

Diesel Exhaust Exposure and Nasal Response to Attenuated Influenza in Normal and Allergic Volunteers

EPA Science Inventory

Rationale: Diesel exhaust enhances allergic inflammation, and pollutants are associated with heightened susceptibility to viral respiratory infections. The effects of combined diesel and virus exposure in humans are unknown. Objective: Test whether acute exposure to diesel modif...

[Allergic inflammation in respiratory system].

PubMed

An, Lifeng; Wang, Yanshu; Li, Lin

2015-02-01

The pathophysiology of allergic disease such as asthma and allergic rhinitis tell the similar story: when the endogenous and exogenous inflammatory mechanisms occur disorder, the body may begin with inflammatory cell activation, namely through the release of cytokine and inflammatory mediator role in the corresponding target cells, activate the sensory nerve fiber, acting on the cell organ specificity effect, clinical symptoms. This article is divided into the following five parts focused on the research progress of allergic inflammatory diseases: (1) inflammatory cells; (2) staphylococcus aureus superantigen; (3) small molecules (cytokines, inflammatory mediators, lipid classes medium); (4) nerve fibers and effect cells; (5) genetic and epigenetic factors.

Tyrosol Suppresses Allergic Inflammation by Inhibiting the Activation of Phosphoinositide 3-Kinase in Mast Cells.

PubMed

Je, In-Gyu; Kim, Duk-Sil; Kim, Sung-Wan; Lee, Soyoung; Lee, Hyun-Shik; Park, Eui Kyun; Khang, Dongwoo; Kim, Sang-Hyun

2015-01-01

Allergic diseases such as atopic dermatitis, rhinitis, asthma, and anaphylaxis are attractive research areas. Tyrosol (2-(4-hydroxyphenyl)ethanol) is a polyphenolic compound with diverse biological activities. In this study, we investigated whether tyrosol has anti-allergic inflammatory effects. Ovalbumin-induced active systemic anaphylaxis and immunoglobulin E-mediated passive cutaneous anaphylaxis models were used for the immediate-type allergic responses. Oral administration of tyrosol reduced the allergic symptoms of hypothermia and pigmentation in both animal models. Mast cells that secrete allergic mediators are key regulators on allergic inflammation. Tyrosol dose-dependently decreased mast cell degranulation and expression of inflammatory cytokines. Intracellular calcium levels and activation of inhibitor of κB kinase (IKK) regulate cytokine expression and degranulation. Tyrosol blocked calcium influx and phosphorylation of the IKK complex. To define the molecular target for tyrosol, various signaling proteins involved in mast cell activation such as Lyn, Syk, phosphoinositide 3-kinase (PI3K), and Akt were examined. Our results showed that PI3K could be a molecular target for tyrosol in mast cells. Taken together, these findings indicated that tyrosol has anti-allergic inflammatory effects by inhibiting the degranulation of mast cells and expression of inflammatory cytokines; these effects are mediated via PI3K. Therefore, we expect tyrosol become a potential therapeutic candidate for allergic inflammatory disorders.

Receptor for advanced glycation end products and its ligand high-mobility group box-1 mediate allergic airway sensitization and airway inflammation.

PubMed

Ullah, Md Ashik; Loh, Zhixuan; Gan, Wan Jun; Zhang, Vivian; Yang, Huan; Li, Jian Hua; Yamamoto, Yasuhiko; Schmidt, Ann Marie; Armour, Carol L; Hughes, J Margaret; Phipps, Simon; Sukkar, Maria B

2014-08-01

The receptor for advanced glycation end products (RAGE) shares common ligands and signaling pathways with TLR4, a key mediator of house dust mite (Dermatophagoides pteronyssinus) (HDM) sensitization. We hypothesized that RAGE and its ligand high-mobility group box-1 (HMGB1) cooperate with TLR4 to mediate HDM sensitization. To determine the requirement for HMGB1 and RAGE, and their relationship with TLR4, in airway sensitization. TLR4(-/-), RAGE(-/-), and RAGE-TLR4(-/-) mice were intranasally exposed to HDM or cockroach (Blatella germanica) extracts, and features of allergic inflammation were measured during the sensitization or challenge phase. Anti-HMGB1 antibody and the IL-1 receptor antagonist Anakinra were used to inhibit HMGB1 and the IL-1 receptor, respectively. The magnitude of allergic airway inflammation in response to either HDM or cockroach sensitization and/or challenge was significantly reduced in the absence of RAGE but not further diminished in the absence of both RAGE and TLR4. HDM sensitization induced the release of HMGB1 from the airway epithelium in a biphasic manner, which corresponded to the sequential activation of TLR4 then RAGE. Release of HMGB1 in response to cockroach sensitization also was RAGE dependent. Significantly, HMGB1 release occurred downstream of TLR4-induced IL-1α, and upstream of IL-25 and IL-33 production. Adoptive transfer of HDM-pulsed RAGE(+/+)dendritic cells to RAGE(-/-) mice recapitulated the allergic responses after HDM challenge. Immunoneutralization of HMGB1 attenuated HDM-induced allergic airway inflammation. The HMGB1-RAGE axis mediates allergic airway sensitization and airway inflammation. Activation of this axis in response to different allergens acts to amplify the allergic inflammatory response, which exposes it as an attractive target for therapeutic intervention. Copyright © 2014 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.

Acute coronary disease Athero-Inflammation: Therapeutic approach

PubMed Central

Altman, Raul

2003-01-01

Antithrombotic therapy is the cornerstone of the treatment of acute coronary syndromes, but there is now evidence which indicates that by blocking inflammation, thrombosis and thus, acute coronary events, could be lowered. The concept of athero-inflammation emerges as the meeting point of different morbidities; dyslipemia, diabetes, hypertension, obesity, immunity, infection, hyperhomocyteinemia, smoking, etc. usual named as risk factors. Thus, beside specific drugs, earliest treatment, in the stage of inflammation, using anti-inflammatory drugs, should be considered since in patients with increased risk of acute coronary process are likely to have many point of origen throughout the coronary arteries. There are a body of evidences for supporting the potential of anti-inflammatory therapy to the prevention of inflammation and atherosclerosis. COX-2 inhibition may decrease endothelial inflammation reducing monocytes infiltration improving vascular cells function, plaque stability and probably resulting in a decrease of coronary atherothrombotic events. Trials including large numbers of patients in prospective double-blind randomized studies worthwhile to confirm the efficacy of NSAID, mainly, COX-2 inhibitors, together with aspirin in the prevention of coronary events in patients with acute coronary disease. PMID:12904261

Steroid Treatment Reduces Allergic Airway Inflammation and Does Not Alter the Increased Numbers of Dendritic Cells and Calcitonin Gene-Related Peptide-Expressing Neurons in Airway Sensory Ganglia.

PubMed

Le, Duc Dung; Funck, Ulrike; Wronski, Sabine; Heck, Sebastian; Tschernig, Thomas; Bischoff, Markus; Sester, Martina; Herr, Christian; Bals, Robert; Welte, Tobias; Braun, Armin; Dinh, Quoc Thai

2016-01-01

Our previous data demonstrated that allergic airway inflammation induces migration of dendritic cells (DC) into airway sensory jugular and nodose ganglia (jugular-nodose ganglion complex; JNC). Here we investigated the effects of steroid treatment regarding the expression and migration of DC and calcitonin gene-related peptide (CGRP)-immunoreactive neurons of vagal sensory ganglia during allergic airway inflammation. A house dust mite (HDM) model for allergic airway inflammation was used. The mice received 0.3 mg fluticasone propionate per kilogram of body weight in the last 9 days. JNC slices were analyzed on MHC II, the neuronal marker PGP9.5, and the neuropeptide CGRP. Allergic airway inflammation increased the numbers of DC and CGRP-expressing neurons in the JNC significantly in comparison to the controls (DC/neurons: HDM 44.58 ± 1.6% vs. saline 33.29 ± 1.6%, p < 0.05; CGRP-positive neurons/total neurons: HDM 30.65 ± 1.9% vs. saline 19.49 ± 2.3%, p < 0.05). Steroid treatment did not have any effect on the numbers of DC and CGRP-expressing neurons in the JNC compared to HDM-treated mice. The present findings indicate an important role of DC and CGRP-containing neurons in the pathogenesis of allergic airway inflammation. However, steroid treatment did not have an effect on the population of DC and neurons displaying CGRP in the JNC, whereas steroid treatment was found to suppress allergic airway inflammation. © 2015 S. Karger AG, Basel.

Mouse models to unravel the role of inhaled pollutants on allergic sensitization and airway inflammation

PubMed Central

2010-01-01

Air pollutant exposure has been linked to a rise in wheezing illnesses. Clinical data highlight that exposure to mainstream tobacco smoke (MS) and environmental tobacco smoke (ETS) as well as exposure to diesel exhaust particles (DEP) could promote allergic sensitization or aggravate symptoms of asthma, suggesting a role for these inhaled pollutants in the pathogenesis of asthma. Mouse models are a valuable tool to study the potential effects of these pollutants in the pathogenesis of asthma, with the opportunity to investigate their impact during processes leading to sensitization, acute inflammation and chronic disease. Mice allow us to perform mechanistic studies and to evaluate the importance of specific cell types in asthma pathogenesis. In this review, the major clinical effects of tobacco smoke and diesel exhaust exposure regarding to asthma development and progression are described. Clinical data are compared with findings from murine models of asthma and inhalable pollutant exposure. Moreover, the potential mechanisms by which both pollutants could aggravate asthma are discussed. PMID:20092634

Diesel exposure suppresses natural killer cell function and resolution of eosinophil inflammation: a randmonized controlled trial of exposure in allergic rhinitics

EPA Science Inventory

Exposure to diesel exhaust (DE) is known to exacerbate allergic inflammation, including virus induced eosinophil activation in laboratory animals. We have previously shown that in human volunteers with allergic rhinitis a short-term exposure to DE prior to infection with the live...

Absence of Foxp3+ Regulatory T Cells during Allergen Provocation Does Not Exacerbate Murine Allergic Airway Inflammation

PubMed Central

Baru, Abdul Mannan; Ganesh, Venkateswaran; Krishnaswamy, Jayendra Kumar; Hesse, Christina; Untucht, Christopher; Glage, Silke; Behrens, Georg; Mayer, Christian Thomas; Puttur, Franz; Sparwasser, Tim

2012-01-01

Regulatory T cells (Tregs) play a non-redundant role in maintenance of immune homeostasis. This is achieved by suppressing both, priming of naïve cells and effector cell functions. Although Tregs have been implicated in modulating allergic immune responses, their influence on distinct phases of development of allergies remains unclear. In this study, by using bacterial artificial chromosome (BAC)-transgenic Foxp3-DTR (DEREG) mice we demonstrate that the absence of Foxp3+ Tregs during the allergen challenge surprisingly does not exacerbate allergic airway inflammation in BALB/c mice. As genetic disposition due to strain specificity may contribute significantly to development of allergies, we performed similar experiment in C57BL/6 mice, which are less susceptible to allergy in the model of sensitization used in this study. We report that the genetic background does not influence the consequence of this depletion regimen. These results signify the temporal regulation exerted by Foxp3+ Tregs in limiting allergic airway inflammation and may influence their application as potential therapeutics. PMID:23071726

The transcription factor Etv5 controls TH17 cell development and allergic airway inflammation

PubMed Central

Pham, Duy; Sehra, Sarita; Sun, Xin; Kaplan, Mark H.

2014-01-01

Background The differentiation of TH17 cells, which promote pulmonary inflammation, requires the cooperation of a network of transcription factors. Objectives We sought to define the role of Etv5, an Ets-family transcription factor, in TH17 cell development and function. Methods TH17 development was examined in primary mouse T cells wherein Etv5 expression was altered by retroviral transduction, small interfering RNA targeting a specific gene, and mice with a conditional deletion of Etv5 in T cells. The direct function of Etv5 on the Il17 locus was tested with chromatin immunoprecipitation and reporter assays. The house dust mite–induced allergic inflammation model was used to test the requirement for Etv5-dependent TH17 functions in vivo. Results We identify Etv5 as a signal transducer and activator of transcription 3–induced positive regulator of TH17 development. Etv5 controls TH17 differentiation by directly promoting 0a and Il17f expression. Etv5 recruits histone-modifying enzymes to the Il17a–Il17f locus, resulting in increased active histone marks and decreased repressive histone marks. In a model of allergic airway inflammation, mice with Etv5-deficient T cells have reduced airway inflammation and IL-17A/F production in the lung and bronchoalveolar lavage fluid compared with wild-type mice, without changes in TH2 cytokine production. Conclusions These data define signal transducer and activator of transcription 3–dependent feed-forward control of TH17 cytokine production and a novel role for Etv5 in promoting T cell–dependent airway inflammation. PMID:24486067

Neurokinin-1 receptor mediates stress-exacerbated allergic airway inflammation and airway hyperresponsiveness in mice.

PubMed

Joachim, Ricarda A; Sagach, Viktoriya; Quarcoo, David; Dinh, Q Thai; Arck, Petra C; Klapp, Burghard F

2004-01-01

A wealth of clinical observation has suggested that stress and asthma morbidity are associated. We have previously established a mouse model of stress-exacerbated allergic airway inflammation, which reflects major clinical findings. The aim of the current study was to investigate the role of the neurokinin- (NK-)1 receptor in the mediation of stress effects in allergic airway inflammation. BALB/c mice were systemically sensitized with ovalbumin (OVA) on assay days 1, 14, and 21 and repeatedly challenged with OVA aerosol on days 26 and 27. Sound stress was applied to the animals for 24 hours, starting with the first airway challenge. Additionally, one group of stressed and one group of nonstressed mice received the highly specific NK-1 receptor antagonist RP 67580. Bronchoalveolar lavage fluid was obtained, and cell numbers and differentiation were determined. Airway hyperreactivity was measured in vitro by electrical field stimulation of tracheal smooth-muscle elements. Application of stress in sensitized and challenged animals resulted in a significant increase in leukocyte number in the bronchoalveolar lavage fluid. Furthermore, stressed animals showed enhanced airway reactivity. The increase of inflammatory cells and airway reactivity was blocked by treatment of animals with the NK-1 receptor antagonist. These data indicate that the NK-1 receptor plays an important role in mediating stress effects in allergen-induced airway inflammation.

mTOR regulates metabolic adaptation of APCs in the lung and controls the outcome of allergic inflammation.

PubMed

Sinclair, Charles; Bommakanti, Gayathri; Gardinassi, Luiz; Loebbermann, Jens; Johnson, Matthew Joseph; Hakimpour, Paul; Hagan, Thomas; Benitez, Lydia; Todor, Andrei; Machiah, Deepa; Oriss, Timothy; Ray, Anuradha; Bosinger, Steven; Ravindran, Rajesh; Li, Shuzhao; Pulendran, Bali

2017-09-08

Antigen-presenting cells (APCs) occupy diverse anatomical tissues, but their tissue-restricted homeostasis remains poorly understood. Here, working with mouse models of inflammation, we found that mechanistic target of rapamycin (mTOR)-dependent metabolic adaptation was required at discrete locations. mTOR was dispensable for dendritic cell (DC) homeostasis in secondary lymphoid tissues but necessary to regulate cellular metabolism and accumulation of CD103 + DCs and alveolar macrophages in lung. Moreover, while numbers of mTOR-deficient lung CD11b + DCs were not changed, they were metabolically reprogrammed to skew allergic inflammation from eosinophilic T helper cell 2 (T H 2) to neutrophilic T H 17 polarity. The mechanism for this change was independent of translational control but dependent on inflammatory DCs, which produced interleukin-23 and increased fatty acid oxidation. mTOR therefore mediates metabolic adaptation of APCs in distinct tissues, influencing the immunological character of allergic inflammation. Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

Acute allergic reactions in children with AEDS after prolonged cow's milk elimination diets.

PubMed

Flinterman, A E; Knulst, A C; Meijer, Y; Bruijnzeel-Koomen, C A F M; Pasmans, S G M A

2006-03-01

Food allergy is not always correctly diagnosed in children with atopic eczema dermatitis syndrome (AEDS) and treatment with an avoidance diet is not without danger. After admission to our clinic, 11 children with a prolonged cow's milk (CM) elimination diet because of AEDS and sensitization underwent double-blind placebo-controlled food challenge (DBPCFC). Retrospectively, the exposure to CM, sensitization and reactions to accidental ingestion were carefully documented. The DBPCFC was used to evaluate the childrens' current status. Before the elimination period (median 2.3 years; started before the admission) all 11 children with AEDS were sensitized and had ingested CM (four bottle-fed; seven breast-fed without CM diet of the mother) without the development of acute reactions. The diagnosis of CM allergy was not confirmed by DBPCFC previously. After elimination the AEDS had not improved, but nevertheless the diet was continued. During the elimination period, eight of 11 children developed severe acute allergic reactions to CM after accidental ingestion. In evaluation, in our clinic all 11 children experienced acute allergic reactions to CM during DBPCFC. There is a considerable chance of developing acute allergic reactions to CM after elimination in children with AEDS without previous problems after CM intake.

Interleukin-17B Antagonizes Interleukin-25-Mediated Mucosal Inflammation.

PubMed

Reynolds, Joseph M; Lee, Young-Hee; Shi, Yun; Wang, Xiaohu; Angkasekwinai, Pornpimon; Nallaparaju, Kalyan C; Flaherty, Stephanie; Chang, Seon Hee; Watarai, Hiroshi; Dong, Chen

2015-04-21

The interleukin-17 (IL-17) family of cytokines has emerged as a critical player in inflammatory diseases. Among them, IL-25 has been shown to be important in allergic inflammation and protection against parasitic infection. Here we have demonstrated that IL-17B, a poorly understood cytokine, functions to inhibit IL-25-driven inflammation. IL-17B and IL-25, both binding to the interleukin-17 receptor B (IL-17RB), were upregulated in their expression after acute colonic inflammation. Individual inhibition of these cytokines revealed opposing functions in colon inflammation: IL-25 was pathogenic but IL-17B was protective. Similarly opposing phenotypes were observed in Citrobacter rodentium infection and allergic asthma. Moreover, IL-25 was found to promote IL-6 production from colon epithelial cells, which was inhibited by IL-17B. Therefore, our data demonstrate that IL-17B is an anti-inflammatory cytokine in the IL-17 family. Copyright © 2015 Elsevier Inc. All rights reserved.

Suppression of allergic airway inflammation in a mouse model by Der p2 recombined BCG.

PubMed

Ou-Yang, Hai-Feng; Hu, Xing-Bin; Ti, Xin-Yu; Shi, Jie-Ran; Li, Shu-Jun; Qi, Hao-Wen; Wu, Chang-Gui

2009-09-01

Allergic asthma is a chronic inflammatory disease mediated by T helper (Th)2 cell immune responses. Currently, immunotherapies based on both immune deviation and immune suppression, including the development of recombinant mycobacteria as immunoregulatory vaccines, are attractive treatment strategies for asthma. In our previous studies, we created a genetically recombinant form of bacille Calmette-Guerin (rBCG) that expressed Der p2 of house dust mites and established that it induced a shift from a Th2 response to a Th1 response in naive mice. However, it is unclear whether rBCG could suppress allergic airway inflammation in a mouse model. In this article we report that rBCG dramatically inhibited airway inflammation, eosinophilia, mucus production and mast cell degranulation in allergic mice. Analysis of interferon-gamma (IFN-gamma) and interleukin-4 (IL-4) levels in bronchoalveolar lavage fluid (BALF) and lung tissue revealed that the suppression was associated with a shift from a Th2 response to a Th1 response. At the same time, rBCG induced a CD4(+) CD25(+) Foxp3(+) T-cell subtype that could suppress the proliferation of Th2 effector cells in vitro in an antigen-specific manner. Moreover, suppression of CD4(+) CD25(+) T cells could be adoptively transferred. Thus, our results demonstrate that rBCG induces both generic and specific immune responses. The generic immune response is associated with a shift from a Th2 to a Th1 cytokine response, whereas the specific immune response against Der p2 appears to be related to the expansion of transforming growth factor-beta (TGF-beta)-producing CD4(+) CD25(+) Foxp3(+) regulatory T cells. rBCG can suppress asthmatic airway inflammation through both immune deviation and immune suppression and may be a feasible, efficient immunotherapy for asthma.

Exposure to low doses of formaldehyde during pregnancy suppresses the development of allergic lung inflammation in offspring

DOE Office of Scientific and Technical Information (OSTI.GOV)

Maiellaro, Marília; Correa-Costa, Matheus; Vitoretti, Luana Beatriz

Formaldehyde (FA) is an environmental and occupational pollutant, and its toxic effects on the immune system have been shown. Nevertheless, no data are available regarding the programming mechanisms after FA exposure and its repercussions for the immune systems of offspring. In this study, our objective was to investigate the effects of low-dose exposure of FA on pregnant rats and its repercussion for the development of allergic lung inflammation in offspring. Pregnant Wistar rats were assigned in 3 groups: P (rats exposed to FA (0.75 ppm, 1 h/day, 5 days/week, for 21 days)), C (rats exposed to vehicle of FA (distillatedmore » water)) and B (rats non-manipulated). After 30 days of age, the offspring was sensitised with ovalbumin (OVA)-alum and challenged with aerosolized OVA (1%, 15 min, 3 days). After 24 h the OVA challenge the parameters were evaluated. Our data showed that low-dose exposure to FA during pregnancy induced low birth weight and suppressed the development of allergic lung inflammation and tracheal hyperresponsiveness in offspring by mechanisms mediated by reduced anaphylactic antibodies synthesis, IL-6 and TNF-alpha secretion. Elevated levels of IL-10 were found. Any systemic alteration was detected in the exposed pregnant rats, although oxidative stress in the uterine environment was evident at the moment of the delivery based on elevated COX-1 expression and reduced cNOS and SOD-2 in the uterus. Therefore, we show the putative programming mechanisms induced by FA on the immune system for the first time and the mechanisms involved may be related to oxidative stress in the foetal microenvironment. - Highlights: • Formaldehyde exposure does not cause lung inflammation in pregnant rats. • Formaldehyde exposure suppresses allergic lung inflammation in the offspring. • Formaldehyde exposure induces oxidative stress in uterine environment.« less

Aging, not age-associated inflammation, determines blood pressure and endothelial responses to acute inflammation.

PubMed

Lane-Cordova, Abbi D; Ranadive, Sushant M; Kappus, Rebecca M; Cook, Marc D; Phillips, Shane A; Woods, Jeffrey A; Wilund, Kenneth R; Baynard, Tracy; Fernhall, Bo

2016-12-01

Aging is characterized by a state of chronic, low-grade inflammation that impairs vascular function. Acute inflammation causes additional decrements in vascular function, but these responses are not uniform in older compared with younger adults. We sought to determine if older adults with low levels of baseline inflammation respond to acute inflammation in a manner similar to younger adults. We hypothesized age-related differences in the vascular responses to acute inflammation, but that older adults with low baseline inflammation would respond similarly to younger adults. Inflammation was induced with an influenza vaccine in 96 participants [older = 67 total, 38 with baseline C-reactive protein (CRP) > 1.5 mg/l and 29 with CRP < 1.5 mg/l; younger = 29]; serum inflammatory markers IL-6 and CRP, blood pressure and flow-mediated dilation (FMD) were measured 24 and 48 h later. Younger adults increased IL-6 and CRP more than the collective older adult group and increased pulse pressure, whereas older adults decreased SBP and reduced pulse pressure. The entire cohort decreased FMD from 11.3 ± 0.8 to 8.3 ± 0.7 to 8.7 ± 0.7% in younger and from 5.8 ± 0.3 to 5.0 ± 0.4 to 4.7 ± 0.4% in older adults, P less than 0.05 for main effect. Older adult groups with differing baseline CRP had the same IL-6, blood pressure, and FMD response to acute inflammation, P less than 0.05 for all interactions, but the low-CRP group increased CRP at 24 and 48 h (from 0.5 ± 0.1 to 1.4 ± 0.2 to 1.7 ± 0.3 mg/l), whereas the high-CRP group did not (from 4.8 ± 0.5 to 5.4 ± 0.5 to 5.4 ± 0.6 mg/l), P less than 0.001 for interaction. Aging, not age-related chronic, low-grade inflammation, determines the vascular responses to acute inflammation.

Bilirubin nanoparticles ameliorate allergic lung inflammation in a mouse model of asthma.

PubMed

Kim, Dong Eon; Lee, Yonghyun; Kim, MinGyo; Lee, Soyoung; Jon, Sangyong; Lee, Seung-Hyo

2017-09-01

Although asthma, a chronic inflammatory airway disease, is relatively well-managed by inhaled corticosteroids, the side effects associated with the long-term use of these agents precipitate the need for alternative therapeutic options based on differing modes of action. Bilirubin, a potent endogenous antioxidant, and anti-inflammatory molecule have been shown to ameliorate asthmatic symptoms; however, its clinical translation has been limited owing to its water insolubility and associated potential toxicity. Here we report the first application of bilirubin-based nanoparticles (BRNPs) as a nanomedicine for the treatment of allergic lung inflammatory disease. BRNPs were prepared directly from self-assembly of PEGylated bilirubin in aqueous solution and had a hydrodynamic diameter of ∼100 nm. Because allergen-specific type 2 T-helper (Th2) cells play a key role in the pathogenesis and progression of allergic asthma, the effects of BRNPs on Th2 immune responses were investigated both in vivo and in vitro. BRNPs after intravenous injection (i.v.) showed much higher serum concentration and a longer circulation time of bilirubin than the intraperitoneal injection (i.p.) of BRNPs or unconjugated bilirubin (UCB). The anti-asthmatic effects of BRNPs were assessed in a mouse model of allergen-induced asthma. Compared with UCB, treatment with BRNPs suppressed the symptoms of experimental allergic asthma and dramatically ameliorated Th2-related allergic lung inflammation. Consistent with these results, BRNPs caused a reduction of Th2 cell populations and the expression of related cytokines by antibody-stimulated CD4 + T cells in vitro. Therefore, our results establish BRNPs as an important immunomodulatory agent that may be useful as a therapeutic for allergic lung inflammatory disease and other immune-mediated disorders. Copyright © 2017 Elsevier Ltd. All rights reserved.

Sea Cucumber Lipid-Soluble Extra Fraction Prevents Ovalbumin-Induced Allergic Airway Inflammation.

PubMed

Lee, Da-In; Kang, Shin Ae; Md, Anisuzzaman; Jeong, U-Cheol; Jin, Feng; Kang, Seok-Joong; Lee, Jeong-Yeol; Yu, Hak Sun

2018-01-01

In a previous study, our research group demonstrated that sea cucumber (Apostichopus japonicus) extracts ameliorated allergic airway inflammation through CD4 + CD25 + Foxp3 + T (regulatory T; Treg) cell activation and recruitment to the lung. In this study, we aimed to determine which components of sea cucumber contribute to the amelioration of airway inflammation. We used n-hexane fractionation to separate sea cucumber into three phases (n-hexane, alcohol, and solid) and evaluated the ability of each phase to elevate Il10 expression in splenocytes and ameliorate symptoms in mice with ovalbumin (OVA)/alum-induced asthma. Splenocytes treated with the n-hexane phase showed a significant increase in Il10 expression. In the n-hexane phase, 47 fatty acids were identified. Individual fatty acids that comprised at least 5% of the total fatty acids were 16:0, 16:1n-7, 18:0, 18:1n-7, 20:4n-6, and 20:5n-3 (eicosapentaenoic acid). After administering the n-hexane phase to mice with OVA/alum-induced asthma, their asthma symptoms were ameliorated. Several immunomodulatory effects were observed in the n-hexane phase-pretreated group, compared with a vehicle control group. First, eosinophil infiltration and goblet cell hyperplasia were significantly reduced around the airways. Second, the concentrations of Th2-related cytokines (IL-4, IL-5, and IL-13) and Th17-related cytokines (IL-17) were significantly decreased in the spleen and bronchoalveolar lavage fluid (BALF). Finally, the concentrations of TGF-β and IL-10, which are associated with Treg cells, were significantly increased in the BALF and splenocyte culture medium. In conclusion, a fatty acid-rich fraction (n-hexane phase) of sea cucumber extract ameliorated allergic airway inflammation in a mouse model.

Thy1+IL-7+ lymphatic endothelial cells in iBALT provide a survival niche for memory T-helper cells in allergic airway inflammation

PubMed Central

Shinoda, Kenta; Hirahara, Kiyoshi; Iinuma, Tomohisa; Ichikawa, Tomomi; Suzuki, Akane S.; Sugaya, Kaoru; Tumes, Damon J.; Yamamoto, Heizaburo; Hara, Takahiro; Tani-ichi, Shizue; Ikuta, Koichi; Okamoto, Yoshitaka; Nakayama, Toshinori

2016-01-01

Memory CD4+ T helper (Th) cells are central to long-term protection against pathogens, but they can also be pathogenic and drive chronic inflammatory disorders. How these pathogenic memory Th cells are maintained, particularly at sites of local inflammation, remains unclear. We found that ectopic lymphoid-like structures called inducible bronchus-associated lymphoid tissue (iBALT) are formed during chronic allergic inflammation in the lung, and that memory-type pathogenic Th2 (Tpath2) cells capable of driving allergic inflammation are maintained within the iBALT structures. The maintenance of memory Th2 cells within iBALT is supported by Thy1+IL-7–producing lymphatic endothelial cells (LECs). The Thy1+IL-7–producing LECs express IL-33 and T-cell–attracting chemokines CCL21 and CCL19. Moreover, ectopic lymphoid structures consisting of memory CD4+ T cells and IL-7+IL-33+ LECs were found in nasal polyps of patients with eosinophilic chronic rhinosinusitis. Thus, Thy1+IL-7–producing LECs control chronic allergic airway inflammation by providing a survival niche for memory-type Tpath2 cells. PMID:27140620

Calcium-sensing receptor antagonists abrogate airway hyperresponsiveness and inflammation in allergic asthma

PubMed Central

Yarova, Polina L.; Stewart, Alecia L.; Sathish, Venkatachalem; Britt, Rodney D; Thompson, Michael A.; Lowe, Alexander P. P.; Freeman, Michelle; Aravamudan, Bharathi; Kita, Hirohito; Brennan, Sarah C.; Schepelmann, Martin; Davies, Thomas; Yung, Sun; Cholisoh, Zakky; Kidd, Emma J.; Ford, William R.; Broadley, Kenneth J.; Rietdorf, Katja; Chang, Wenhan; Khayat, Mohd E. Bin; Ward, Donald T.; Corrigan, Christopher J.; Ward, Jeremy P. T.; Kemp, Paul J.; Pabelick, Christina M.; Prakash, Y. S.; Riccardi, Daniela

2016-01-01

Airway hyperresponsiveness and inflammation are fundamental hallmarks of allergic asthma that are accompanied by increases in certain polycations, such as eosinophil cationic protein. Levels of these cations in body fluids correlate with asthma severity. We show that polycations and elevated extracellular calcium activate the human recombinant and native calcium-sensing receptor (CaSR), leading to intracellular calcium mobilization, cyclic adenosine monophosphate breakdown, and p38 mitogen-activated protein kinase phosphorylation in airway smooth muscle (ASM) cells. These effects can be prevented by CaSR antagonists, termed calcilytics. Moreover, asthmatic patients and allergen-sensitized mice expressed more CaSR in ASMs than did their healthy counterparts. Indeed, polycations induced hyper-reactivity in mouse bronchi, and this effect was prevented by calcilytics and absent in mice with CaSR ablation from ASM. Calcilytics also reduced airway hyperresponsiveness and inflammation in allergen-sensitized mice in vivo. These data show that a functional CaSR is up-regulated in asthmatic ASM and targeted by locally produced polycations to induce hyperresponsiveness and inflammation. Thus, calcilytics may represent effective asthma therapeutics. PMID:25904744

Allergic conjunctivitis in Asia.

PubMed

Thong, Bernard Yu-Hor

2017-04-01

Allergic conjunctivitis (AC), which may be acute or chronic, is associated with rhinitis in 30%-70% of affected individuals, hence the term allergic rhinoconjunctivitis (AR/C). Seasonal and perennial AC is generally milder than the more chronic and persistent atopic and vernal keratoconjunctivitis. Natural allergens like house dust mites (HDM), temperate and subtropical grass and tree pollen are important triggers that drive allergic inflammation in AC in the Asia-Pacific region. Climate change, environmental tobacco smoke, pollutants derived from fuel combustion, Asian dust storms originating from central/north Asia and phthalates may also exacerbate AR/C. The Allergies in Asia Pacific study and International Study of Asthma and Allergies in Childhood provide epidemiological data on regional differences in AR/C within the region. AC significantly impacts the quality of life of both children and adults, and these can be measured by validated quality of life questionnaires on AR/C. Management guidelines for AC involve a stepped approach depending on the severity of disease, similar to that for allergic rhinitis and asthma. Topical calcineurin inhibitors are effective in certain types of persistent AC, and sublingual immunotherapy is emerging as an effective treatment option in AR/C to grass pollen and HDM. Translational research predominantly from Japan and Korea involving animal models are important for the potential development of targeted pharmacotherapies for AC.

No Adjuvant Effect of Bacillus thuringiensis-Maize on Allergic Responses in Mice

PubMed Central

Dekan, Gerhard; Epstein, Michelle M.

2014-01-01

Genetically modified (GM) foods are evaluated carefully for their ability to induce allergic disease. However, few studies have tested the capacity of a GM food to act as an adjuvant, i.e. influencing allergic responses to other unrelated allergens at acute onset and in individuals with pre-existing allergy. We sought to evaluate the effect of short-term feeding of GM Bacillus thuringiensis (Bt)-maize (MON810) on the initiation and relapse of allergic asthma in mice. BALB/c mice were provided a diet containing 33% GM or non-GM maize for up to 34 days either before ovalbumin (OVA)-induced experimental allergic asthma or disease relapse in mice with pre-existing allergy. We observed that GM-maize feeding did not affect OVA-induced eosinophilic airway and lung inflammation, mucus hypersecretion or OVA-specific antibody production at initiation or relapse of allergic asthma. There was no adjuvant effect upon GM-maize consumption on the onset or severity of allergic responses in a mouse model of allergic asthma. PMID:25084284

Allergic rhinitis and inflammatory airway disease: interactions within the unified airspace.

PubMed

Marple, Bradley F

2010-01-01

Allergic rhinitis (AR), the most common chronic allergic condition in outpatient medicine, is associated with immense health care costs and socioeconomic consequences. AR's impact may be partly from interacting of respiratory conditions via allergic inflammation. This study was designed to review potential interactive mechanisms of AR and associated conditions and consider the relevance of a bidirectional "unified airway" respiratory inflammation model on diagnosis and treatment of inflammatory airway disease. MEDLINE was searched for pathophysiology and pathophysiological and epidemiologic links between AR and diseases of the sinuses, lungs, middle ear, and nasopharynx. Allergic-related inflammatory responses or neural and systemic processes fostering inflammatory changes distant from initial allergen provocation may link AR and comorbidities. Treating AR may benefit associated respiratory tract comorbidities. Besides improving AR outcomes, treatment inhibiting eosinophil recruitment and migration, normalizing cytokine profiles, and reducing asthma-associated health care use in atopic subjects would likely ameliorate other upper airway diseases such as acute rhinosinusitis, chronic rhinosinusitis (CRS) with nasal polyposis (NP), adenoidal hypertrophy, and otitis media with effusion. Epidemiological concordance of AR with several airway diseases conforms to a bidirectional "unified airway" respiratory inflammation model based on anatomic and histological upper and lower airway connections. Epidemiology and current understanding of inflammatory, humoral, and neural processes make links between AR and disorders including asthma, otitis media, NP, and CRS plausible. Combining AR with associated conditions increases disease burden; worsened associated illness may accompany worsened AR. AR pharmacotherapies include antihistamines, leukotriene antagonists, intranasal corticosteroids, and immunotherapy; treatments attenuating proinflammatory responses may also benefit

dNP2-ctCTLA-4 inhibits German cockroach extract-induced allergic airway inflammation and hyper-responsiveness via inhibition of Th2 responses

PubMed Central

Lim, Sangho; Ho Sohn, Jung; Koo, Ja-Hyun; Park, Jung-Won; Choi, Je-Min

2017-01-01

German cockroaches are major household allergens that can trigger allergic airway inflammatory diseases with sensitive T-cell responses. Although the use of immune modulatory biologics, such as antibodies, to mediate allergic responses has recently been examined, only systemic administration is available because of the size limitations on intranasal administration. Here we utilized a cell-permeable peptide, dNP2, to deliver the cytoplasmic domain of cytotoxic T-lymphocyte antigen-4 (ctCTLA-4) through the airway epithelium to modulate Th2 responses in a German cockroach extract (GCE)-induced allergic airway inflammation model. The intranasal delivery efficiency of the dNP2-dTomato protein to the lungs was higher in GCE-induced asthmatic lung parenchymal cells compared to the sham cells. Intranasal administration of the dNP2-ctCTLA-4 protein inhibited airway hyper-responsiveness and reduced airway inflammation and remodeling, including goblet cell metaplasia and collagen deposition around the bronchi. The number of infiltrated cells, including eosinophils, and the levels of IL-4, IL-5, IL-13 and IFN-γ in the lungs were significantly reduced, presumably owing to inhibition of Th2 differentiation. However, intranasal administration of CTLA4-Ig did not inhibit airway inflammation. These results collectively suggest that dNP2-ctCTLA-4 is an efficient intranasally applicable candidate biologic for treating allergic asthma. PMID:28775364

dNP2-ctCTLA-4 inhibits German cockroach extract-induced allergic airway inflammation and hyper-responsiveness via inhibition of Th2 responses.

PubMed

Lim, Sangho; Ho Sohn, Jung; Koo, Ja-Hyun; Park, Jung-Won; Choi, Je-Min

2017-08-04

German cockroaches are major household allergens that can trigger allergic airway inflammatory diseases with sensitive T-cell responses. Although the use of immune modulatory biologics, such as antibodies, to mediate allergic responses has recently been examined, only systemic administration is available because of the size limitations on intranasal administration. Here we utilized a cell-permeable peptide, dNP2, to deliver the cytoplasmic domain of cytotoxic T-lymphocyte antigen-4 (ctCTLA-4) through the airway epithelium to modulate Th2 responses in a German cockroach extract (GCE)-induced allergic airway inflammation model. The intranasal delivery efficiency of the dNP2-dTomato protein to the lungs was higher in GCE-induced asthmatic lung parenchymal cells compared to the sham cells. Intranasal administration of the dNP2-ctCTLA-4 protein inhibited airway hyper-responsiveness and reduced airway inflammation and remodeling, including goblet cell metaplasia and collagen deposition around the bronchi. The number of infiltrated cells, including eosinophils, and the levels of IL-4, IL-5, IL-13 and IFN-γ in the lungs were significantly reduced, presumably owing to inhibition of Th2 differentiation. However, intranasal administration of CTLA4-Ig did not inhibit airway inflammation. These results collectively suggest that dNP2-ctCTLA-4 is an efficient intranasally applicable candidate biologic for treating allergic asthma.

Effects of ultrafine particles on the allergic inflammation in the lung of asthmatics: results of a double-blinded randomized cross-over clinical pilot study

PubMed Central

2014-01-01

Background Epidemiological and experimental studies suggest that exposure to ultrafine particles (UFP) might aggravate the allergic inflammation of the lung in asthmatics. Methods We exposed 12 allergic asthmatics in two subgroups in a double-blinded randomized cross-over design, first to freshly generated ultrafine carbon particles (64 μg/m3; 6.1 ± 0.4 × 105 particles/cm3 for 2 h) and then to filtered air or vice versa with a 28-day recovery period in-between. Eighteen hours after each exposure, grass pollen was instilled into a lung lobe via bronchoscopy. Another 24 hours later, inflammatory cells were collected by means of bronchoalveolar lavage (BAL). (Trial registration: NCT00527462) Results For the entire study group, inhalation of UFP by itself had no significant effect on the allergen induced inflammatory response measured with total cell count as compared to exposure with filtered air (p = 0.188). However, the subgroup of subjects, which inhaled UFP during the first exposure, exhibited a significant increase in total BAL cells (p = 0.021), eosinophils (p = 0.031) and monocytes (p = 0.013) after filtered air exposure and subsequent allergen challenge 28 days later. Additionally, the potential of BAL cells to generate oxidant radicals was significantly elevated at that time point. The subgroup that was exposed first to filtered air and 28 days later to UFP did not reveal differences between sessions. Conclusions Our data demonstrate that pre-allergen exposure to UFP had no acute effect on the allergic inflammation. However, the subgroup analysis lead to the speculation that inhaled UFP particles might have a long-term effect on the inflammatory course in asthmatic patients. This should be reconfirmed in further studies with an appropriate study design and sufficient number of subjects. PMID:25204642

Recent developments in the role of reactive oxygen species in allergic asthma

PubMed Central

Qu, Jingjing; Li, Yuanyuan; Zhong, Wen

2017-01-01

Allergic asthma has a global prevalence, morbidity, and mortality. Many environmental factors, such as pollutants and allergens, are highly relevant to allergic asthma. The most important pathological symptom of allergic asthma is airway inflammation. Accordingly, the unique role of reactive oxygen species (ROS) had been identified as a main reason for this respiratory inflammation. Many studies have shown that inhalation of different allergens can promote ROS generation. Recent studies have demonstrated that several pro-inflammatory mediators are responsible for the development of allergic asthma. Among these mediators, endogenous or exogenous ROS are responsible for the airway inflammation of allergic asthma. Furthermore, several inflammatory cells induce ROS and allergic asthma development. Airway inflammation, airway hyper-responsiveness, tissue injury, and remodeling can be induced by excessive ROS production in animal models. Based on investigations of allergic asthma and ROS formation mechanisms, we have identified several novel anti-inflammatory therapeutic treatments. This review describes the recent data linking ROS to the pathogenesis of allergic asthma. PMID:28203435

Airway Fibrinogenolysis and the Initiation of Allergic Inflammation

PubMed Central

Millien, Valentine Ongeri; Lu, Wen; Mak, Garbo; Yuan, Xiaoyi; Knight, J. Morgan; Porter, Paul; Kheradmand, Farrah

2014-01-01

The past 15 years of allergic disease research have produced extraordinary improvements in our understanding of the pathogenesis of airway allergic diseases such as asthma. Whereas it was previously viewed as largely an immunoglobulin E-mediated process, the gradual recognition that T cells, especially Type 2 T helper (Th2) cells and Th17 cells, play a major role in asthma and related afflictions has inspired clinical trials targeting cytokine-based inflammatory pathways that show great promise. What has yet to be clarified about the pathogenesis of allergic inflammatory disorders, however, are the fundamental initiating factors, both exogenous and endogenous, that drive and sustain B- and T-cell responses that underlie the expression of chronic disease. Here we review how proteinases derived from diverse sources drive allergic responses. A central discovery supporting the proteinase hypothesis of allergic disease pathophysiology is the role played by airway fibrinogen, which in part appears to serve as a sensor of unregulated proteinase activity and which, when cleaved, both participates in a novel allergic signaling pathway through Toll-like receptor 4 and forms fibrin clots that contribute to airway obstruction. Unresolved at present is the ultimate source of airway allergenic proteinases. From among many potential candidates, perhaps the most intriguing is the possibility such enzymes derive from airway fungi. Together, these new findings expand both our knowledge of allergic disease pathophysiology and options for therapeutic intervention. PMID:25525732

G Protein βγ-Subunit Signaling Mediates Airway Hyperresponsiveness and Inflammation in Allergic Asthma

PubMed Central

Grunstein, Judith S.; McDonough, Joseph; Kreiger, Portia A.; Josephson, Maureen B.; Choi, John K.; Grunstein, Michael M.

2012-01-01

Since the Gβγ subunit of Gi protein has been importantly implicated in regulating immune and inflammatory responses, this study investigated the potential role and mechanism of action of Gβγ signaling in regulating the induction of airway hyperresponsiveness (AHR) in a rabbit model of allergic asthma. Relative to non-sensitized animals, OVA-sensitized rabbits challenged with inhaled OVA exhibited AHR, lung inflammation, elevated BAL levels of IL-13, and increased airway phosphodiesterase-4 (PDE4) activity. These proasthmatic responses were suppressed by pretreatment with an inhaled membrane-permeable anti-Gβγ blocking peptide, similar to the suppressive effect of glucocorticoid pretreatment. Extended mechanistic studies demonstrated that: 1) corresponding proasthmatic changes in contractility exhibited in isolated airway smooth muscle (ASM) sensitized with serum from OVA-sensitized+challenged rabbits or IL-13 were also Gβγ-dependent and mediated by MAPK-upregulated PDE4 activity; and 2) the latter was attributed to Gβγ-induced direct stimulation of the non-receptor tyrosine kinase, c-Src, resulting in downstream activation of ERK1/2 and its consequent transcriptional upregulation of PDE4. Collectively, these data are the first to identify that a mechanism involving Gβγ-induced direct activation of c-Src, leading to ERK1/2-mediated upregulation of PDE4 activity, plays a decisive role in regulating the induction of AHR and inflammation in a rabbit model of allergic airway disease. PMID:22384144

Complement Component 3C3 and C3a Receptor Are Required in Chitin-Dependent Allergic Sensitization to Aspergillus fumigatus but Dispensable in Chitin-Induced Innate Allergic Inflammation

PubMed Central

Roy, René M.; Paes, Hugo C.; Nanjappa, Som G.; Sorkness, Ron; Gasper, David; Sterkel, Alana; Wüthrich, Marcel; Klein, Bruce S.

2013-01-01

ABSTRACT Levels of the anaphylatoxin C3a are increased in patients with asthma compared with those in nonasthmatics and increase further still during asthma exacerbations. However, the role of C3a during sensitization to allergen is poorly understood. Sensitization to fungal allergens, such as Aspergillus fumigatus, is a strong risk factor for the development of asthma. Exposure to chitin, a structural polysaccharide of the fungal cell wall, induces innate allergic inflammation and may promote sensitization to fungal allergens. Here, we found that coincubation of chitin with serum or intratracheal administration of chitin in mice resulted in the generation of C3a. We established a model of chitin-dependent sensitization to soluble Aspergillus antigens to test the contribution of complement to these events. C3−/− and C3aR−/− mice were protected from chitin-dependent sensitization to Aspergillus and had reduced lung eosinophilia and type 2 cytokines and serum IgE. In contrast, complement-deficient mice were not protected against chitin-induced innate allergic inflammation. In sensitized mice, plasmacytoid dendritic cells from complement-deficient animals acquired a tolerogenic profile associated with enhanced regulatory T cell responses and suppressed Th2 and Th17 responses specific for Aspergillus. Thus, chitin induces the generation of C3a in the lung, and chitin-dependent allergic sensitization to Aspergillus requires C3aR signaling, which suppresses regulatory dendritic cells and T cells and induces allergy-promoting T cells. PMID:23549917

Arctigenin, a phenylpropanoid dibenzylbutyrolactone lignan, inhibits type I-IV allergic inflammation and pro-inflammatory enzymes.

PubMed

Lee, Ji Yun; Kim, Chang Jong

2010-06-01

We previously reported that arctigenin, a phenylpropanoid dibenzylbutyrolactone lignan isolated from Forsythia koreana, exhibits anti-inflammatory, antioxidant, and analgesic effects in animal models. In addition, arctigenin inhibited eosinophil peroxidase and activated myeloperoxidase in inflamed tissues. In this study, we tested the effects of arctigenin on type I-IV allergic inflammation and pro-inflammatory enzymes in vitro and in vivo. Arctigenin significantly inhibited the heterologous passive cutaneous anaphylaxis induced by ovalbumin in mice at 15 mg/kg, p.o., and compound 48/80-induced histamine release from rat peritoneal mast cells at 10 microM. Arctigenin (15 mg/kg, p.o.) significantly inhibited reversed cutaneous anaphylaxis. Further, arctigenin (15 mg/kg, p.o.) significantly inhibited the Arthus reaction to sheep's red blood cells, decreasing the hemolysis titer, the hemagglutination titer, and the plaque-forming cell number for SRBCs. In addition, arctigenin significantly inhibited delayed type hypersensitivity at 15 mg/kg, p.o. and the formation of rosette-forming cells at 45 mg/kg, p.o. Contact dermatitis induced by picrylchloride and dinitrofluorobenzene was significantly (p < 0.05) inhibited by surface treatment with arctigenin (0.3 mg/ear). Furthermore, arctigenin dose-dependently inhibited pro-inflammatory enzymes, such as cyclooxygenase-1 and 2, 5-lipoxygenase, phospholipase A2, and phosphodiesterase. Our results show that arctigenin significantly inhibited B- and T-cell mediated allergic inflammation as well as pro-inflammatory enzymes.

Chrysin suppresses mast cell-mediated allergic inflammation: Involvement of calcium, caspase-1 and nuclear factor-{kappa}B

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bae, Yunju; Lee, Soyoung; Kim, Sang-Hyun, E-mail: shkim72@knu.ac.kr

A great number of people are suffering from allergic inflammatory diseases such as asthma, atopic dermatitis, and sinusitis. Therefore discovery of drugs for the treatment of these diseases is an important subject in human health. Chrysin (5,7-dihydroxyflavone) is a natural flavonoid contained in propolis, blue passion flower, and fruits. Several studies reported that chrysin has beneficial effects including anti-tumor and anti-oxidant activities. The aim of the present study was to elucidate whether chrysin modulates the allergic inflammatory reaction and to study its possible mechanisms of action using mast cell-based in vitro and in vivo models. Chrysin inhibited immediate-type systemic hypersensitivitymore » and serum histamine release. Chrysin attenuated immunoglobulin E-mediated local anaphylaxis. These inhibitory effects of chrysin on the systemic and local allergic reaction were more potent than cromolyn, a known anti-allergic drug. Chrysin reduced histamine release from mast cells. The inhibitory effect of chrysin on the histamine release was mediated by the modulation of intracellular calcium. In addition, chrysin decreased gene expression of pro-inflammatory cytokines such as, tumor necrosis factor-{alpha}, IL (interleukin)-1{beta}, IL-4, and IL-6 in mast cells. The inhibitory effect of chrysin on the pro-inflammatory cytokine was nuclear factor-{kappa}B and caspase-1 dependent. Our findings provide evidence that chrysin inhibits mast cell-derived allergic inflammatory reactions by blocking histamine release and pro-inflammatory cytokine expression, and suggest the mechanisms of action. Furthermore, in vivo and in vitro anti-allergic inflammatory effect of chrysin suggests a possible therapeutic application of this agent in allergic inflammatory diseases. - Research Highlights: > Discovery of drugs for the allergic inflammation is important in human health. > Chrysin is a natural flavonoid contained in propolis, blue passion flower, and fruits

Mast cells and basophils are essential for allergies: mechanisms of allergic inflammation and a proposed procedure for diagnosis

PubMed Central

He, Shao-heng; Zhang, Hui-yun; Zeng, Xiao-ning; Chen, Dong; Yang, Ping-chang

2013-01-01

The current definition of allergy is a group of IgE-mediated diseases. However, a large portion of patients with clinical manifestations of allergies do not exhibit elevated serum levels of IgE (sIgEs). In this article, three key factors, ie soluble allergens, sIgEs and mast cells or basophils, representing the causative factors, messengers and primary effector cells in allergic inflammation, respectively, were discussed. Based on current knowledge on allergic diseases, we propose that allergic diseases are a group of diseases mediated through activated mast cells and/or basophils in sensitive individuals, and allergic diseases include four subgroups: (1) IgE dependent; (2) other immunoglobulin dependent; (3) non-immunoglobulin mediated; (4) mixture of the first three subgroups. According to our proposed definition, pseudo-allergic-reactions, in which mast cell or basophil activation is not mediated via IgE, or to a lesser extent via IgG or IgM, should be non-IgE-mediated allergic diseases. Specific allergen challenge tests (SACTs) are gold standard tests for diagnosing allergies in vivo, but risky. The identification of surface membrane activation markers of mast cells and basophils (CD203c, CCR3, CD63, etc) has led to development of the basophil activation test (BAT), an in vitro specific allergen challenge test (SACT). Based on currently available laboratory allergy tests, we here propose a laboratory examination procedure for allergy. PMID:23974516

Water-soluble phenol TS-13 combats acute but not chronic inflammation.

PubMed

Menshchikova, Elena; Tkachev, Victor; Lemza, Anna; Sharkova, Tatyana; Kandalintseva, Natalya; Vavilin, Valentin; Safronova, Olga; Zenkov, Nikolay

2014-09-01

This study was conducted to evaluate the effect of the synthetic water-soluble phenolic antioxidant TS-13 (sodium 3-(4'-methoxyphenyl)propyl thiosulfonate), an inducer of the redox-dependent Keap1/Nrf2/ARE signaling system, in experimental models of acute and chronic inflammation. Acute local inflammation was induced by intraplantar carrageenan injection into rat hind paws, and acute systemic inflammation was modeled by intravenous zymosan injection (in rats) or LPS-induced endotoxic shock (in mice). Chronic inflammation was investigated in rat models of air pouch and collagen-induced arthritis. The effects of TS-13 treatment were estimated by changes in the intensity of inflammation (paw edema, liver infiltration, animal survival, exudation, and clinical score of arthritis) and by the effects on reactive oxygen species (ROS) generation by leukocytes from peripheral blood and inflammatory exudates. We found the significant increase in expression of mRNA, content of protein and activity of a well-characterized Nrf2 target enzyme glutathione S-transferase P1, as well as nuclear extract protein binding to the ARE consensus sequence in liver of mice fed with diet containing TS-13. TS-13 markedly attenuated carrageenan-induced paw edema, reduced blood granulocyte number and volume density of liver infiltrates in the systemic zymosan-induced inflammation model, and increased mice survival after lipopolysaccharide-induced septic shock. However, TS-13 administration did not influence cell and protein exudation into air pouches and suppressed clinical manifestation of collagen-induced polyarthritis only at early stages. Nevertheless, TS-13 inhibited the generation of ROS by leukocytes in all inflammation models. The data suggest that the anti-inflammatory effects of Keap1/Nrf2/ARE system are more prominent against acute innate-mediated inflammation than chronic immune inflammation. This narrows the potential therapeutic efficacy of ARE inducers in inflammation treatment.

Clusterin Modulates Allergic Airway Inflammation by Attenuating CCL20-Mediated Dendritic Cell Recruitment.

PubMed

Hong, Gyong Hwa; Kwon, Hyouk-Soo; Moon, Keun-Ai; Park, So Young; Park, Sunjoo; Lee, Kyoung Young; Ha, Eun Hee; Kim, Tae-Bum; Moon, Hee-Bom; Lee, Heung Kyu; Cho, You Sook

2016-03-01

Recruitment and activation of dendritic cells (DCs) in the lungs are critical for Th2 responses in asthma, and CCL20 secreted from bronchial epithelial cells (BECs) is known to influence the recruitment of DCs. Because asthma is a disease that is closely associated with oxidative stress, we hypothesized that clusterin, an oxidative stress regulatory molecule, may have a role in the development of allergic airway inflammation. The aim of this study was to examine whether clusterin regulates CCL20 production from the BECs and the subsequent DC recruitment in the lungs. To verify the idea, clusterin knockout (Clu(-/-)), clusterin heterogeneous (Clu(+/-)), and wild-type mice were exposed intranasally to house dust mite (HDM) extract to induce allergic airway inflammation. We found that the total number of immune cells in bronchoalveolar lavage fluid and the lung was increased in Clu(-/-) and Clu(+/-) mice. Of these immune cells, inflammatory DCs (CD11b(+)CD11c(+)) and Ly6C(high) monocyte populations in the lung were significantly increased, which was accompanied by increased levels of various chemokines, including CCL20 in bronchoalveolar lavage fluid, and increased oxidative stress markers in the lung. Moreover, HDM-stimulated human BECs with either up- or downregulated clusterin expression showed that CCL20 secretion was negatively associated with clusterin expression. Interestingly, clusterin also reduced the level of intracellular reactive oxygen species, which is related to induction of CCL20 expression after HDM stimulation. Thus, the antioxidant property of clusterin is suggested to regulate the expression of CCL20 in BECs and the subsequent recruitment of inflammatory DCs in the airway. Copyright © 2016 by The American Association of Immunologists, Inc.

Disturbed sleep: linking allergic rhinitis, mood and suicidal behavior.

PubMed

Fang, Beverly J; Tonelli, Leonardo H; Soriano, Joseph J; Postolache, Teodor T

2010-01-01

Allergic inflammation is associated with mood disorders, exacerbation of depression, and suicidal behavior. Mediators of inflammation modulate sleep , with Th1 cytokines promoting NREM sleep and increasing sleepiness and Th2 cytokines (produced during allergic inflammation) impairing sleep. As sleep impairment is a rapidly modifiable suicide risk factor strongly associated with mood disorders, we review the literature leading to the hypothesis that allergic rhinitis leads to mood and anxiety disorders and an increased risk of suicide via sleep impairment. Specifically, allergic rhinitis can impair sleep through mechanical (obstructive) and molecular (cytokine production) processes. The high prevalence of mood and anxiety disorders and allergy, the nonabating suicide incidence, the currently available treatment modalities to treat sleep impairment and the need for novel therapeutic targets for mood and anxiety disorders, justify multilevel efforts to explore disturbance of sleep as a pathophysiological link.

Effect of acute moderate exercise on induced inflammation and arterial function in older adults.

PubMed

Ranadive, Sushant Mohan; Kappus, Rebecca Marie; Cook, Marc D; Yan, Huimin; Lane, Abbi Danielle; Woods, Jeffrey A; Wilund, Kenneth R; Iwamoto, Gary; Vanar, Vishwas; Tandon, Rudhir; Fernhall, Bo

2014-04-01

Acute inflammation reduces flow-mediated vasodilatation and increases arterial stiffness in young healthy individuals. However, this response has not been studied in older adults. The aim of this study, therefore, was to evaluate the effect of acute induced systemic inflammation on endothelial function and wave reflection in older adults. Furthermore, an acute bout of moderate-intensity aerobic exercise can be anti-inflammatory. Taken together, we tested the hypothesis that acute moderate-intensity endurance exercise, immediately preceding induced inflammation, would be protective against the negative effects of acute systemic inflammation on vascular function. Fifty-nine healthy volunteers between 55 and 75 years of age were randomized to an exercise or a control group. Both groups received a vaccine (induced inflammation) and sham (saline) injection in a counterbalanced crossover design. Inflammatory markers, endothelial function (flow-mediated vasodilatation) and measures of wave reflection and arterial stiffness were evaluated at baseline and at 24 and 48 h after injections. There were no significant differences in endothelial function and arterial stiffness between the exercise and control group after induced inflammation. The groups were then analysed together, and we found significant differences in the inflammatory markers 24 and 48 h after induction of acute inflammation compared with sham injection. However, flow-mediated vasodilatation, augmentation index normalized for heart rate (AIx75) and β-stiffness did not change significantly. Our results suggest that acute inflammation induced by influenza vaccination did not affect endothelial function in older adults.

Regulation of alveolar macrophage death in acute lung inflammation.

PubMed

Fan, Erica K Y; Fan, Jie

2018-03-27

Acute lung injury (ALI) and its severe form, known as acute respiratory distress syndrome (ARDS), are caused by direct pulmonary insults and indirect systemic inflammatory responses that result from conditions such as sepsis, trauma, and major surgery. The reciprocal influences between pulmonary and systemic inflammation augments the inflammatory process in the lung and promotes the development of ALI. Emerging evidence has revealed that alveolar macrophage (AM) death plays important roles in the progression of lung inflammation through its influence on other immune cell populations in the lung. Cell death and tissue inflammation form a positive feedback cycle, ultimately leading to exaggerated inflammation and development of disease. Pharmacological manipulation of AM death signals may serve as a logical therapeutic strategy for ALI/ARDS. This review will focus on recent advances in the regulation and underlying mechanisms of AM death as well as the influence of AM death on the development of ALI.

Linking Inflammation, Cardiorespiratory Variability, and Neural Control in Acute Inflammation via Computational Modeling

PubMed Central

Dick, Thomas E.; Molkov, Yaroslav I.; Nieman, Gary; Hsieh, Yee-Hsee; Jacono, Frank J.; Doyle, John; Scheff, Jeremy D.; Calvano, Steve E.; Androulakis, Ioannis P.; An, Gary; Vodovotz, Yoram

2012-01-01

Acute inflammation leads to organ failure by engaging catastrophic feedback loops in which stressed tissue evokes an inflammatory response and, in turn, inflammation damages tissue. Manifestations of this maladaptive inflammatory response include cardio-respiratory dysfunction that may be reflected in reduced heart rate and ventilatory pattern variabilities. We have developed signal-processing algorithms that quantify non-linear deterministic characteristics of variability in biologic signals. Now, coalescing under the aegis of the NIH Computational Biology Program and the Society for Complexity in Acute Illness, two research teams performed iterative experiments and computational modeling on inflammation and cardio-pulmonary dysfunction in sepsis as well as on neural control of respiration and ventilatory pattern variability. These teams, with additional collaborators, have recently formed a multi-institutional, interdisciplinary consortium, whose goal is to delineate the fundamental interrelationship between the inflammatory response and physiologic variability. Multi-scale mathematical modeling and complementary physiological experiments will provide insight into autonomic neural mechanisms that may modulate the inflammatory response to sepsis and simultaneously reduce heart rate and ventilatory pattern variabilities associated with sepsis. This approach integrates computational models of neural control of breathing and cardio-respiratory coupling with models that combine inflammation, cardiovascular function, and heart rate variability. The resulting integrated model will provide mechanistic explanations for the phenomena of respiratory sinus-arrhythmia and cardio-ventilatory coupling observed under normal conditions, and the loss of these properties during sepsis. This approach holds the potential of modeling cross-scale physiological interactions to improve both basic knowledge and clinical management of acute inflammatory diseases such as sepsis and trauma

Linking Inflammation, Cardiorespiratory Variability, and Neural Control in Acute Inflammation via Computational Modeling.

PubMed

Dick, Thomas E; Molkov, Yaroslav I; Nieman, Gary; Hsieh, Yee-Hsee; Jacono, Frank J; Doyle, John; Scheff, Jeremy D; Calvano, Steve E; Androulakis, Ioannis P; An, Gary; Vodovotz, Yoram

2012-01-01

Acute inflammation leads to organ failure by engaging catastrophic feedback loops in which stressed tissue evokes an inflammatory response and, in turn, inflammation damages tissue. Manifestations of this maladaptive inflammatory response include cardio-respiratory dysfunction that may be reflected in reduced heart rate and ventilatory pattern variabilities. We have developed signal-processing algorithms that quantify non-linear deterministic characteristics of variability in biologic signals. Now, coalescing under the aegis of the NIH Computational Biology Program and the Society for Complexity in Acute Illness, two research teams performed iterative experiments and computational modeling on inflammation and cardio-pulmonary dysfunction in sepsis as well as on neural control of respiration and ventilatory pattern variability. These teams, with additional collaborators, have recently formed a multi-institutional, interdisciplinary consortium, whose goal is to delineate the fundamental interrelationship between the inflammatory response and physiologic variability. Multi-scale mathematical modeling and complementary physiological experiments will provide insight into autonomic neural mechanisms that may modulate the inflammatory response to sepsis and simultaneously reduce heart rate and ventilatory pattern variabilities associated with sepsis. This approach integrates computational models of neural control of breathing and cardio-respiratory coupling with models that combine inflammation, cardiovascular function, and heart rate variability. The resulting integrated model will provide mechanistic explanations for the phenomena of respiratory sinus-arrhythmia and cardio-ventilatory coupling observed under normal conditions, and the loss of these properties during sepsis. This approach holds the potential of modeling cross-scale physiological interactions to improve both basic knowledge and clinical management of acute inflammatory diseases such as sepsis and trauma.

The Role of TNF Family Molecules Light in Cellular Interaction Between Airway Smooth Muscle Cells and T Cells During Chronic Allergic Inflammation.

PubMed

Shi, Fei; Xiong, Yi; Zhang, Yarui; Qiu, Chen; Li, Manhui; Shan, Aijun; Yang, Ying; Li, Binbin

2018-06-01

Interaction between T cells and airway smooth muscle (ASM) cells has been identified as an important factor in the development of asthma. LIGHT (known as TNFSF14) -mediated signaling likely contributes to various inflammatory disorders and airway remodeling. The objective of this study was to investigate the roles of LIGHT-mediated pathways in the interaction between ASM cells and T cells during chronic allergic inflammation. Mice were sensitized and challenged by ovalbumin (OVA) to induce chronic airway allergic inflammation. The control group received PBS only. The histological features and LIGHT expressions in lungs were assessed in vivo. Furthermore, T cells and ASM cells derived from the model mice were co-cultured both in the presence and absence of anti-LIGHT Ab for 72 h. The effects of LIGHT blockade on expressions of downstream signaling molecules, proliferation, and apoptosis of ASM cells, differentiation of T cells, and inflammatory cytokines release were evaluated. We demonstrated that LIGHT blockade strikingly inhibited the mRNA and protein expressions of HVEM, c-JUN, and NFκB. Additionally, LIGHT blockade resulted in decreased proliferation and increased apoptosis of ASM cells. Moreover, depletion of LIGHT dramatically reduced the differentiation of CD4 + T cells into Th1, Th2, and Th17 cells, as well as inhibited inflammatory cytokines release including IL-13, TGF-β, and IFN-γ, which are associated with CD4 + T cell differentiation and ASM cell proliferation. LIGHT plays an important role in the interaction between T cells and ASM cells in chronic allergic asthma. Blockade of LIGHT markedly suppressed ASM hyperplasia and inflammatory responses, which might be modulated through HVEM-NFκB or c-JUN pathways. Therefore, targeting LIGHT is a promising therapeutic strategy for airway inflammation and remodeling in chronic allergic asthma.

X-Ray based Lung Function measurement-a sensitive technique to quantify lung function in allergic airway inflammation mouse models

NASA Astrophysics Data System (ADS)

Dullin, C.; Markus, M. A.; Larsson, E.; Tromba, G.; Hülsmann, S.; Alves, F.

2016-11-01

In mice, along with the assessment of eosinophils, lung function measurements, most commonly carried out by plethysmography, are essential to monitor the course of allergic airway inflammation, to examine therapy efficacy and to correlate animal with patient data. To date, plethysmography techniques either use intubation and/or restraining of the mice and are thus invasive, or are limited in their sensitivity. We present a novel unrestrained lung function method based on low-dose planar cinematic x-ray imaging (X-Ray Lung Function, XLF) and demonstrate its performance in monitoring OVA induced experimental allergic airway inflammation in mice and an improved assessment of the efficacy of the common treatment dexamethasone. We further show that XLF is more sensitive than unrestrained whole body plethysmography (UWBP) and that conventional broncho-alveolar lavage and histology provide only limited information of the efficacy of a treatment when compared to XLF. Our results highlight the fact that a multi-parametric imaging approach as delivered by XLF is needed to address the combined cellular, anatomical and functional effects that occur during the course of asthma and in response to therapy.

An Interleukin-33-Mast Cell-Interleukin-2 Axis Suppresses Papain-Induced Allergic Inflammation by Promoting Regulatory T Cell Numbers.

PubMed

Morita, Hideaki; Arae, Ken; Unno, Hirotoshi; Miyauchi, Kousuke; Toyama, Sumika; Nambu, Aya; Oboki, Keisuke; Ohno, Tatsukuni; Motomura, Kenichiro; Matsuda, Akira; Yamaguchi, Sachiko; Narushima, Seiko; Kajiwara, Naoki; Iikura, Motoyasu; Suto, Hajime; McKenzie, Andrew N J; Takahashi, Takao; Karasuyama, Hajime; Okumura, Ko; Azuma, Miyuki; Moro, Kazuyo; Akdis, Cezmi A; Galli, Stephen J; Koyasu, Shigeo; Kubo, Masato; Sudo, Katsuko; Saito, Hirohisa; Matsumoto, Kenji; Nakae, Susumu

2015-07-21

House dust mite-derived proteases contribute to allergic disorders in part by disrupting epithelial barrier function. Interleukin-33 (IL-33), produced by lung cells after exposure to protease allergens, can induce innate-type airway eosinophilia by activating natural helper (NH) cells, a member of group 2 innate lymphoid cells (ILC2), to secrete Th2 type-cytokines. Because IL-33 also can induce mast cells (MCs) to secrete Th2 type-cytokines, MCs are thought to cooperate with NH cells in enhancing protease or IL-33-mediated innate-type airway eosinophilia. However, we found that MC-deficient Kit(W-sh/W-sh) mice exhibited exacerbated protease-induced lung inflammation associated with reduced numbers of regulatory T (Treg) cells. Moreover, IL-2 produced by IL-33-stimulated MCs promoted expansion of numbers of Treg cells, thereby suppressing development of papain- or IL-33-induced airway eosinophilia. We have thus identified a unique anti-inflammatory pathway that can limit induction of innate-type allergic airway inflammation mediated by NH cells. Copyright © 2015 Elsevier Inc. All rights reserved.

G-CSF maintains controlled neutrophil mobilization during acute inflammation by negatively regulating CXCR2 signaling

PubMed Central

Bajrami, Besnik; Zhu, Haiyan; Zhang, Yu C.

2016-01-01

Cytokine-induced neutrophil mobilization from the bone marrow to circulation is a critical event in acute inflammation, but how it is accurately controlled remains poorly understood. In this study, we report that CXCR2 ligands are responsible for rapid neutrophil mobilization during early-stage acute inflammation. Nevertheless, although serum CXCR2 ligand concentrations increased during inflammation, neutrophil mobilization slowed after an initial acute fast phase, suggesting a suppression of neutrophil response to CXCR2 ligands after the acute phase. We demonstrate that granulocyte colony-stimulating factor (G-CSF), usually considered a prototypical neutrophil-mobilizing cytokine, was expressed later in the acute inflammatory response and unexpectedly impeded CXCR2-induced neutrophil mobilization by negatively regulating CXCR2-mediated intracellular signaling. Blocking G-CSF in vivo paradoxically elevated peripheral blood neutrophil counts in mice injected intraperitoneally with Escherichia coli and sequestered large numbers of neutrophils in the lungs, leading to sterile pulmonary inflammation. In a lipopolysaccharide-induced acute lung injury model, the homeostatic imbalance caused by G-CSF blockade enhanced neutrophil accumulation, edema, and inflammation in the lungs and ultimately led to significant lung damage. Thus, physiologically produced G-CSF not only acts as a neutrophil mobilizer at the relatively late stage of acute inflammation, but also prevents exaggerated neutrophil mobilization and the associated inflammation-induced tissue damage during early-phase infection and inflammation. PMID:27551153

Antileukotriene Reverts the Early Effects of Inflammatory Response of Distal Parenchyma in Experimental Chronic Allergic Inflammation

PubMed Central

Gobbato, Nathália Brandão; de Souza, Flávia Castro Ribas; Fumagalli, Stella Bruna Napolitano; Lopes, Fernanda Degobbi Tenório Quirino dos Santos; Prado, Carla Máximo; Martins, Milton Arruda; Tibério, Iolanda de Fátima Lopes Calvo; Leick, Edna Aparecida

2013-01-01

Aims. Compare the effects of montelukast or dexamethasone in distal lung parenchyma and airway walls of guinea pigs (GP) with chronic allergic inflammation. Methods. GP have inhaled ovalbumin (OVA group-2x/week/4weeks). After the 4th inhalation, GP were treated with montelukast or dexamethasone. After 72 hours of the 7th inhalation, GP were anesthetised, and lungs were removed and submitted to histopathological evaluation. Results. Montelukast and dexamethasone treatments reduced the number of eosinophils in airway wall and distal lung parenchyma compared to OVA group (P < 0.05). On distal parenchyma, both treatments were effective in reducing RANTES, NF-κB, and fibronectin positive cells compared to OVA group (P < 0.001). Montelukast was more effective in reducing eotaxin positive cells on distal parenchyma compared to dexamethasone treatment (P < 0.001), while there was a more expressive reduction of IGF-I positive cells in OVA-D group (P < 0.001). On airway walls, montelukast and dexamethasone were effective in reducing IGF-I, RANTES, and fibronectin positive cells compared to OVA group (P < 0.05). Dexamethasone was more effective in reducing the number of eotaxin and NF-κB positive cells than Montelukast (P < 0.05). Conclusions. In this animal model, both treatments were effective in modulating allergic inflammation and remodeling distal lung parenchyma and airway wall, contributing to a better control of the inflammatory response. PMID:24151607

Soy biodiesel emissions have reduced inflammatory effects compared to diesel emissions in healthy and allergic mice.

PubMed

Gavett, Stephen H; Wood, Charles E; Williams, Marc A; Cyphert, Jaime M; Boykin, Elizabeth H; Daniels, Mary J; Copeland, Lisa B; King, Charly; Krantz, Todd Q; Richards, Judy H; Andrews, Debora L; Jaskot, Richard H; Gilmour, M Ian

2015-01-01

Toxicity of exhaust from combustion of petroleum diesel (B0), soy-based biodiesel (B100), or a 20% biodiesel/80% petrodiesel mix (B20) was compared in healthy and house dust mite (HDM)-allergic mice. Fuel emissions were diluted to target fine particulate matter (PM(2.5)) concentrations of 50, 150, or 500 μg/m(3). Studies in healthy mice showed greater levels of neutrophils and MIP-2 in bronchoalveolar lavage (BAL) fluid 2 h after a single 4-h exposure to B0 compared with mice exposed to B20 or B100. No consistent differences in BAL cells and biochemistry, or hematological parameters, were observed after 5 d or 4 weeks of exposure to any of the emissions. Air-exposed HDM-allergic mice had significantly increased responsiveness to methacholine aerosol challenge compared with non-allergic mice. Exposure to any of the emissions for 4 weeks did not further increase responsiveness in either non-allergic or HDM-allergic mice, and few parameters of allergic inflammation in BAL fluid were altered. Lung and nasal pathology were not significantly different among B0-, B20-, or B100-exposed groups. In HDM-allergic mice, exposure to B0, but not B20 or B100, significantly increased resting peribronchiolar lymph node cell proliferation and production of T(H)2 cytokines (IL-4, IL-5, and IL-13) and IL-17 in comparison with air-exposed allergic mice. These results suggest that diesel exhaust at a relatively high concentration (500 μg/m(3)) can induce inflammation acutely in healthy mice and exacerbate some components of allergic responses, while comparable concentrations of B20 or B100 soy biodiesel fuels did not elicit responses different from those caused by air exposure alone.

Low-Dose Intestinal Trichuris muris Infection Alters the Lung Immune Microenvironment and Can Suppress Allergic Airway Inflammation.

PubMed

Chenery, Alistair L; Antignano, Frann; Burrows, Kyle; Scheer, Sebastian; Perona-Wright, Georgia; Zaph, Colby

2016-02-01

Immunological cross talk between mucosal tissues such as the intestine and the lung is poorly defined during homeostasis and disease. Here, we show that a low-dose infection with the intestinally restricted helminth parasite Trichuris muris results in the production of Th1 cell-dependent gamma interferon (IFN-γ) and myeloid cell-derived interleukin-10 (IL-10) in the lung without causing overt airway pathology. This cross-mucosal immune response in the lung inhibits the development of papain-induced allergic airway inflammation, an innate cell-mediated type 2 airway inflammatory disease. Thus, we identify convergent and nonredundant roles of adaptive and innate immunity in mediating cross-mucosal suppression of type 2 airway inflammation during low-dose helminth-induced intestinal inflammation. These results provide further insight in identifying novel intersecting immune pathways elicited by gut-to-lung mucosal cross talk. Copyright © 2016 Chenery et al.

The development of allergic inflammation in a murine house dust mite asthma model is suppressed by synbiotic mixtures of non-digestible oligosaccharides and Bifidobacterium breve M-16V.

PubMed

Verheijden, K A T; Willemsen, L E M; Braber, S; Leusink-Muis, T; Jeurink, P V; Garssen, J; Kraneveld, A D; Folkerts, G

2016-04-01

The incidence and severity of allergic asthma is rising, and novel strategies to prevent or treat this disease are needed. This study investigated the effects of different mixtures of non-digestible oligosaccharides combined with Bifidobacterium breve M-16V (BB) on the development of allergic airway inflammation in an animal model for house dust mite (HDM)-induced allergic asthma. BALB/c mice were sensitized intranasally (i.n.) with HDM and subsequently challenged (i.n.) with PBS or HDM while being fed diets containing different oligosaccharide mixtures in combination with BB or an isocaloric identical control diet. Bronchoalveolar lavage fluid (BALF) inflammatory cell influx, chemokine and cytokine concentrations in lung homogenates and supernatants of ex vivo HDM-restimulated lung cells were analyzed. The HDM-induced influx of eosinophils and lymphocytes was reduced by the diet containing the short-chain and long-chain fructo-oligosaccharides and BB (FFBB). In addition to the HDM-induced cell influx, concentrations of IL-33, CCL17, CCL22, IL-6, IL-13 and IL-5 were increased in supernatants of lung homogenates or BALF and IL-4, IFN-γ and IL-10 were increased in restimulated lung cell suspensions of HDM-allergic mice. The diet containing FFBB reduced IL-6, IFN-γ, IL-4 and IL-10 concentrations, whereas the combination of galacto-oligosaccharides and long-chain fructo-oligosaccharides with BB was less potent in this model. These findings show that synbiotic dietary supplementation can affect respiratory allergic inflammation induced by HDM. The combination of FFBB was most effective in the prevention of HDM-induced airway inflammation in mice.

Dietary Fiber Intake Regulates Intestinal Microflora and Inhibits Ovalbumin-Induced Allergic Airway Inflammation in a Mouse Model

PubMed Central

Zhang, Zhiyu; Shi, Lei; Pang, Wenhui; Liu, Wenwen; Li, Jianfeng; Wang, Haibo; Shi, Guanggang

2016-01-01

Background Recently, academic studies suggest that global growth of airway allergic disease has a close association with dietary changes including reduced consumption of fiber. Therefore, appropriate dietary fiber supplementation might be potential to prevent airway allergic disease (AAD). Objective We investigated whether dietary fiber intake suppressed the induction of AAD and tried to elucidate the possible underlying mechanisms. Methods The control mice and AAD model mice fed with 4% standard-fiber chow, while low-fiber group of mice fed with a 1.75% low-fiber chow. The two fiber-intervened groups including mice, apart from a standard-fiber diet, were also intragastric (i.g.) administrated daily with poorly fermentable cellulose or readily fermentable pectin (0.4% of daily body weight), respectively. All animals except normal mice were sensitized and challenged with ovalbumin (OVA) to induce airway allergic inflammation. Hallmarks of AAD were examined by histological analysis and ELISA. The variation in intestinal bacterial composition was assessed by qualitative analysis of 16S ribosomal DNA (rDNA) content in fecal samples using real-time PCR. Results Low-fiber diet aggravated inflammatory response in ovalbumin-induced allergic mice, whereas dietary fiber intake significantly suppressed the allergic responses, attenuated allergic symptoms of nasal rubbing and sneezing, decreased the pathology of eosinophil infiltration and goblet cell metaplasia in the nasal mucosa and lung, inhibited serum OVA-specific IgE levels, and lowered the levels of Th2 cytokines in NALF and BALF, but, increased Th1 (IFN-γ) cytokines. Additionally, dietary fiber intake also increased the proportion of Bacteroidetes and Actinobacteria, and decreased Firmicutes and Proteobacteria. Levels of probiotic bacteria, such as Lactobacillus and Bifidobacterium, were upgraded significantly. Conclusion Long-term deficiency of dietary fiber intake increases the susceptibility to AAD, whereas proper

Dietary Fiber Intake Regulates Intestinal Microflora and Inhibits Ovalbumin-Induced Allergic Airway Inflammation in a Mouse Model.

PubMed

Zhang, Zhiyu; Shi, Lei; Pang, Wenhui; Liu, Wenwen; Li, Jianfeng; Wang, Haibo; Shi, Guanggang

2016-01-01

Recently, academic studies suggest that global growth of airway allergic disease has a close association with dietary changes including reduced consumption of fiber. Therefore, appropriate dietary fiber supplementation might be potential to prevent airway allergic disease (AAD). We investigated whether dietary fiber intake suppressed the induction of AAD and tried to elucidate the possible underlying mechanisms. The control mice and AAD model mice fed with 4% standard-fiber chow, while low-fiber group of mice fed with a 1.75% low-fiber chow. The two fiber-intervened groups including mice, apart from a standard-fiber diet, were also intragastric (i.g.) administrated daily with poorly fermentable cellulose or readily fermentable pectin (0.4% of daily body weight), respectively. All animals except normal mice were sensitized and challenged with ovalbumin (OVA) to induce airway allergic inflammation. Hallmarks of AAD were examined by histological analysis and ELISA. The variation in intestinal bacterial composition was assessed by qualitative analysis of 16S ribosomal DNA (rDNA) content in fecal samples using real-time PCR. Low-fiber diet aggravated inflammatory response in ovalbumin-induced allergic mice, whereas dietary fiber intake significantly suppressed the allergic responses, attenuated allergic symptoms of nasal rubbing and sneezing, decreased the pathology of eosinophil infiltration and goblet cell metaplasia in the nasal mucosa and lung, inhibited serum OVA-specific IgE levels, and lowered the levels of Th2 cytokines in NALF and BALF, but, increased Th1 (IFN-γ) cytokines. Additionally, dietary fiber intake also increased the proportion of Bacteroidetes and Actinobacteria, and decreased Firmicutes and Proteobacteria. Levels of probiotic bacteria, such as Lactobacillus and Bifidobacterium, were upgraded significantly. Long-term deficiency of dietary fiber intake increases the susceptibility to AAD, whereas proper fiber supplementation promotes effectively the

Ulinastatin activates haem oxygenase 1 antioxidant pathway and attenuates allergic inflammation

PubMed Central

Song, Dongmei; Song, Geng; Niu, Yinghao; Song, Wei; Wang, Jiantao; Yu, Lei; Yang, Jianwang; Lv, Xin; Steinberg, Harry; Liu, Shu Fang; Wang, Baoshan

2014-01-01

Background and Purpose Ulinastatin (UTI), a serine protease inhibitor, was recently found to have an anti-inflammatory action. However, the mechanisms mediating this anti-inflammatory effect are not well understood. This study tested the hypothesis that UTI suppresses allergic inflammation by inducing the expression of haem oxygenase 1 (HO1). Experimental Approach Control mice and mice sensitized (on days 1, 9 and 14) and challenged (on days 21 to 27) with ovalbumin (OVA) were treated with UTI. The effects of UTI on basal expression of HO1 and that induced by OVA challenge were examined. The involvement of UTI-induced HO1 expression in anti-inflammatory and antioxidant effects of UTI was also evaluated. Key Results UTI markedly increased basal HO1 protein expression in lungs of control mice in a time- and dose-dependent manner, and augmented HO1 protein expression induced by OVA. The up-regulation of HO1 mediated by UTI in sensitized and OVA-challenged mice was associated with reduced airway inflammation, alleviated tissue injury, reduced oxidant stress and enhanced antioxidant enzyme activities. Inhibition of HO1 activity using HO1 inhibitor, zinc protoporphyrin, attenuated inhibitory effects of UTI on inflammation and oxidant stress, and its stimulant effects on antioxidant enzyme activities. Mechanistic analysis showed that UTI increased nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2), stimulated Nrf2 DNA binding activity and concomitantly up-regulated HO1 mRNA expression. Conclusions and Implications UTI is a potent and naturally occurring inducer of HO1 expression. HO1 up-regulation contributes significantly to the anti-inflammatory and organ-protective effects of UTI, which has important research and therapeutic implications. PMID:24835359

Re-defining the Unique Roles for Eosinophils in Allergic Respiratory Inflammation

PubMed Central

Jacobsen, Elizabeth A.; Lee, Nancy A.; Lee, James J.

2014-01-01

Summary The role of eosinophils in the progression and resolution of allergic respiratory inflammation is poorly defined despite the commonality of their presence and in some cases their use as a biomarker for disease severity and/or symptom control. However, this ambiguity belies the wealth of insights that have recently been gained through the use of eosinophil-deficient/attenuated strains of mice that have demonstrated novel immunoregulatory and remodeling/repair functions for these cells in the lung following allergen provocation. Specifically, studies of eosinophil-deficient mice suggest that eosinophils contribute to events occurring in the lungs following allergen provocation at several key moments: (i) The initiating phase of events leading to Th2-polarized pulmonary inflammation, (ii) The suppression Th1/Th17 pathways in lung draining lymph nodes, (iii) The recruitment of effector Th2 T cells to the lung, and finally (iv) Mechanisms of inflammatory resolution that re-establish pulmonary homeostasis. These suggested functions have recently been confirmed and expanded upon using allergen provocation of an inducible eosinophil-deficient strain of mice (iPHIL) that demonstrated an eosinophil-dependent mechanism(s) leading to Th2 dominated immune responses in the presence of eosinophils in contrast to neutrophilic as well as mixed Th1/Th17/Th2 variant phenotypes in the absence of eosinophils. These findings highlighted that eosinophils are not exclusively downstream mediators controlled by T cells, dendritic cells (DC), and/or innate lymphocytic cells (ILC2). Instead, eosinophils appear to be more aptly described as significant contributors in complex interrelated pathways that lead to pulmonary inflammation and subsequently promote resolution and the re-establishment of homeostatic baseline. In this review we summarize and put into the context the evolving hypotheses that are now expanding our understanding of the roles eosinophils likely have in the lung

Red blood cell distribution width and haemoglobin are associated with hospital admission in patients with acute allergic reactions.

PubMed

Lippi, Giuseppe; Buonocore, Ruggero; Picanza, Alessandra; Schirosa, Fabio; Cervellin, Gianfranco

2016-01-01

Red blood cell distribution width (RDW) is significantly associated with a variety of human disorders. This study aimed to investigate whether RDW value at admission may predict the need of hospitalisation in patients presenting to the emergency department (ED) with acute allergic reactions. The study population consisted of adult patients (aged > 17) admitted to the ED for acute allergic reactions. One hundred and thirty-two subjects were included, 12 of whom (9%) required hospital admission for severity of symptoms. Patients who needed hospital admission displayed significantly lower values of haemoglobin and significantly higher values of RDW-coefficient of variation (RDW-CV). In multivariate analysis, haemoglobin and RDW-CV were found to be independent predictors of hospital admission. The area under the curve (AUC), sensitivity and specificity for predicting hospital admission were 0.72, 0.88 and 0.42 for haemoglobin and 0.73, 0.88 and 0.50 for RDW-CV, respectively. The combination of these tests (both positive) was characterised by 0.76 AUC, 0.83 sensitivity, 0.67 specificity, 0.96 negative predictive value and 0.30 positive predictive. The results of this study suggest that two common and inexpensive parameters such as haemoglobin and RDW are independent predictors of hospital admission in patients presenting to the ED with acute allergic reactions.

Is a high-fiber diet able to influence ovalbumin-induced allergic airway inflammation in a mouse model?

PubMed Central

Zhang, Zhiyu; Shi, Lei; Pang, Wenhui; Wang, Xiaoting; Li, Jianfeng; Wang, Haibo

2016-01-01

Background: More recently, a large amount of experimental and clinical discovered that dietary- fiber intake would decrease the susceptibility to allergic airway disease (AAD) and respiratory inflammation. Objective: To investigate whether a fiber-intake supplement is able to influence the induction of AAD and to elucidate the interactive relationship. Methods: AAD model mice and control mice were raised on a fundamental diet with standard 4% fiber content, whereas other mice were fed a 10% fiber-content diet in the high fiber-content group, along with a 25% fiber-content diet instead in very-high fiber-content group. All experimental mice were sensitized and challenged with ovalbumin to induce allergic inflammation in both the upper and lower airways. Hallmarks of AAD were examined in terms of eosinophil infiltration and goblet cell metaplasia in subepithelial mucosa, T-helper type 1 (Th1) to Th2 skewing of the immune response. Furthermore, to elucidate the interrelations, we generated 16S ribosomal DNA from fecal samples and further validated the variation of colony composition in each group. Results: The excessive high-fiber supplement induced a promoting effect rather than a suppressive effect, including a rise in nasal rubbing and sneezing, an increase in eosinophil inflammation and goblet cell metaplasia in subepithelial mucosa, and promoted Th2 skewing of the immune response as well as the production of serum levels of ovalbumin-specific immunoglobulin E. Moreover, overconsumption of dietary fiber greatly altered the construction of bacterial flora in the intestinal tract, including an increased proportion of Firmicutes, Actinobacteria, and Proteobacteria, and a decreased proportion of Bacteroidetes. Conclusion: Our work indicated that, instead of a protecting impact, excessive fiber intake preformed a negative influence on the induction of AAD. Therefore, we suspected that an excessive supplement of dietary fiber might not be an advisable method for the

38 CFR 3.380 - Diseases of allergic etiology.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 38 Pensions, Bonuses, and Veterans' Relief 1 2010-07-01 2010-07-01 false Diseases of allergic... Specific Diseases § 3.380 Diseases of allergic etiology. Diseases of allergic etiology, including bronchial... progress nor as due to the inherent nature of the disease. Seasonal and other acute allergic manifestations...

38 CFR 3.380 - Diseases of allergic etiology.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 38 Pensions, Bonuses, and Veterans' Relief 1 2011-07-01 2011-07-01 false Diseases of allergic... Specific Diseases § 3.380 Diseases of allergic etiology. Diseases of allergic etiology, including bronchial... progress nor as due to the inherent nature of the disease. Seasonal and other acute allergic manifestations...

38 CFR 3.380 - Diseases of allergic etiology.

Code of Federal Regulations, 2014 CFR

2014-07-01

... 38 Pensions, Bonuses, and Veterans' Relief 1 2014-07-01 2014-07-01 false Diseases of allergic... Specific Diseases § 3.380 Diseases of allergic etiology. Diseases of allergic etiology, including bronchial... progress nor as due to the inherent nature of the disease. Seasonal and other acute allergic manifestations...

38 CFR 3.380 - Diseases of allergic etiology.

Code of Federal Regulations, 2013 CFR

2013-07-01

... 38 Pensions, Bonuses, and Veterans' Relief 1 2013-07-01 2013-07-01 false Diseases of allergic... Specific Diseases § 3.380 Diseases of allergic etiology. Diseases of allergic etiology, including bronchial... progress nor as due to the inherent nature of the disease. Seasonal and other acute allergic manifestations...

38 CFR 3.380 - Diseases of allergic etiology.

Code of Federal Regulations, 2012 CFR

2012-07-01

... 38 Pensions, Bonuses, and Veterans' Relief 1 2012-07-01 2012-07-01 false Diseases of allergic... Specific Diseases § 3.380 Diseases of allergic etiology. Diseases of allergic etiology, including bronchial... progress nor as due to the inherent nature of the disease. Seasonal and other acute allergic manifestations...

Monitoring inflammation (including fever) in acute brain injury.

PubMed

Provencio, J Javier; Badjatia, Neeraj

2014-12-01

Inflammation is an important part of the normal physiologic response to acute brain injury (ABI). How inflammation is manifest determines if it augments or hinders the resolution of ABI. Monitoring body temperature, the cellular arm of the inflammatory cascade, and inflammatory proteins may help guide therapy. This summary will address the utility of inflammation monitoring in brain-injured adults. An electronic literature search was conducted for English language articles describing the testing, utility, and optimal methods to measure inflammation in ABI. Ninety-four articles were included in this review. Current evidence suggests that control of inflammation after ABI may hold promise for advances in good outcomes. However, our understanding of how much inflammation is good and how much is deleterious is not yet clear. Several important concepts emerge form our review. First, while continuous temperature monitoring of core body temperature is recommended, temperature pattern alone is not useful in distinguishing infectious from noninfectious fever. Second, when targeted temperature management is used, shivering should be monitored at least hourly. Finally, white blood cell levels and protein markers of inflammation may have a limited role in distinguishing infectious from noninfectious fever. Our understanding of optimal use of inflammation monitoring after ABI is limited currently but is an area of active investigation.

Inhibitory effects of Pycnogenol® (French maritime pine bark extract) on airway inflammation in ovalbumin-induced allergic asthma.

PubMed

Shin, In-Sik; Shin, Na-Rae; Jeon, Chan-Mi; Hong, Ju-Mi; Kwon, Ok-Kyoung; Kim, Jong-Choon; Oh, Sei-Ryang; Hahn, Kyu-Woung; Ahn, Kyung-Seop

2013-12-01

Pycnogenol® (PYC) is a standardized extracts from the bark of the French maritime pine (Pinus maritime) and used as a herbal remedy for various diseases. In this study, we evaluated the effects of PYC on airway inflammation using a model of ovalbumin (OVA)-induced allergic asthma and RAW264.7 cells. PYC decreased nitric oxide production and reduced the interleukine (IL)-1β and IL-6 levels in LPS-stimulated RAW264.7 cells. PYC also reduced the expression of inducible nitric oxide synthase (iNOS) and matrix metalloproteinase (MMP)-9 and enhanced the expression of hemeoxygenase (HO)-1. In the in vivo experiment, PYC decreased the inflammatory cell count and the levels of IL-4, IL-5, IL-13, and immunoglobulin (Ig) E in BALF or serum. These results are consistent with the histological analysis findings, which showed that PYC attenuated the airway inflammation and mucus hypersecretion induced by OVA challenge. In addition, PYC enhanced the expression of HO-1. In contrast, PYC inhibited the elevated expression of iNOS and MMP-9 proteins induced by OVA challenge. In conclusion, PYC exhibits protective effects against OVA-induced asthma and LPS-stimulated RAW264.7 cells. These results suggest that PYC has potential as a therapeutic agent for the treatment of allergic asthma. Copyright © 2013 Elsevier Ltd. All rights reserved.

Vinpocetine Inhibits NF-κB-Dependent Inflammation in Acute Ischemic Stroke Patients.

PubMed

Zhang, Fang; Yan, Chen; Wei, Changjuan; Yao, Yang; Ma, Xiaofeng; Gong, Zhongying; Liu, Shoufeng; Zang, Dawei; Chen, Jieli; Shi, Fu-Dong; Hao, Junwei

2018-04-01

Immunity and inflammation play critical roles in the pathogenesis of acute ischemic stroke. Therefore, immune intervention, as a new therapeutic strategy, is worthy of exploration. Here, we tested the inflammation modulator, vinpocetine, for its effect on the outcomes of stroke. For this multi-center study, we recruited 60 patients with anterior cerebral circulation occlusion and onset of stroke that had exceeded 4.5 h but lasted less than 48 h. These patients, after random division into two groups, received either standard management alone (controls) or standard management plus vinpocetine (30 mg per day intravenously for 14 consecutive days, Gedeon Richter Plc., Hungary). Vinpocetine treatment did not change the lymphocyte count; however, nuclear factor kappa-light-chain-enhancer of activated B cell activation was inhibited as seen not only by the increased transcription of IκBα mRNA but also by the impeded phosphorylation and degradation of IκBα and subsequent induction of pro-inflammatory mediators. These effects led to significantly reduced secondary lesion enlargement and an attenuated inflammation reaction. Compared to controls, patients treated with vinpocetine had a better recovery of neurological function and improved clinical outcomes during the acute phase and at 3-month follow-up. These findings identify vinpocetine as an inflammation modulator that could improve clinical outcomes after acute ischemic stroke. This study also indicated the important role of immunity and inflammation in the pathogenesis of acute ischemic stroke and the significance of immunomodulatory treatment. www.clinicaltrials.gov . Identifier: NCT02878772.

Age-related ventricular-vascular coupling during acute inflammation in humans: Effect of physical activity.

PubMed

Lane, Abbi D; Kappus, Rebecca M; Bunsawat, Kanokwan; Ranadive, Sushant M; Yan, Huimin; Phillips, Shane; Baynard, Tracy; Woods, Jeffrey A; Motl, Robert; Fernhall, Bo

2015-07-01

Aging is commonly accompanied by increased arterial and ventricular stiffness (determined by arterial elastance (Ea) and ventricular elastance (Elv)), augmented ventricular-vascular coupling ratios (Ea/Elv) and systemic inflammation. Acute inflammation may impact ventricular-vascular coupling and predispose older adults to cardiovascular events. However, physically active older adults have more compliant large arteries and left ventricles and lower inflammation than sedentary older adults. We hypothesized that acute inflammation would alter Ea, Elv, and Ea/Elv more in older versus younger adults but that higher levels of physical activity would attenuate inflammation-induced changes. End-systolic and central blood pressures were obtained using applanation tonometry before and at 24 and 48 h post-influenza vaccination in 24 older and 38 younger adults. Ultrasonography was used to measure ventricular volumes and other indices of cardiac performance. Physical activity was measured with accelerometry. Ea and Ea/Elv were maintained (p > 0.05), but Elv was reduced (p < 0.05) 24 h post-inflammation. Other indices of systolic performance were reduced in older but not younger adults; diastolic performance was attenuated in both groups 24 h post-inflammation (p < 0.05 for all). Older, but not younger, adults decreased central pressure during inflammation (p < 0.05). When controlled for age, physical activity was not related to the inflammation-induced changes in elastance (p > 0.05) except in the most active group of seniors (p < 0.05). Aging did not affect the elastance responses but did affect central blood pressure and other ventricular systolic responses to acute inflammation. Aging, not physical activity, appears to modulate cardiovascular responses to acute inflammation, except in the most active older adults. © The European Society of Cardiology 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.

Inhibitory effect of 1,2,4,5-tetramethoxybenzene on mast cell-mediated allergic inflammation through suppression of IκB kinase complex

DOE Office of Scientific and Technical Information (OSTI.GOV)

Je, In-Gyu; Choi, Hyun Gyu; Kim, Hui-Hun

As the importance of allergic disorders such as atopic dermatitis and allergic asthma, research on potential drug candidates becomes more necessary. Mast cells play an important role as initiators of allergic responses through the release of histamine; therefore, they should be the target of pharmaceutical development for the management of allergic inflammation. In our previous study, anti-allergic effect of extracts of Amomum xanthioides was demonstrated. To further investigate improved candidates, 1,2,4,5-tetramethoxybenzene (TMB) was isolated from methanol extracts of A. xanthioides. TMB dose-dependently attenuated the degranulation of mast cells without cytotoxicity by inhibiting calcium influx. TMB decreased the expression of pro-inflammatorymore » cytokines such as tumor necrosis factor-α and interleukin (IL)-4 at both the transcriptional and translational levels. Increased expression of these cytokines was caused by translocation of nuclear factor-κB into the nucleus, and it was hindered by suppressing activation of IκB kinase complex. To confirm the effect of TMB in vivo, the ovalbumin (OVA)-induced active systemic anaphylaxis (ASA) and IgE-mediated passive cutaneous anaphylaxis (PCA) models were used. In the ASA model, hypothermia was decreased by oral administration of TMB, which attenuated serum histamine, OVA-specific IgE, and IL-4 levels. Increased pigmentation of Evans blue was reduced by TMB in a dose-dependent manner in the PCA model. Our results suggest that TMB is a possible therapeutic candidate for allergic inflammatory diseases that acts through the inhibition of mast cell degranulation and expression of pro-inflammatory cytokines. - Highlights: • TMB reduced the degranulation of mast cells. • TMB inhibited the production of pro-inflammatory cytokines. • TMB suppressed both active and passive anaphylaxis. • Anti-allergic inflammatory effects of TMB might be due to the blocking IKK complex. • TMB might be a candidate for the

Human Helminths and Allergic Disease: The Hygiene Hypothesis and Beyond

PubMed Central

Santiago, Helton C.; Nutman, Thomas B.

2016-01-01

There is much debate about the interaction between helminths and allergic disease. The “Hygiene Hypothesis,” a very popular concept among scientists and the lay public, states that infections, especially during childhood, can protect against allergic diseases. Indeed, helminth infections are known to induce regulatory responses in the host that can help the control of inflammation (including allergic inflammation). However, these infections also induce type-2-associated immune responses including helminth-specific IgE that can cross-react against environmental allergens and mediate IgE-driven effector responses. Thus, it is the delicate balance between the parasites' anti- and pro-allergenic effects that define the helminth/allergy interface. PMID:27573628

Influence of fitness and age on the endothelial response to acute inflammation.

PubMed

Schroeder, Elizabeth C; Lane-Cordova, Abbi D; Ranadive, Sushant M; Baynard, Tracy; Fernhall, Bo

2018-06-01

What is the central question of the study? What are the effects of age and fitness on the vascular response to acute inflammation in younger and older adults? What is the main finding and its importance? In older adults, cardiorespiratory fitness level has a differential impact on endothelial function after acute inflammation. Compared with older adults with low fitness, older, moderately fit adults have a greater decrease in endothelial function, similar to that of younger adults. These findings have important implications in support of the beneficial effects of higher cardiorespiratory fitness in maintaining vascular reactivity and the ability to respond to stressors. Inflammation is associated with greater risk of cardiovascular events and reduced vascular function with ageing. Higher cardiorespiratory fitness is associated with lower risk of cardiovascular events and better vascular function. We evaluated the role of fitness in the vascular response to acute inflammation in 26 younger adults (YA) and 62 older adults (OA). We used an influenza vaccine to induce acute inflammation. Blood pressure, flow-mediated dilatation (FMD), augmentation index, carotid elastic modulus and inflammatory markers were measured before and 24 h after vaccination. Peak oxygen uptake was measured via a treadmill test. 'Fit' was defined as a peak oxygen uptake greater than the age- and sex-determined 50th percentile according to the American College of Sports Medicine. An interaction effect existed for the FMD response during acute inflammation (P < 0.05). The YA (low fit, from 11.5 ± 1.8 to 9.2 ± 1.3%; moderately fit, from 11.9 ± 0.8 to 9.0 ± 0.8%) and moderately fit OA (from 7.5 ± 1.0 to 3.9 ± 0.8%) had similar reductions in FMD at 24 h (P < 0.05). Low-fit OA did not reduce FMD at 24 h (from 5.5 ± 0.4 to 5.2 ± 0.5%, P > 0.05). The reduction in FMD in YA was similar between fitness groups (P > 0.05). All groups had similar reductions in mean

Smoking Is Associated with Acute and Chronic Prostatic Inflammation: Results from the REDUCE Study.

PubMed

Moreira, Daniel M; Nickel, J Curtis; Gerber, Leah; Muller, Roberto L; Andriole, Gerald L; Castro-Santamaria, Ramiro; Freedland, Stephen J

2015-04-01

Both anti- and proinflammatory effects of cigarette smoking have been described. As prostate inflammation is common, we hypothesized smoking could contribute to prostate inflammation. Thus, we evaluated the association of smoking status with acute and chronic inflammation within the prostate of men undergoing prostate biopsy. We retrospectively analyzed 8,190 men ages 50 to 75 years with PSA levels between 2.5 and 10 ng/mL enrolled in the Reduction by Dutasteride of Prostate Cancer Events study. Smoking status was self-defined as never, former, or current. Prostate inflammation was assessed by systematic central review blinded to smoking status. The association of smoking with inflammation in the baseline, 2-year, and 4-year biopsies was evaluated with univariable and multivariable logistic regressions. At study enrollment, 1,233 (15%), 3,203 (39%), and 3,754 (46%) men were current, former, and never smokers, respectively. Current smokers were significantly younger and had smaller prostates than former and never smokers (all P < 0.05). Former smokers were significantly heavier than current and never smokers (P < 0.001). Acute and chronic prostate inflammations were identified in 1,261 (15%) and 6,352 (78%) baseline biopsies, respectively. In univariable analysis, current smokers were more likely to have acute inflammation than former (OR, 1.35; P, 0.001) and never smokers (OR, 1.36; P, 0.001). The results were unchanged at 2- and 4-year biopsies. In contrast, current smoking was linked with chronic inflammation in the baseline biopsy, but not at 2- and 4-year biopsies. In conclusion, among men undergoing prostate biopsy, current smoking was independently associated with acute and possibly chronic prostate inflammations. ©2015 American Association for Cancer Research.

Prostaglandin I2 promotes the development of IL-17-producing γδ T cells that associate with the epithelium during allergic lung inflammation

PubMed Central

Jaffar, Zeina; Ferrini, Maria E.; Shaw, Pamela K.; FitzGerald, Garret A.; Roberts, Kevan

2011-01-01

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. PMID:21976777

IL-17 and TNF-α Are Key Mediators of Moraxella catarrhalis Triggered Exacerbation of Allergic Airway Inflammation

PubMed Central

Alnahas, Safa; Hagner, Stefanie; Raifer, Hartmann; Kilic, Ayse; Gasteiger, Georg; Mutters, Reinier; Hellhund, Anne; Prinz, Immo; Pinkenburg, Olaf; Visekruna, Alexander; Garn, Holger; Steinhoff, Ulrich

2017-01-01

Alterations of the airway microbiome are often associated with pulmonary diseases. For example, detection of the bacterial pathogen Moraxella catarrhalis in the upper airways is linked with an increased risk to develop or exacerbate asthma. However, the mechanisms by which M. catarrhalis augments allergic airway inflammation (AAI) remain unclear. We here characterized the cellular and soluble mediators of M. catarrhalis triggered excacerbation of AAI in wt and IL-17 deficient as well as in animals treated with TNF-α and IL-6 neutralizing antibodies. We compared the type of inflammatory response in M. catarrhalis infected, house dust mite (HDM)-allergic and animals infected with M. catarrhalis at different time points of HDM sensitization. We found that airway infection of mice with M. catarrhalis triggers a strong inflammatory response with massive neutrophilic infiltrates, high amounts of IL-6 and TNF-α and moderate levels of CD4+ T-cell-derived IFN-γ and IL-17. If bacterial infection occurred during HDM allergen sensitization, the allergic airway response was exacerbated, particularly by the expansion of Th17 cells and increased TNF-α levels. Neutralization of IL-17 or TNF-α but not IL-6 resulted in accelerated clearance of M. catarrhalis and effectively prevented infection-induced exacerbation of AAI. Taken together, our data demonstrate an essential role for TNF-α and IL-17 in infection-triggered exacerbation of AAI. PMID:29184554

Diesel Exhaust Exposure and Nasal Response to Attenuated Influenza in Normal and Allergic Volunteers

PubMed Central

Zhou, Haibo; Zhang, Hongtao; Horvath, Katie; Robinette, Carole; Kesic, Matthew; Meyer, Megan; Diaz-Sanchez, David; Jaspers, Ilona

2012-01-01

Rationale: Diesel exhaust enhances allergic inflammation, and pollutants are associated with heightened susceptibility to viral respiratory infections. The effects of combined diesel and virus exposure in humans are unknown. Objectives: Test whether acute exposure to diesel modifies inflammatory responses to influenza virus in normal humans and those with allergies. Methods: We conducted a double-blind, randomized, placebo-controlled study of nasal responses to live attenuated influenza virus in normal volunteers and those with allergic rhinitis exposed to diesel (100 μg/m3) or clean air for 2 hours, followed by standard dose of virus and serial nasal lavages. Endpoints were inflammatory mediators (ELISA) and virus quantity (quantitative reverse-transcriptase polymerase chain reaction). To test for exposure effect, we used multiple regression with exposure group (diesel vs. air) as the main explanatory variable and allergic status as an additional factor. Measurements and Main Results: Baseline levels of mediators did not differ among groups. For most postvirus nasal cytokine responses, there was no significant diesel effect, and no significant interaction with allergy. However, diesel was associated with significantly increased IFN-γ responses (P = 0.02), with no interaction with allergy in the regression model. Eotaxin-1 (P = 0.01), eosinophil cationic protein (P < 0.01), and influenza RNA sequences in nasal cells (P = 0.03) were significantly increased with diesel exposure, linked to allergy. Conclusions: Short-term exposure to diesel exhaust leads to increased eosinophil activation and increased virus quantity after virus inoculation in those with allergic rhinitis. This is consistent with previous literature suggesting a diesel “adjuvant” effect promoting allergic inflammation, and our data further suggest this change may be associated with reduced virus clearance. Clinical trial registered with www.clinicaltrials.gov (NCT00617110). PMID:22071326

Clearance of Aspergillus fumigatus is impaired in the airway in allergic inflammation.

PubMed

Fukahori, Susumu; Matsuse, Hiroto; Tsuchida, Tomoko; Kawano, Tetsuya; Nishino, Tomoya; Fukushima, Chizu; Kohno, Shigeru

2014-08-01

Aspergillus fumigatus (Af) sometimes colonizes and persists within the respiratory tree in some patients with asthma. To date, the precise reasons why the clearance of Af is impaired in patients with asthma remain unknown. To characterize the effects of allergic airway inflammation on clearance of Af. Control and Dermatophagoides farinae (Df) allergen-sensitized BALB/c mice were intranasally infected with Af. After 2 and 9 days of infection, the pathology, fungal burden, and cytokine profile in lung tissue were compared. In a different set of experiments, the phagocytotic activity of alveolar macrophages and the expression of their pathogen recognition receptors also were determined. The Af conidia and neutrophilic airway inflammation disappeared by day 9 after infection in control mice. In Df-sensitized mice, Af conidia and neutrophilic and eosinophilic airway inflammation persisted at day 9 after infection. Compared with control mice, Df allergen-sensitized mice showed significant increases in interleukin (IL)-5 and decreases in IL-12 and interferon-γ in lung tissues at day 2 after infection. Most importantly, compared with Af-infected non-Df-sensitized mice, IL-17 in lung tissues was significantly decreased in Df allergen-sensitized Af-infected mice at day 2 after infection but was significantly increased at day 9. Alveolar macrophages isolated from Df allergen-sensitized mice exhibited significant decreases in phagocytotic activity and expression of Toll-like receptor-4 and dectin-1 compared with those from control mice. In the airway of patients with allergy, T-helper cell type 2-dominant immunity potentially affects the expression of pathogen recognition receptors and attenuates cellular defense against Af. Prolonged IL-17 production also could play an important role. Copyright © 2014 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Ligation of TLR7 on CD19(+) CD1d(hi) B cells suppresses allergic lung inflammation via regulatory T cells.

PubMed

Khan, Adnan R; Amu, Sylvie; Saunders, Sean P; Hams, Emily; Blackshields, Gordon; Leonard, Martin O; Weaver, Casey T; Sparwasser, Tim; Sheils, Orla; Fallon, Padraic G

2015-06-01

B cells have been described as having the capacity to regulate cellular immune responses and suppress inflammatory processes. One such regulatory B-cell population is defined as IL-10-producing CD19(+) CD1d(hi) cells. Previous work has identified an expansion of these cells in mice infected with the helminth, Schistosoma mansoni. Here, microarray analysis of CD19(+) CD1d(hi) B cells from mice infected with S. mansoni demonstrated significantly increased Tlr7 expression, while CD19(+) CD1d(hi) B cells from uninfected mice also demonstrated elevated Tlr7 expression. Using IL-10 reporter, Il10(-/-) and Tlr7(-/-) mice, we formally demonstrate that TLR7 ligation of CD19(+) CD1d(hi) B cells increases their capacity to produce IL-10. In a mouse model of allergic lung inflammation, the adoptive transfer of TLR7-elicited CD19(+) CD1d(hi) B cells reduced airway inflammation and associated airway hyperresponsiveness. Using DEREG mice to deplete FoxP3(+) T regulatory cells in allergen-sensitized mice, we show that that TLR7-elicited CD19(+) CD1d(hi) B cells suppress airway hyperresponsiveness via a T regulatory cell dependent mechanism. These studies identify that TLR7 stimulation leads to the expansion of IL-10-producing CD19(+) CD1d(hi) B cells, which can suppress allergic lung inflammation via T regulatory cells. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Blockade of IL-23 ameliorates allergic lung inflammation via decreasing the infiltration of Tc17 cells.

PubMed

Cheng, Sheng; Chen, Huilong; Wang, Aili; Bunjhoo, Hansvin; Cao, Yong; Xie, Jungang; Xu, Yongjian; Xiong, Weining

2016-12-01

Tc17 cells are interleukin (IL)-17-producing CD8 + T cells and have been found to participate in the development of allergic asthma. Interleukin-23 is a cytokine that may be involved in modulating the IL-17 response via Th17 cells. This study aimed to investigate whether IL-23 also has immunomodulatory effects on Tc17 cells. An allergic asthmatic mouse model was induced by sensitizing and challenging with ovalbumin (OVA). Anti-IL-23 antibody was administered intratracheally before challenge to the OVA-induced asthmatic mouse model. Airway hyperresponsiveness, lung inflammation, Tc17 cell percentages and IL-17 level in the lung tissue homogenate were measured. Anti-IL-23 treatment reduced airway hyperresponsiveness (Rn 2.471 ±0.5077 vs. 4.051 ±0.2334, p < 0.05), inflammatory cell infiltration in bronchoalveolar lavage fluid (eosinophils 140.0 ±9.869 vs. 222.4 ±31.55, p < 0.05, neutrophils 75.93 ±6.745 vs. 127.4 ±19.73, p < 0.05), airway inflammation and mucus secretion. Treatment with anti-IL-23 antibody also markedly reduced IL-17 level (398.1 ±28.74 vs. 590.6 ±36.13, p < 0.01) and percentage of Th17 and Tc17 cells in lung tissue homogenate (4.200 ±0.1581 vs. 9.314 ±1.027, p < 0.01 and 2.852 ±0.2566 vs. 5.588 ±0.3631, p < 0.01, Th17 and Tc17 cells respectively). Our data suggest that the IL-23/Tc17 cell axis may be involved in the pathogenesis of asthma as the complement of IL-23/Th17 cells.

Chronic Low Dose Chlorine Exposure Aggravates Allergic Inflammation and Airway Hyperresponsiveness and Activates Inflammasome Pathway

PubMed Central

Kim, Sae-Hoon; Park, Da-Eun; Lee, Hyun-Seung; Kang, Hye-Ryun; Cho, Sang-Heon

2014-01-01

Background Epidemiologic clinical studies suggested that chronic exposure to chlorine products is associated with development of asthma and aggravation of asthmatic symptoms. However, its underlying mechanism was not clearly understood. Studies were undertaken to define the effects and mechanisms of chronic low-dose chlorine exposure in the pathogenesis of airway inflammation and airway hyperresponsiveness (AHR). Methods Six week-old female BALB/c mice were sensitized and challenged with OVA in the presence and absence of chronic low dose chlorine exposure of naturally vaporized gas of 5% sodium hypochlorite solution. Airway inflammation and AHR were evaluated by bronchoalveolar lavage (BAL) cell recovery and non-invasive phlethysmography, respectively. Real-time qPCR, Western blot assay, and ELISA were used to evaluate the mRNA and protein expressions of cytokines and other inflammatory mediators. Human A549 and murine epithelial (A549 and MLE12) and macrophage (AMJ2-C11) cells were used to define the responses to low dose chlorine exposure in vitro. Results Chronic low dose chlorine exposure significantly augmented airway inflammation and AHR in OVA-sensitized and challenged mice. The expression of Th2 cytokines IL-4 and IL-5 and proinflammatory cytokine IL-1β and IL-33 were significantly increased in OVA/Cl group compared with OVA group. The chlorine exposure also activates the major molecules associated with inflammasome pathway in the macrophages with increased expression of epithelial alarmins IL-33 and TSLP in vitro. Conclusion Chronic low dose exposure of chlorine aggravates allergic Th2 inflammation and AHR potentially through activation of inflammasome danger signaling pathways. PMID:25202911

Dioscin relieves endotoxemia induced acute neuro-inflammation and protect neurogenesis via improving 5-HT metabolism

PubMed Central

Yang, Rui; Chen, Wei; Lu, Ye; Li, Yingke; Du, Hongli; Gao, Songyan; Dong, Xin; Yuan, Hongbin

2017-01-01

Sepsis, in addition to causing fatality, is an independent risk factor for cognitive impairment among sepsis survivors. The pathologic mechanism of endotoxemia induced acute neuro-inflammation still has not been fully understood. For the first time, we found the disruption of neurotransmitters 5-HT, impaired neurogenesis and activation of astrocytes coupled with concomitant neuro-inflammation were the potential pathogenesis of endotoxemia induced acute neuro-inflammation in sepsis survivors. In addition, dioscin a natural steroidal saponin isolated from Chinese medicinal herbs, enhanced the serotonergic system and produced anti-depressant effect by enhancing 5-HT levels in hippocampus. What is more, this finding was verified by metabolic analyses of hippocampus, indicating 5-HT related metabolic pathway was involved in the pathogenesis of endotoxemia induced acute neuro-inflammation. Moreover, neuro-inflammation and neurogenesis within hippocampus were indexed using quantitative immunofluorescence analysis of GFAP DCX and Ki67, as well as real-time RT-PCR analysis of some gene expression levels in hippocampus. Our in vivo and in vitro studies show dioscin protects hippocampus from endotoxemia induced cascade neuro-inflammation through neurotransmitter 5-HT and HMGB-1/TLR4 signaling pathway, which accounts for the dioscin therapeutic effect in behavioral tests. Therefore, the current findings suggest that dioscin could be a potential approach for the therapy of endotoxemia induced acute neuro-inflammation. PMID:28059131

Vocal exercise may attenuate acute vocal fold inflammation

PubMed Central

Abbott, Katherine Verdolini; Li, Nicole Y.K.; Branski, Ryan C.; Rosen, Clark A.; Grillo, Elizabeth; Steinhauer, Kimberly; Hebda, Patricia A.

2012-01-01

Objectives/Hypotheses The objective was to assess the utility of selected “resonant voice” exercises for the reduction of acute vocal fold inflammation. The hypothesis was that relatively large-amplitude, low-impact exercises associated with resonant voice would reduce inflammation more than spontaneous speech and possibly more than voice rest. Study Design The study design was prospective, randomized, double-blind. Methods Nine vocally healthy adults underwent a 1-hr vocal loading procedure, followed by randomization to (a) a spontaneous speech condition, (b) a vocal rest condition, or (c) a resonant voice exercise condition. Treatments were monitored in clinic for 4 hr, and continued extra-clinically until the next morning. At baseline, immediately following loading, after the 4-hr in-clinic treatment, and 24 hr post baseline, secretions were suctioned from the vocal folds bilaterally and submitted to enzyme-linked immunosorbent assay (ELISA) to estimate concentrations of key markers of tissue injury and inflammation: IL-1β, IL-6, IL-8, TNF-α, MMP-8, and IL-10. Results Complete data sets were obtained for 3 markers -- IL-1β, IL-6, and MMP-8 -- for one subject in each treatment condition. For those markers, results were poorest at 24-hr follow-up in the spontaneous speech condition, sharply improved in the voice rest condition, and best in the resonant voice condition. Average results for all markers, for all responsive subjects with normal baseline mediator concentrations, revealed an almost identical pattern. Conclusions Some forms of tissue mobilization may be useful to attenuate acute vocal fold inflammation. PMID:23177745

Mast Cell Interactions and Crosstalk in Regulating Allergic Inflammation.

PubMed

Velez, Tania E; Bryce, Paul J; Hulse, Kathryn E

2018-04-17

This review summarizes recent findings on mast cell biology with a focus on IgE-independent roles of mast cells in regulating allergic responses. Recent studies have described novel mast cell-derived molecules, both secreted and membrane-bound, that facilitate cross-talk with a variety of immune effector cells to mediate type 2 inflammatory responses. Mast cells are complex and dynamic cells that are persistent in allergy and are capable of providing signals that lead to the initiation and persistence of allergic mechanisms.

Human Helminths and Allergic Disease: The Hygiene Hypothesis and Beyond.

PubMed

Santiago, Helton C; Nutman, Thomas B

2016-10-05

There is much debate about the interaction between helminths and allergic disease. The "Hygiene Hypothesis," a very popular concept among scientists and the lay public, states that infections, especially during childhood, can protect against allergic diseases. Indeed, helminth infections are known to induce regulatory responses in the host that can help the control of inflammation (including allergic inflammation). However, these infections also induce type-2-associated immune responses including helminth-specific IgE that can cross-react against environmental allergens and mediate IgE-driven effector responses. Thus, it is the delicate balance between the parasites' anti- and pro-allergenic effects that define the helminth/allergy interface. © The American Society of Tropical Medicine and Hygiene.

Alveolar Macrophages Play a Key Role in Cockroach-Induced Allergic Inflammation via TNF-α Pathway

PubMed Central

Kim, Joo Young; Sohn, Jung Ho; Choi, Je-Min; Lee, Jae-Hyun; Hong, Chein-Soo; Lee, Joo-Shil; Park, Jung-Won

2012-01-01

The activity of the serine protease in the German cockroach allergen is important to the development of allergic disease. The protease-activated receptor (PAR)-2, which is expressed in numerous cell types in lung tissue, is known to mediate the cellular events caused by inhaled serine protease. Alveolar macrophages express PAR-2 and produce considerable amounts of tumor necrosis factor (TNF)-α. We determined whether the serine protease in German cockroach extract (GCE) enhances TNF-α production by alveolar macrophages through the PAR-2 pathway and whether the TNF-α production affects GCE-induced pulmonary inflammation. Effects of GCE on alveolar macrophages and TNF-α production were evaluated using in vitro MH-S and RAW264.6 cells and in vivo GCE-induced asthma models of BALB/c mice. GCE contained a large amount of serine protease. In the MH-S and RAW264.7 cells, GCE activated PAR-2 and thereby produced TNF-α. In the GCE-induced asthma model, intranasal administration of GCE increased airway hyperresponsiveness (AHR), inflammatory cell infiltration, productions of serum immunoglobulin E, interleukin (IL)-5, IL-13 and TNF-α production in alveolar macrophages. Blockade of serine proteases prevented the development of GCE induced allergic pathologies. TNF-α blockade also prevented the development of such asthma-like lesions. Depletion of alveolar macrophages reduced AHR and intracellular TNF-α level in pulmonary cell populations in the GCE-induced asthma model. These results suggest that serine protease from GCE affects asthma through an alveolar macrophage and TNF-α dependent manner, reflecting the close relation of innate and adaptive immune response in allergic asthma model. PMID:23094102

Acute transient cognitive dysfunction and acute brain injury induced by systemic inflammation occur by dissociable IL-1-dependent mechanisms.

PubMed

Skelly, Donal T; Griffin, Éadaoin W; Murray, Carol L; Harney, Sarah; O'Boyle, Conor; Hennessy, Edel; Dansereau, Marc-Andre; Nazmi, Arshed; Tortorelli, Lucas; Rawlins, J Nicholas; Bannerman, David M; Cunningham, Colm

2018-06-06

Systemic inflammation can impair cognition with relevance to dementia, delirium and post-operative cognitive dysfunction. Episodes of delirium also contribute to rates of long-term cognitive decline, implying that these acute events induce injury. Whether systemic inflammation-induced acute dysfunction and acute brain injury occur by overlapping or discrete mechanisms remains unexplored. Here we show that systemic inflammation, induced by bacterial LPS, produces both working-memory deficits and acute brain injury in the degenerating brain and that these occur by dissociable IL-1-dependent processes. In normal C57BL/6 mice, LPS (100 µg/kg) did not affect working memory but impaired long-term memory consoliodation. However prior hippocampal synaptic loss left mice selectively vulnerable to LPS-induced working memory deficits. Systemically administered IL-1 receptor antagonist (IL-1RA) was protective against, and systemic IL-1β replicated, these working memory deficits. Dexamethasone abolished systemic cytokine synthesis and was protective against working memory deficits, without blocking brain IL-1β synthesis. Direct application of IL-1β to ex vivo hippocampal slices induced non-synaptic depolarisation and irrevesible loss of membrane potential in CA1 neurons from diseased animals and systemic LPS increased apoptosis in the degenerating brain, in an IL-1RI -/- -dependent fashion. The data suggest that LPS induces working memory dysfunction via circulating IL-1β but direct hippocampal action of IL-1β causes neuronal dysfunction and may drive neuronal death. The data suggest that acute systemic inflammation produces both reversible cognitive deficits, resembling delirium, and acute brain injury contributing to long-term cognitive impairment but that these events are mechanistically dissociable. These data have significant implications for management of cognitive dysfunction during acute illness.

TLR-7 agonist attenuates airway reactivity and inflammation through Nrf2-mediated antioxidant protection in a murine model of allergic asthma.

PubMed

Nadeem, Ahmed; Siddiqui, Nahid; Al-Harbi, Naif O; Al-Harbi, Mohammed M; Ahmad, Sheikh F

2016-04-01

Toll-like receptors (TLRs) through innate immune system recognize pathogen associated molecular patterns and play an important role in host defense against bacteria, fungi and viruses. TLR-7 is responsible for sensing single stranded nucleic acids of viruses but its activation has been shown to be protective in mouse models of asthma. The NADPH oxidase (NOX) enzymes family mainly produces reactive oxygen species (ROS) in the lung and is involved in regulation of airway inflammation in response to TLRs activation. However, NOX-4 mediated signaling in response to TLR-7 activation in a mouse model of allergic asthma has not been explored previously. Therefore, this study investigated the role TLR-7 activation and downstream oxidant-antioxidant signaling in a murine model of asthma. Mice were sensitized with ovalbumin (OVA) intraperitoneally and treated with TLR-7 agonist, resiquimod (RSQ) intranasally before each OVA challenge from days 14 to 16. Mice were then assessed for airway reactivity, inflammation, and NOX-4 and nuclear factor E2-related factor 2 (Nrf2) related signaling [inducible nitric oxide synthase (iNOS), nitrotyrosine, lipid peroxides and copper/zinc superoxide dismutase (Cu/Zn SOD)]. Treatment with RSQ reduced allergen induced airway reactivity and inflammation. This was paralleled by a decrease in ROS which was due to induction of Nrf2 and Cu/Zn SOD in RSQ treated group. Inhibition of MyD88 reversed RSQ-mediated protective effects on airway reactivity/inflammation due to reduction in Nrf2 signaling. SOD inhibition produced effects similar to MyD88 inhibition. The current study suggests that TLR-7 agonist is beneficial and may be developed into a therapeutic option in allergic asthma. Copyright © 2016 Elsevier Ltd. All rights reserved.

Piper nigrum extract ameliorated allergic inflammation through inhibiting Th2/Th17 responses and mast cells activation.

PubMed

Bui, Thi Tho; Piao, Chun Hua; Song, Chang Ho; Shin, Hee Soon; Shon, Dong-Hwa; Chai, Ok Hee

2017-12-01

Piper nigrum (Piperaceae) is commonly used as a spice and traditional medicine in many countries. P. nigrum has been reported to have anti-oxidant, anti-bacterial, anti-tumor, anti-mutagenic, anti-diabetic, and anti-inflammatory properties. However, the effect of P. nigrum on allergic asthma has not been known. This study investigated the effect of P. nigrum ethanol extracts (PNE) on airway inflammation in asthmatic mice model. In the ovalbumin (OVA)-induced allergic asthma model, we analysed the number of inflammatory cells and cytokines production in bronchoalveolar lavage fluid (BALF) and lung tissue; histological structure; as well as the total immunoglobulin (Ig)E, anti-OVA IgE, anti-OVA IgG 1 and histamine levels in serum. The oral administration (200 mg/kg) of PNE reduced the accumulation of inflammatory cells (eosinophils, neutrophils in BALF and mast cells in lung tissue); regulated the balance of the cytokines production of Th1, Th2, Th17 and Treg cells, specifically, inhibited the expressions of GATA3, IL-4, IL-6, IL-1β, RORγt, IL-17A, TNF-α and increased the secretions of IL-10, INF-γ in BALF and lung homogenate. Moreover, PNE suppressed the levels of total IgE, anti-OVA IgE, anti-OVA IgG 1 and histamine release in serum. The histological analysis showed that the fibrosis and infiltration of inflammatory cells were also ameliorated in PNE treated mice. On the other hand, PNE inhibited the allergic responses via inactivation of rat peritoneal mast cells degranulation. These results suggest that PNE has therapeutic potential for treating allergic asthma through inhibiting Th2/Th17 responses and mast cells activation. Copyright © 2017 Elsevier Inc. All rights reserved.

Alkylphenols--potential modulators of the allergic response.

PubMed

Suen, Jau-Ling; Hung, Chih-Hsin; Yu, Hsin-Su; Huang, Shau-Ku

2012-07-01

The prevalence of allergic diseases has increased in recent decades. Allergic diseases, particularly asthma, are complex diseases with strong gene-environment interactions. Epidemiological studies have identified a variety of risk factors for the development of allergic diseases. Among them, endocrine-disrupting chemicals (EDCs) play an important role in triggering or exacerbating these diseases. 4-Nonylphenol (NP) and 4-octylphenol (OP)--two major alkylphenols--have been recognized as common toxic and xenobiotic endocrine disrupters. Due to their low solubility, high hydrophobicity, and low estrogenic activity, they tend to accumulate in the human body and may be associated with the adverse effects of allergic diseases. Recently, new evidence has supported the importance of alkylphenols in the in vitro allergic response. This review focuses on the effects of alkylphenols on several key cell types in the context of allergic inflammation. Copyright © 2012. Published by Elsevier B.V.

A limited CpG-containing oligodeoxynucleotide therapy regimen induces sustained suppression of allergic airway inflammation in mice

PubMed Central

Kozy, Heather M.; Lum, Jeremy A.; Sweetwood, Rosemary; Chu, Mabel; Cunningham, Cameron R.; Salamon, Hugh; Lloyd, Clare M.; Coffman, Robert L.; Hessel, Edith M.

2015-01-01

Background CpG-containing oligodeoxynucleotides (CpG-ODN) are potent inhibitors of Th2-mediated allergic airway disease in sensitized mice challenged with allergen. A single treatment has transient effects but a limited series of treatments has potential to achieve clinically meaningful sustained inhibition of allergic airway disease. Objective To optimize the treatment regimen and determine the mechanisms of action in mice of an inhaled form of CpG-ODN being developed for human asthma treatment. Methods A limited series of weekly intranasal 1018 ISS (CpG-ODN; B-class) treatments were given to ragweed allergen-sensitized mice chronically exposed to allergen during and after the 1018 ISS treatment regimen. Treatment effects were evaluated by measuring effect on lung Th2 cytokines and eosinophilia as well as lung dendritic cell function and T cell responses. Results Twelve intranasal 1018 ISS treatments induced significant suppression of BAL eosinophilia and IL-4, IL-5, and IL-13 levels and suppression was maintained through 13 weekly ragweed exposures administered after treatment cessation. At least 5 treatments were required for lasting Th2 suppression. CpG-ODN induced moderate Th1 responses but Th2 suppression did not require IFN-γ. Th2 suppression was associated with induction of a regulatory T cell response. Conclusion A short series of CpG-ODN treatments results in sustained suppression of allergic lung inflammation induced by a clinically relevant allergen. PMID:24464743

Allergic inflammation induces a persistent mechanistic switch in thromboxane-mediated airway constriction in the mouse

PubMed Central

Cyphert, Jaime M.; Allen, Irving C.; Church, Rachel J.; Latour, Anne M.; Snouwaert, John N.; Coffman, Thomas M.

2012-01-01

Actions of thromboxane (TXA2) to alter airway resistance were first identified over 25 years ago. However, the mechanism underlying this physiological response has remained largely undefined. Here we address this question using a novel panel of mice in which expression of the thromboxane receptor (TP) has been genetically manipulated. We show that the response of the airways to TXA2 is complex: it depends on expression of other G protein-coupled receptors but also on the physiological context of the signal. In the healthy airway, TXA2-mediated airway constriction depends on expression of TP receptors by smooth muscle cells. In contrast, in the inflamed lung, the direct actions of TXA2 on smooth muscle cell TP receptors no longer contribute to bronchoconstriction. Instead, in allergic lung disease, TXA2-mediated airway constriction depends on neuronal TP receptors. Furthermore, this mechanistic switch persists long after resolution of pulmonary inflammation. Our findings demonstrate the powerful ability of lung inflammation to modify pathways leading to airway constriction, resulting in persistent changes in mechanisms of airway reactivity to key bronchoconstrictors. Such alterations are likely to shape the pathogenesis of asthmatic lung disease. PMID:21984570

Pidotimod exacerbates allergic pulmonary infection in an OVA mouse model of asthma.

PubMed

Fu, Luo-Qin; Li, Ya-Li; Fu, Ai-Kun; Wu, Yan-Ping; Wang, Yuan-Yuan; Hu, Sheng-Lan; Li, Wei-Fen

2017-10-01

Pidotimod is a synthetic dipeptide with biological and immuno‑modulatory properties. It has been widely used for treatment and prevention of recurrent respiratory infections. However, its impact on the regulation of allergic pulmonary inflammation is still not clear. In the current study, an ovalbumin (OVA)‑induced allergic asthma model was used to investigate the immune‑modulating effects of pidotimod on airway eosinophilia, mucus metaplasia and inflammatory factor expression compared with dexamethasone (positive control). The authors determined that treatment with pidotimod exacerbated pulmonary inflammation as demonstrated by significantly increased eosinophil infiltration, dramatically elevated immunoglobulin E production, and enhanced T helper 2 response. Moreover, treatment failed to attenuate mucus production in lung tissue, and did not reduce OVA‑induced high levels of FIZZ1 and Arg1 expression in asthmatic mice. In contrast, administration of dexamethasone was efficient in alleviating allergic airway inflammation in OVA‑induced asthmatic mice. These data indicated that pidotimod as an immunotherapeutic agent should be used cautiously and the effectiveness for controlling allergic asthma needs further evaluation and research.

Shikonin inhibits maturation of bone marrow-derived dendritic cells and suppresses allergic airway inflammation in a murine model of asthma

PubMed Central

Lee, Chen-Chen; Wang, Chien-Neng; Lai, Yu-Ting; Kang, Jaw-Jou; Liao, Jiunn-Wang; Chiang, Bor-Luen; Chen, Hui-Chen; Cheng, Yu-Wen

2010-01-01

BACKGROUND AND PURPOSE Shikonin exhibits a wide range of anti-inflammatory actions. Here, we assessed its effects on maturation of murine bone marrow-derived dendritic cells (BM-DCs) and on allergic reactions in a murine model of asthma. EXPERIMENTAL APPROACH Cultured murine BM-DCs were used to investigate the effects of shikonin on expression of cell surface markers and their stimulation of T-cell proliferation and cytokine production. The therapeutic potential of shikonin was evaluated in a model of allergic airway disease. KEY RESULTS Shikonin dose-dependently inhibited expression of major histocompatibility complex class II, CD80, CD86, CCR7 and OX40L on BM-DCs, induced by a mixture of ovalbumin (OVA; 100 µg·mL−1) and thymic stromal lymphopoietin (TSLP; 20 ng·mL−1). Shikonin-treated BM-DCs were poor stimulators of CD4+ T lymphocyte and induced lower levels of interleukin (IL)-4, IL-5, IL-13 and tumour necrosis factor (TNF)-α release by responding T-cells. After intratracheal instillation of shikonin in OVA-immunized mice, OVA challenge induced lower IL-4, IL-5, IL-13, TNF-α and eotaxin release in bronchial alveolar lavage fluid, lower IL-4 and IL-5 production in lung cells and mediastinal lymph node cells and attenuated OVA-induced lung eosinophilia and airway hyperresponsiveness. CONCLUSION AND IMPLICATIONS Shikonin effectively suppressed OVA + TSLP-induced BM-DC maturation in vitro and inhibited allergic inflammation and airway hyperresponsiveness in a murine model of asthma, showing good potential as a treatment for allergic asthma. Also, our model provides a novel platform for screening drugs for allergic diseases. PMID:20735407

Scaffolding protein Gab1 regulates myeloid dendritic cell migration in allergic asthma

PubMed Central

Zhang, Yun; Xu, Yun; Liu, Shuwan; Guo, Xiaohong; Cen, Dong; Xu, Jiaqi; Li, Heyuan; Li, Kaijun; Zeng, Chunlai; Lu, Linrong; Zhou, Yiting; Shen, Huahao; Cheng, Hongqiang; Zhang, Xue; Ke, Yuehai

2016-01-01

Asthma is a common allergic disorder involving a complex interplay among multiple genetic and environmental factors. Recent studies identified genetic variants of human GAB1 as a novel asthma susceptibility factor. However, the functions of Gab1 in lung remain largely unexplored. In this study, we first observed an elevation of Gab1 level in peripheral blood mononuclear cells from asthmatic patients during acute exacerbation compared with convalescence. Mice with a selectively disrupted Gab1 in myeloid dendritic cells (mDCs) considerably attenuated allergic inflammation in experimental models of asthma. Further investigations revealed a prominent reduction in CCL19-mediated migration of Gab1-deficient mDCs to draining lymph nodes and subsequent impairment of Th2-driven adaptive activation. Mechanistically, Gab1 is an essential component of the CCL19/CCR7 chemokine axis that regulates mDC migration during asthmatic responses. Together, these findings provide the first evidence for the roles of Gab1 in lung, giving us deeper understanding of asthmatic pathogenesis. PMID:27811945

Effect of a chemical chaperone, tauroursodeoxycholic acid, on HDM-induced allergic airway disease

PubMed Central

Siddesha, Jalahalli M.; Nakada, Emily M.; Mihavics, Bethany R.; Hoffman, Sidra M.; Rattu, Gurkiranjit K.; Chamberlain, Nicolas; Cahoon, Jonathon M.; Lahue, Karolyn G.; Daphtary, Nirav; Aliyeva, Minara; Chapman, David G.; Desai, Dhimant H.; Poynter, Matthew E.

2016-01-01

Endoplasmic reticulum (ER) stress-induced unfolded protein response plays a critical role in inflammatory diseases, including allergic airway disease. However, the benefits of inhibiting ER stress in the treatment of allergic airway disease are not well known. Herein, we tested the therapeutic potential of a chemical chaperone, tauroursodeoxycholic acid (TUDCA), in combating allergic asthma, using a mouse model of house dust mite (HDM)-induced allergic airway disease. TUDCA was administered during the HDM-challenge phase (preventive regimen), after the HDM-challenge phase (therapeutic regimen), or therapeutically during a subsequent HDM rechallenge (rechallenge regimen). In the preventive regimen, TUDCA significantly decreased HDM-induced inflammation, markers of ER stress, airway hyperresponsiveness (AHR), and fibrosis. Similarly, in the therapeutic regimen, TUDCA administration efficiently decreased HDM-induced airway inflammation, mucus metaplasia, ER stress markers, and AHR, but not airway remodeling. Interestingly, TUDCA administered therapeutically in the HDM rechallenge regimen markedly attenuated HDM-induced airway inflammation, mucus metaplasia, ER stress markers, methacholine-induced AHR, and airway fibrotic remodeling. These results indicate that the inhibition of ER stress in the lungs through the administration of chemical chaperones could be a valuable strategy in the treatment of allergic airway diseases. PMID:27154200

NBR1 is a new PB1 signalling adapter in Th2 differentiation and allergic airway inflammation in vivo

PubMed Central

Yang, Jun-Qi; Liu, Hongzhu; Diaz-Meco, Maria T; Moscat, Jorge

2010-01-01

Allergic airway inflammation is a disease in which T helper 2 (Th2) cells have a critical function. The molecular mechanisms controlling Th2 differentiation and function are of paramount importance in biology and immunology. Recently, a network of PB1-containing adapters and kinases has been shown to be essential in this process owing to its function in regulating cell polarity and the activation of critical transcription factors. Here, we show in vivo data showing that T-cell-specific NBR1-deficient mice show impaired lung inflammation and have defective Th2 differentiation ex vivo with alterations in T-cell polarity and the selective inhibition of Gata3 and nuclear factor of activated T c1 activation. These results establish NBR1 as a novel PB1 adapter in Th2 differentiation and asthma. PMID:20808283

A Jagged 1-Notch 4 molecular switch mediates airway inflammation induced by ultrafine particles.

PubMed

Xia, Mingcan; Harb, Hani; Saffari, Arian; Sioutas, Constantinos; Chatila, Talal A

2018-04-05

Exposure to traffic-related particulate matter promotes asthma and allergic diseases. However, the precise cellular and molecular mechanisms by which particulate matter exposure acts to mediate these effects remain unclear. We sought to elucidate the cellular targets and signaling pathways critical for augmentation of allergic airway inflammation induced by ambient ultrafine particles (UFP). We used in vitro cell-culture assays with lung-derived antigen-presenting cells and allergen-specific T cells and in vivo mouse models of allergic airway inflammation with myeloid lineage-specific gene deletions, cellular reconstitution approaches, and antibody inhibition studies. We identified lung alveolar macrophages (AM) as the key cellular target of UFP in promoting airway inflammation. Aryl hydrocarbon receptor-dependent induction of Jagged 1 (Jag1) expression in AM was necessary and sufficient for augmentation of allergic airway inflammation by UFP. UFP promoted T H 2 and T H 17 cell differentiation of allergen-specific T cells in a Jag1- and Notch 4-dependent manner. Treatment of mice with an anti-Notch 4 antibody abrogated exacerbation of allergic airway inflammation induced by UFP. UFP exacerbate allergic airway inflammation by promoting a Jag1-Notch 4-dependent interaction between AM and allergen-specific T cells, leading to augmented T H cell differentiation. Copyright © 2018 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Outcomes Following Discontinuation of E. coli l-Asparaginase Upon Severe Allergic Reactions in Children With Acute Lymphoblastic Leukemia.

PubMed

Yen, Hsiu-Ju; Chang, Wan-Hui; Liu, Hsi-Che; Yeh, Ting-Chi; Hung, Giun-Yi; Wu, Kang-Hsi; Peng, Ching-Tien; Chang, Yu-Hsiang; Chang, Te-Kao; Hsiao, Chih-Cheng; Sheen, Jiunn-Ming; Chao, Yu-Hua; Chang, Tai-Tsung; Chiou, Shyh-Shin; Lin, Pei-Chin; Wang, Shih-Chung; Lin, Ming-Tsan; Ho, Wan-Ling; Chen, Yu-Chieh; Liang, Der-Cherng

2016-04-01

Discontinuation of E. coli l-asparaginase in patients with acute lymphoblastic leukemia (ALL) is unavoidable upon severe allergic reaction. We sought to examine outcomes following E. coli l-asparaginase discontinuation due to severe allergic reactions. We evaluated the outcome of children enrolled in Taiwan Pediatric Oncology Group-2002-ALL protocol between 2002 and 2012, who had E. coli l-asparaginase discontinued due to severe allergic reactions, and compared the outcomes of those who continued with Erwinia l-asparaginase (Erwinase) with those who did not. Among 700 patients enrolled in this study, 33 patients had E. coli l-asparaginase treatment discontinued due to severe allergic reactions. Five-year overall survival did not differ significantly among the 648 patients without discontinuation (81 ± 1.6%, mean ± SE), compared to 17 patients with allergic reactions and treated with Erwinase (88 ± 7.8%) and 16 patients with allergic reactions but not treated with Erwinase (87 ± 8.6%). Among 16 patients who did not receive Erwinase, all 10 who received ≥50% of the scheduled doses of E. coli l-asparaginase before discontinuation survived without events. Erwinase treatment may not be needed for some ALL patients with severe allergy to E. coli l-asparaginase if ≥50% of prescribed doses were received and/or therapy is augmented with other agents. © 2015 Wiley Periodicals, Inc.

Toxoplasma gondii tachyzoite-extract acts as a potent immunomodulator against allergic sensitization and airway inflammation.

PubMed

Drinić, Mirjana; Wagner, Angelika; Sarate, Priya; Zwicker, Christian; Korb, Elke; Loupal, Gerhard; Peschke, Roman; Joachim, Anja; Wiedermann, Ursula; Schabussova, Irma

2017-11-09

Epidemiological and experimental studies have shown an inverse relationship between infections with certain parasites and a reduced incidence of allergic diseases. We and others have shown that infection with Toxoplasma gondii prevents the development of allergy in mice. To establish whether this beneficial effect could be recapitulated by soluble products of this parasite, we tested an extract derived from T. gondii tachyzoites. Immunization of BALB/c mice with tachyzoites lysate antigen (TLA) elicited mixed Th1/Th2 responses. When TLA was applied together with the sensitizing ovalbumin (OVA), the development of allergic airway inflammation was reduced, with decreased airway hyperresponsiveness associated with reduced peribronchial and perivascular cellular infiltration, reduced production of OVA-specific Th2 cytokines in lungs and spleens and reduced levels of serum OVA-specific IgG1 as well as IgE-dependent basophil degranulation. Of note, TLA retained its immunomodulatory properties, inducing high levels of IL-6, TNFα, IL-10 and IL-12p70 in bone marrow-derived dendritic cells after heat-inactivation or proteinase K-treatment for disruption of proteins, but not after sodium metaperiodate-treatment that degrades carbohydrate structures, suggesting that carbohydrates may play a role in immunomodulatory properties of TLA. Here we show that extracts derived from parasites may replicate the benefits of parasitic infection, offering new therapies for immune-mediated disorders.

Contributions of transferrin to acute inflammation in the goldfish, C. auratus.

PubMed

Trites, M J; Barreda, D R

2017-02-01

Transferrin is an evolutionary conserved protein that in addition to having a critical role in iron transport also has been shown to have a crucial role in host defence, by depriving iron from invading pathogens. Recently cleaved transferrin products was shown to activate macrophages in vitro. We now use an in vivo model of self-resolving peritonitis in goldfish, coupled with gene expression and protein analysis to evaluate the contributions of cleaved transferrin to acute inflammation. We show, for the first time, that cleaved transferrin products are produced in vivo early during an acute inflammatory response. These cleaved transferrin fragments were produced during pathogen-induced, but not sterile, inflammation. Both macrophages and neutrophils were able to contribute to transferrin cleavage. However, only macrophages contributed to this innate process through inducible expression of transferrin. The appearance of transferrin cleavage products in vivo correlated with the influx of leukocytes but did not necessarily correlate the induction of robust respiratory burst and nitric oxide responses. Overall, this study adds to a growing body of work highlighting the role of transferrin as an immune regulator during acute inflammation. Given the significant conservation of this and related molecules, these findings have potentially broad implications for host defences and inflammation control across evolution. Copyright © 2016 Elsevier Ltd. All rights reserved.

Allergen-specific Th1 cells fail to counterbalance Th2 cell-induced airway hyperreactivity but cause severe airway inflammation.

PubMed

Hansen, G; Berry, G; DeKruyff, R H; Umetsu, D T

1999-01-01

Allergic asthma, which is present in as many as 10% of individuals in industrialized nations, is characterized by chronic airway inflammation and hyperreactivity induced by allergen-specific Th2 cells secreting interleukin-4 (IL-4) and IL-5. Because Th1 cells antagonize Th2 cell functions, it has been proposed that immune deviation toward Th1 can protect against asthma and allergies. Using an adoptive transfer system, we assessed the roles of Th1, Th2, and Th0 cells in a mouse model of asthma and examined the capacity of Th1 cells to counterbalance the proasthmatic effects of Th2 cells. Th1, Th2, and Th0 lines were generated from ovalbumin (OVA)-specific T-cell receptor (TCR) transgenic mice and transferred into lymphocyte-deficient, OVA-treated severe combined immunodeficiency (SCID) mice. OVA-specific Th2 and Th0 cells induced significant airway hyperreactivity and inflammation. Surprisingly, Th1 cells did not attenuate Th2 cell-induced airway hyperreactivity and inflammation in either SCID mice or in OVA-immunized immunocompetent BALB/c mice, but rather caused severe airway inflammation. These results indicate that antigen-specific Th1 cells may not protect or prevent Th2-mediated allergic disease, but rather may cause acute lung pathology. These findings have significant implications with regard to current therapeutic goals in asthma and allergy and suggest that conversion of Th2-dominated allergic inflammatory responses into Th1-dominated responses may lead to further problems.

[Allergic colitis in exclusively breast-fed infants].

PubMed

Sierra Salinas, C; Blasco Alonso, J; Olivares Sánchez, L; Barco Gálvez, A; del Río Mapelli, L

2006-02-01

Eosinophilic colitis is induced by antigens present in cow's milk proteins in formula or human milk. In the last few years, an increasing number of cases have been diagnosed in exclusively breast-fed infants. We performed a retrospective study of 13 infants diagnosed with allergic colitis in our unit between January 1997 and January 2004. All the infants had been exclusively breast-fed. In all patients, initial symptoms were digestive (12 with mucus and bloody stools). Onset of symptoms occurred at 0-3 months in 77 %. Laboratory data of the allergic compound were negative. The main locations were the descending and sigmoid colon (75 %). Biopsy demonstrated acute inflammation, with neutrophil infiltration and an increase in eosinophils. In all patients, initial treatment consisted of exclusion of cow's milk proteins from the mother's diet. Ten of the 13 patients showed no improvement, requiring exclusive administration of protein-free hydrolyzate. In 3 infants, breastfeeding was maintained (breastfeeding without cow's milk proteins plus hydrolyzate). Diagnosis of eosinophilic colitis is based on exclusion of other causes of specific colitis and typical endoscopic and ultrastructural findings. Moreover, a satisfactory response to dietary treatment must be demonstrated. This diagnosis should be considered in breast-fed infants with rectal bleeding without involvement of general health status.

Vitamin E Isoforms as Modulators of Lung Inflammation

PubMed Central

Abdala-Valencia, Hiam; Berdnikovs, Sergejs; Cook-Mills, Joan M.

2013-01-01

Asthma and allergic diseases are complex conditions caused by a combination of genetic and environmental factors. Clinical studies suggest a number of protective dietary factors for asthma, including vitamin E. However, studies of vitamin E in allergy commonly result in seemingly conflicting outcomes. Recent work indicates that allergic inflammation is inhibited by supplementation with the purified natural vitamin E isoform α-tocopherol but elevated by the isoform γ-tocopherol when administered at physiological tissue concentrations. In this review, we discuss opposing regulatory effects of α-tocopherol and γ-tocopherol on allergic lung inflammation in clinical trials and in animal studies. A better understanding of the differential regulation of inflammation by isoforms of vitamin E provides a basis towards the design of clinical studies and diets that would effectively modulate inflammatory pathways in lung disease. PMID:24184873

Effects of an acute bout of moderate-intensity exercise on postprandial lipemia and airway inflammation.

PubMed

Johnson, Ariel M; Kurti, Stephanie P; Smith, Joshua R; Rosenkranz, Sara K; Harms, Craig A

2016-03-01

A high-fat meal (HFM) induces an increase in blood lipids (postprandial lipemia; PPL), systemic inflammation, and acute airway inflammation. While acute exercise has been shown to have anti-inflammatory and lipid-lowering effects, it is unknown whether exercise prior to an HFM will translate to reduced airway inflammation post-HFM. Our purpose was to determine the effects of an acute bout of exercise on airway inflammation post-HFM and to identify whether any protective effect of exercise on airway inflammation was associated with a reduction in PPL or systemic inflammation. In a randomized cross-over study, 12 healthy, 18- to 29-year-old men (age, 23.0 ± 3.2 years; height, 178.9 ± 5.5 cm; weight, 78.5 ± 11.7 kg) consumed an HFM (1 g fat/1 kg body weight) 12 h following exercise (EX; 60 min at 60% maximal oxygen uptake) or without exercise (CON). Fractional exhaled nitric oxide (FENO; measure of airway inflammation), triglycerides (TG), and inflammatory markers (high-sensitivity C-reactive protein, tumor-necrosis factor-alpha, and interleukin-6) were measured while fasted at 2 h and 4 h post-HFM. FENO increased over time (2 h: CON, p = 0.001; EX, p = 0.002, but not by condition (p = 0.991). TG significantly increased 2 and 4 h post-HFM (p < 0.001), but was not significant between conditions (p = 0.256). Inflammatory markers did not significantly increase by time or condition (p > 0.05). There were no relationships between FENO and TG or systemic inflammatory markers for any time point or condition (p > 0.05). In summary, an acute bout of moderate-intensity exercise performed 12 h prior to an HFM did not change postprandial airway inflammation or lipemia in healthy, 18- to 29-year-old men.

Novel lipid mediators promote resolution of acute inflammation: impact of aspirin and statins

PubMed Central

Spite, Matthew; Serhan, Charles N.

2010-01-01

The resolution of acute inflammation is a process that allows for inflamed tissues to return to homeostasis. Resolution was held to be a passive process, a concept now overturned with new evidence demonstrating that resolution is actively orchestrated by distinct cellular events and endogenous chemical mediators. Among these, lipid mediators, such as the lipoxins, resolvins, protectins and newly identified maresins, have emerged as a novel genus of potent and stereoselective players that counter-regulate excessive acute inflammation and stimulate molecular and cellular events that define resolution. Given that uncontrolled, chronic inflammation is associated with many cardiovascular pathologies, an appreciation of the endogenous pathways and mediators that control timely resolution can open new terrain for therapeutic approaches targeted at stimulating resolution of local inflammation, as well as correcting the impact of chronic inflammation in cardiovascular disorders. Here, we overview and update the biosynthesis and actions of pro-resolving lipid mediators, highlighting their diverse protective roles relevant to vascular systems and their relation to aspirin and statin therapies. PMID:21071715

Absence of the common gamma chain (γ(c)), a critical component of the Type I IL-4 receptor, increases the severity of allergic lung inflammation.

PubMed

Dasgupta, Preeta; Qi, Xiulan; Smith, Elizabeth P; Keegan, Achsah D

2013-01-01

The T(H)2 cytokines, IL-4 and IL-13, play critical roles in inducing allergic lung inflammation and drive the alternative activation of macrophages (AAM). Although both cytokines share receptor subunits, IL-4 and IL-13 have differential roles in asthma pathogenesis: IL-4 regulates T(H)2 cell differentiation, while IL-13 regulates airway hyperreactivity and mucus production. Aside from controlling T(H)2 differentiation, the unique contribution of IL-4 signaling via the Type I receptor in airway inflammation remains unclear. Therefore, we analyzed responses in mice deficient in gamma c (γ(c)) to elucidate the role of the Type I IL-4 receptor. OVA primed CD4⁺ OT-II T cells were adoptively transferred into RAG2⁻/⁻ and γ(c)⁻/⁻ mice and allergic lung disease was induced. Both γ(c)⁻/⁻ and γcxRAG2⁻/⁻ mice developed increased pulmonary inflammation and eosinophilia upon OVA challenge, compared to RAG2⁻/⁻ mice. Characteristic AAM proteins FIZZ1 and YM1 were expressed in lung epithelial cells in both mouse strains, but greater numbers of FIZZ1+ or YM1+ airways were present in γ(c)⁻/⁻ mice. Absence of γc in macrophages, however, resulted in reduced YM1 expression. We observed higher T(H)2 cytokine levels in the BAL and an altered DC phenotype in the γ(c)⁻/⁻ recipient mice suggesting the potential for dysregulated T cell and dendritic cell (DC) activation in the γ(c)-deficient environment. These results demonstrate that in absence of the Type I IL-4R, the Type II R can mediate allergic responses in the presence of T(H)2 effectors. However, the Type I R regulates AAM protein expression in macrophages.

Impact of lipopolysaccharide-induced acute inflammation on baroreflex-controlled sympathetic arterial pressure regulation

PubMed Central

Tohyama, Takeshi; Kawada, Toru; Kishi, Takuya; Yoshida, Keimei; Nishikawa, Takuya; Mannoji, Hiroshi; Kamada, Kazuhiro; Sunagawa, Kenji; Tsutsui, Hiroyuki

2018-01-01

Background Lipopolysaccharide (LPS) induces acute inflammation, activates sympathetic nerve activity (SNA) and alters hemodynamics. Since the arterial baroreflex is a negative feedback system to stabilize arterial pressure (AP), examining the arterial baroreflex function is a prerequisite to understanding complex hemodynamics under LPS challenge. We investigated the impact of LPS-induced acute inflammation on SNA and AP regulation by performing baroreflex open-loop analysis. Methods Ten anesthetized Sprague-Dawley rats were used. Acute inflammation was induced by an intravenous injection of LPS (60 μg/kg). We isolated the carotid sinuses from the systemic circulation and controlled carotid sinus pressure (CSP) by a servo-controlled piston pump. We matched CSP to AP to establish the baroreflex closed-loop condition, whereas we decoupled CSP from AP to establish the baroreflex open-loop condition and changed CSP stepwise to evaluate the baroreflex open-loop function. We recorded splanchnic SNA and hemodynamic parameters under baroreflex open- and closed-loop conditions at baseline and at 60 and 120 min after LPS injection. Results In the baroreflex closed-loop condition, SNA continued to increase after LPS injection, reaching three-fold the baseline value at 120 min (baseline: 94.7 ± 3.6 vs. 120 min: 283.9 ± 31.9 a.u.). In contrast, AP increased initially (until 75 min), then declined to the baseline level. In the baroreflex open-loop condition, LPS reset the neural arc (CSP-SNA relationship) upward to higher SNA, while shifted the peripheral arc (SNA-AP relationship) downward at 120 min after the injection. As a result, the operating point determined by the intersection between function curves of neural arc and peripheral arc showed marked sympatho-excitation without substantial changes in AP. Conclusions LPS-induced acute inflammation markedly increased SNA via resetting of the baroreflex neural arc, and suppressed the peripheral arc. The balance between the

Impact of lipopolysaccharide-induced acute inflammation on baroreflex-controlled sympathetic arterial pressure regulation.

PubMed

Tohyama, Takeshi; Saku, Keita; Kawada, Toru; Kishi, Takuya; Yoshida, Keimei; Nishikawa, Takuya; Mannoji, Hiroshi; Kamada, Kazuhiro; Sunagawa, Kenji; Tsutsui, Hiroyuki

2018-01-01

Lipopolysaccharide (LPS) induces acute inflammation, activates sympathetic nerve activity (SNA) and alters hemodynamics. Since the arterial baroreflex is a negative feedback system to stabilize arterial pressure (AP), examining the arterial baroreflex function is a prerequisite to understanding complex hemodynamics under LPS challenge. We investigated the impact of LPS-induced acute inflammation on SNA and AP regulation by performing baroreflex open-loop analysis. Ten anesthetized Sprague-Dawley rats were used. Acute inflammation was induced by an intravenous injection of LPS (60 μg/kg). We isolated the carotid sinuses from the systemic circulation and controlled carotid sinus pressure (CSP) by a servo-controlled piston pump. We matched CSP to AP to establish the baroreflex closed-loop condition, whereas we decoupled CSP from AP to establish the baroreflex open-loop condition and changed CSP stepwise to evaluate the baroreflex open-loop function. We recorded splanchnic SNA and hemodynamic parameters under baroreflex open- and closed-loop conditions at baseline and at 60 and 120 min after LPS injection. In the baroreflex closed-loop condition, SNA continued to increase after LPS injection, reaching three-fold the baseline value at 120 min (baseline: 94.7 ± 3.6 vs. 120 min: 283.9 ± 31.9 a.u.). In contrast, AP increased initially (until 75 min), then declined to the baseline level. In the baroreflex open-loop condition, LPS reset the neural arc (CSP-SNA relationship) upward to higher SNA, while shifted the peripheral arc (SNA-AP relationship) downward at 120 min after the injection. As a result, the operating point determined by the intersection between function curves of neural arc and peripheral arc showed marked sympatho-excitation without substantial changes in AP. LPS-induced acute inflammation markedly increased SNA via resetting of the baroreflex neural arc, and suppressed the peripheral arc. The balance between the augmented neural arc and suppressed

[Clinical features and management of acute myositis in idiopathic orbital inflammation].

PubMed

Halimi, E; Rosenberg, R; Wavreille, O; Bouckehove, S; Franquet, N; Labalette, P

2013-09-01

Acute myositis is the second most common component of non-specific orbital inflammation. We will describe its clinical features and natural history. This is a retrospective study of 10 cases. The diagnosis of acute myositis was based on clinical and imaging criteria. Our study includes five men and five women. The average age was 35.8 years (17-59 years). Clinical symptoms were: pain increased on eye movement (10/10), diplopia (4/10), proptosis (6/10), visual loss (3/10), lid edema (6/10), conjunctival hyperemia (7/10), anterior scleritis (2/10), episcleritis (2/10), chemosis (4/10), upper lid retraction (1/10), limitation of eye movement (3/10), fundus abnormalities (2/10). Imaging showed thickening of one or more extraocular muscles (10/10). Recovery was complete with anti-inflammatory therapy in six patients. Three patients experienced recurrence, and one patient had a clinical rebound upon tapering the treatment. Acute myositis can be defined by pain on eye movement, signs of inflammation, and extraocular muscle thickening on imaging. If the clinical presentation is typical, histopathological analysis can be deferred but remains necessary in cases of poor response to treatment, chronic duration or suspicion of tumor infiltration. The diagnosis of acute myositis may be suspected in the presence of consistent, well-defined clinical signs. Contiguous inflammation is often associated. Treatment is based on steroids or non-steroidal treatment anti-inflammatory therapy, administered alone or consecutively. Recurrences are frequent but do not alter the final prognosis. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

Group 2 Innate Lymphoid Cells Exhibit a Dynamic Phenotype in Allergic Airway Inflammation

PubMed Central

Li, Bobby W. S.; Stadhouders, Ralph; de Bruijn, Marjolein J. W.; Lukkes, Melanie; Beerens, Dior M. J. M.; Brem, Maarten D.; KleinJan, Alex; Bergen, Ingrid; Vroman, Heleen; Kool, Mirjam; van IJcken, Wilfred F. J.; Rao, Tata Nageswara; Fehling, Hans Jörg; Hendriks, Rudi W.

2017-01-01

Group 2 innate lymphoid cells (ILC2) are implicated in allergic asthma as an early innate source of the type 2 cytokines IL-5 and IL-13. However, their induction in house dust mite (HDM)-mediated airway inflammation additionally requires T cell activation. It is currently unknown whether phenotypic differences exist between ILC2s that are activated in a T cell-dependent or T cell-independent fashion. Here, we compared ILC2s in IL-33- and HDM-driven airway inflammation. Using flow cytometry, we found that surface expression levels of various markers frequently used to identify ILC2s were dependent on their mode of activation, highly variable over time, and differed between tissue compartments, including bronchoalveolar lavage (BAL) fluid, lung, draining lymph nodes, and spleen. Whereas in vivo IL-33-activated BAL fluid ILC2s exhibited an almost uniform CD25+CD127+T1/ST2+ICOS+KLRG1+ phenotype, at a comparable time point after HDM exposure BAL fluid ILC2s had a very heterogeneous surface marker phenotype. A major fraction of HDM-activated ILC2s were CD25lowCD127+T1/ST2low ICOSlowKLRG1low, but nevertheless had the capacity to produce large amounts of type 2 cytokines. HDM-activated CD25low ILC2s in BAL fluid and lung rapidly reverted to CD25high ILC2s upon in vivo stimulation with IL-33. Genome-wide transcriptional profiling of BAL ILC2s revealed ~1,600 differentially expressed genes: HDM-stimulated ILC2s specifically expressed genes involved in the regulation of adaptive immunity through B and T cell interactions, whereas IL-33-stimulated ILC2s expressed high levels of proliferation-related and cytokine genes. In both airway inflammation models ILC2s were present in the lung submucosa close to epithelial cells, as identified by confocal microscopy. In chronic HDM-driven airway inflammation ILC2s were also found inside organized cellular infiltrates near T cells. Collectively, our findings show that ILC2s are phenotypically more heterogeneous than previously thought

Systemic metabolic signaling in acute and chronic gastrointestinal inflammation of inflammatory bowel diseases.

PubMed

Karrasch, T; Obermeier, F; Straub, R H

2014-06-01

Acute and chronic intestinal inflammation stimulates innate and adaptive immune systems, thereby increasing energy demand of activated immune cells. Energy regulation by systemically released mediators is of critical importance for homeostasis. We wanted to find out how systemic metabolic mediators are affected during intestinal inflammation. A total of 123 patients suffering from Crohn's disease (CD), 76 patients with ulcerative colitis (UC), and 21 healthy controls were recruited. Patients receiving systemic steroids or therapy regimens including biologicals (anti-TNF) were excluded from the study. Serum levels of IL-6, CRP, insulin, glucose, free fatty acid, and RBP-4 were measured by ELISA and RIA. Intestinal inflammation was accompanied by elevated systemic inflammatory para-meters such as IL-6 and CRP in UC and CD and, concomitantly, with elevated insulin levels and increased insulin/glucose ratio in patients with UC. This indicates insulin resistance in liver, muscle, and fat. In addition, intestinal inflammation was associated with elevated levels of circulating free fatty acids in UC and CD, indicating an activation of the organism's appeal for energy-rich substrates (energy appeal reaction). RBP-4 serum levels were also high in acute and chronic intestinal inflammation in UC and CD, which can support insulin resistance. The organism's "energy appeal reaction" in response to acute and chronic inflammation provides free energy in the circulation, which is needed by inflammatory cells. A major mechanism of the redirection program is insulin resistance. New therapeutic strategies might be developed in the future, directly impacting on the storage and utilization of energy-rich fuels. © Georg Thieme Verlag KG Stuttgart · New York.

Role of inflammation and its mediators in acute ischemic stroke

PubMed Central

Jin, Rong; Liu, Lin; Zhang, Shihao; Nanda, Anil; Li, Guohong

2013-01-01

Inflammation plays an important role in the pathogenesis of ischemic stroke and other forms of ischemic brain injury. Increasing evidence suggests that inflammatory response is a double-edged sword, as it not only exacerbates secondary brain injury in the acute stage of stroke but also beneficially contributes to brain recovery after stroke. In this article, we provide an overview on the role of inflammation and its mediators in acute ischemic stroke. We discuss various pro-inflammatory and anti-inflammatory responses in different phases after ischemic stroke and the possible reasons for their failures in clinical trials. Undoubtedly, there is still much to be done in order to translate promising pre-clinical findings into clinical practice. A better understanding of the dynamic balance between pro- and anti-inflammatory responses and identifying the discrepancies between pre-clinical studies and clinical trials may serve as a basis for designing effective therapies. PMID:24006091

Lung parenchyma remodeling in a murine model of chronic allergic inflammation.

PubMed

Xisto, Debora G; Farias, Luciana L; Ferreira, Halina C; Picanço, Miguel R; Amitrano, Daniel; Lapa E Silva, Jose R; Negri, Elnara M; Mauad, Thais; Carnielli, Denise; Silva, Luiz Fernando F; Capelozzi, Vera L; Faffe, Debora S; Zin, Walter A; Rocco, Patricia R M

2005-04-15

This study tested the hypotheses that chronic allergic inflammation induces not only bronchial but also lung parenchyma remodeling, and that these histologic changes are associated with concurrent changes in respiratory mechanics. For this purpose, airway and lung parenchyma remodeling were evaluated by quantitative analysis of collagen and elastin, immunohistochemistry (smooth-muscle actin expression, eosinophil, and dendritic cell densities), and electron microscopy. In vivo (airway resistance, viscoelastic pressure, and static elastance) and in vitro (tissue elastance, resistance, and hysteresivity) respiratory mechanics were also analyzed. BALB/c mice were sensitized with ovalbumin and exposed to repeated ovalbumin challenges. A marked eosinophilic infiltration was seen in lung parenchyma and in large and distal airways. Neutrophils, lymphocytes, and dendritic cells also infiltrated the lungs. There was subepithelial fibrosis, myocyte hypertrophy and hyperplasia, elastic fiber fragmentation, and increased numbers of myofibroblasts in airways and lung parenchyma. Collagen fiber content was increased in the alveolar walls. The volume proportion of smooth muscle-specific actin was augmented in distal airways and alveolar duct walls. Airway resistance, viscoelastic pressure, static elastance, and tissue elastance and resistance were significantly increased. In conclusion, prolonged allergen exposure induced remodeling not only of the airway wall but also of the lung parenchyma, leading to in vivo and in vitro mechanical changes.

γ-Tocopherol supplementation of allergic female mice augments development of CD11c+CD11b+ dendritic cells in utero and allergic inflammation in neonates

PubMed Central

Abdala-Valencia, Hiam; Soveg, Frank

2016-01-01

γ-Tocopherol increases responses to allergen challenge in allergic adult mice, but it is not known whether γ-tocopherol regulates the development of allergic disease. Development of allergic disease often occurs early in life. In clinical studies and animal models, offspring of allergic mothers have increased responsiveness to allergen challenge. Therefore, we determined whether γ-tocopherol augments development of allergic responses in offspring of allergic female mice. Allergic female mice were supplemented with γ-tocopherol starting at mating. The pups from allergic mothers developed allergic lung responses, whereas pups from saline-treated mothers did not respond to allergen challenge. The γ-tocopherol supplementation of allergic female mice increased the numbers of eosinophils twofold in the pup bronchoalveolar lavage and lungs after allergen challenge. There was also about a twofold increase in pup lung CD11b+ subsets of CD11c+ dendritic cells and in numbers of these dendritic cells expressing the transcription factor IRF4. There was no change in several CD11b− dendritic cell subsets. Furthermore, maternal supplementation with γ-tocopherol increased the number of fetal liver CD11b+CD11c+ dendritic cells twofold in utero. In the pups, γ-tocopherol increased lung expression of the inflammatory mediators CCL11, amphiregulin, activin A, and IL-5. In conclusion, maternal supplementation with γ-tocopherol increased fetal development of subsets of dendritic cells that are critical for allergic responses and increased development of allergic responses in pups from allergic mothers. These results have implications for supplementation of allergic mothers with γ-tocopherol in prenatal vitamins. PMID:26801566

Protective effect of Clerodendrum colebrookianum Walp., on acute and chronic inflammation in rats

PubMed Central

Deb, Lokesh; Dey, Amitabha; Sakthivel, G.; Bhattamishra, Subrat Kumar; Dutta, Amitsankar

2013-01-01

Aim: To evaluate antioxidant, anti-inflammatory potential of the aqueous extracts and its aqueous, n-butanol, ethyl-acetate, and chloroform fractions of Clerodendrum colebrookianum Walp. leaves. Materials and Methods: In this present study, all the test samples were evaluated on in-vivo inflammatory model such as carrageenan and histamine-induced acute-inflammation and cotton pellet induced granuloma formation in albino male rats. Test samples were also employed in in-vitro assays like DPPH* free radical scavenging activity and COX inhibition assay. Results: The test samples at the dose of 200mg/kg/p.o. were found to cause significant inhibition of carrageenan and histamine-induced inflammation and cotton pallet-induced granuloma formation on acute and chronic inflammation in rats. The test samples, except n-butanol fraction, exhibited inhibitory effect for both COX-1 and COX-2, in in-vitro assay but their percentage of inhibition values differs from each other. The test samples (aqueous extracts, aqueous, n-butanol, ethyl-acetate, and chloroform fractions) at 100 μg concentration exhibits 54.37%, 33.88%, 62.85%, 56.28%, and 57.48% DPPH* radical-scavenging effect respectively in in-vitro antioxidant study. Conclusion: These observations established the anti-inflammatory effect of C. colebrookianum leaves in acute and chronic stages of inflammation by free radical scavenging and inhibition of COX-1 and COX-2. PMID:24014914

Effect of Ergothioneine on Acute Lung Injury and Inflammation in Cytokine Insufflated Rats

PubMed Central

Repine, John E.; Elkins, Nancy D.

2012-01-01

Objective The Acute Respiratory Distress Syndrome (ARDS), the most severe form of Acute Lung Injury (ALI), is a highly-fatal, diffuse non-cardiogenic edematous lung disorder. The pathogenesis of ARDS is unknown but lung inflammation and lung oxidative stress are likely contributing factors. Since no specific pharmacologic intervention exists for ARDS, our objective was to determine the effect of treatment with ergothioneine---a safe agent with multiple anti-inflammatory and antioxidant properties on the development of lung injury and inflammation in rats insufflated with cytokines found in lung lavages of ARDS patients. Method Sprague-Dawley rats (3-10/group) were given 15 mg/kg or 150 mg/kg L-ergothioneine intravenously 1 hour before or 18 hours after cytokine (IL-1 and IFNγ) insufflation. Lung injury (lavage LDH levels) and lung inflammation (lavage neutrophil numbers) were measured 24 hours after cytokine insufflation. Results Ergothioneine pre- and post- treatment generally decreased lung injury and lung inflammation in cytokine insufflated rats. Conclusion Ergothioneine should be considered for additional testing as a potential therapy for treating and preventing ARDS. PMID:22197759

Pyrrolidine dithiocarbamate attenuates the development of acute and chronic inflammation

PubMed Central

Cuzzocrea, Salvatore; Chatterjee, Prabal K; Mazzon, Emanuela; Dugo, Laura; Serraino, Ivana; Britti, Domenico; Mazzullo, Giuseppe; Caputi, Achille P; Thiemermann, Christoph

2002-01-01

The nuclear factor-κB (NF-κB) is a transcription factor which plays a pivotal role in the induction of genes involved in physiological processes as well as in the response to injury and inflammation. Dithiocarbamates are antioxidants which are potent inhibitors of NF-κB. We postulated that pyrrolidine dithiocarbamate (PDTC) would attenuate inflammation. In the present study we investigate the effects of PDTC in animal models of acute and chronic inflammation (carrageenan-induced pleurisy and collagen-induced arthritis). We report here for the first time that PDTC (given at 100, 30 or 10 mg kg−1 i.p. in the pleurisy model or at 10 mg kg−1 i.p. every 48 h in the arthritis model) exerts potent anti-inflammatory effects (e.g. significant reduction of (A) pleural exudate formation, (B) polymorphonuclear cell infiltration, (C) lipid peroxidation, (D) inducible nitric oxide synthase (iNOS) activity and nitric oxide production (E) plasma and pleural exudates levels of interleukin-1β and tumour necrosis factor-α, (F) histological injury and (G) delayed development of clinical indicators). Furthermore, PDTC reduced immunohistochemical evidence of (A) formation of nitrotyrosine, (B) activation of poly (ADP-ribose) polymerase (PARP), (C) expression of iNOS and (D) expression of cyclo-oxygenase-2 (COX-2) in the lungs of carrageenan-treated mice and in the joints from collagen-treated mice. Additionally, Western blotting and immunohistochemical analysis of lung tissue revealed that PDTC prevented degradation of IKB-α and translocation of NF-κB from the cytoplasm into the nucleus. Taken together, our results clearly demonstrate that prevention of the activation of NF-κB by PDTC reduces the development of acute and chronic inflammation. Therefore, inhibition of NF-κB may represent a novel approach for the therapy of inflammation. PMID:11815386

[Acute asthma attacks introduced by anesthesia before nasal endoscopic surgery].

PubMed

Lü, Xiaofei; Han, Demin; Zhou, Bing; Ding, Bin

2004-05-01

In order to pay our attention to the perioperative treatment before nasal endoscopic surgery. Three patients with asthma accompanied chronic sinusitis were analyzed systemically, who had undergone acute attacks of asthma introduced by anesthesia. Anesthetic drugs and instruments can lead to acute attacks of asthma, because sinusitis with asthma means allergic airway inflammation, broncho-hyperreactivity and lower compensatory pulmonary function. Then all of the 3 cases had missed the preoperative treatment. Anesthetic drugs and instruments can lead to acute attacks of asthma. The perioperative treatment before nasal endoscopic surgery is very important for the prevention of the occurrences of this severe complication. Except emergency, the operation should be can celled for avoiding the acute attack of asthma introduced by anesthesia.

Screening Active Components from Yu-Ping-Feng-San for Regulating Initiative Key Factors in Allergic Sensitization

PubMed Central

Zhu, Zhijie; Yu, Xi; Liu, Hailiang; Wang, Huizhu; Fan, Hongwei; Wang, Dawei; Jiang, Guorong; Hong, Min

2014-01-01

Yu-ping-feng-san (YPFS) is a Chinese medical formula that is used clinically for allergic diseases and characterized by reducing allergy relapse. Our previous studies demonstrated that YPFS efficiently inhibited T helper 2 cytokines in allergic inflammation. The underlying mechanisms of action of YPFS and its effective components remain unclear. In this study, it was shown that YPFS significantly inhibited production of thymic stromal lymphopoietin (TSLP), an epithelial cell-derived initiative factor in allergic inflammation, in vitro and in vivo. A method of human bronchial epithelial cell (16HBE) binding combined with HPLC-MS (named 16HBE-HPLC-MS) was established to explore potential active components of YPFS. The following five components bound to 16HBE cells: calycosin-7-glucoside, ononin, claycosin, sec-o-glucosylhamaudol and formononetin. Serum from YPFS-treated mice was analyzed and three major components were detected claycosin, formononetin and cimifugin. Among these, claycosin and formononetin were detected by 16HBE-HPLC-MS and in the serum of YPFS-treated mice. Claycosin and formononetin decreased the level of TSLP markedly at the initial stage of allergic inflammation in vivo. Nuclear factor (NF)-κB, a key transcription factor in TSLP production, was also inhibited by claycosin and formononetin, either in terms of transcriptional activation or its nuclear translocation in vitro. Allergic inflammation was reduced by claycosin and formononetin when they are administered only at the initial stage in a murine model of atopic contact dermatitis. Thus, epithelial cell binding combined with HPLC-MS is a valid method for screening active components from complex mixtures of Chinese medicine. It was demonstrated that the compounds screened from YPFS significantly attenuated allergic inflammation probably by reducing TSLP production via regulating NF-κB activation. PMID:25198676

Chronic, not acute, skin-specific inflammation promotes thrombosis in psoriasis murine models.

PubMed

Golden, Jackelyn B; Wang, Yunmei; Fritz, Yi; Diaconu, Doina; Zhang, Xiufen; Debanne, Sara M; Simon, Daniel I; McCormick, Thomas S; Ward, Nicole L

2015-12-16

Psoriasis patients exhibit an increased risk of atherothrombotic events, including myocardial infarction and stroke. Clinical evidence suggests that psoriasis patients with early onset and more severe disease have the highest risk for these co-morbidities, perhaps due to the extent of body surface involvement, subsequent levels of systemic inflammation, or chronicity of disease. We sought to determine whether acute or chronic skin-specific inflammation was sufficient to promote thrombosis. We used two experimental mouse models of skin-specific inflammation generated in either an acute (topical Aldara application onto wild-type C57Bl/6 mice for 5 days) or chronic (a genetically engineered K5-IL-17C mouse model of psoriasiform skin inflammation) manner. Arterial thrombosis was induced using carotid artery photochemical injury (Rose Bengal-green light laser) and carotid artery diameters were measured post-clot formation. We also examined measures of clot formation including prothrombin (PT) and activated partial thromboplastin time (aPTT). Skin inflammation was examined histologically and we profiled plasma-derived lipids. The number of skin-draining lymph-node (SDLN) and splenic derived CD11b(+)Ly6C(high) pro-inflammatory monocytes and CD11b(+)Ly6G(+) neutrophils was quantified using multi-color flow cytometry. Mice treated with topical Aldara for 5 days had similar carotid artery thrombotic occlusion times to mice treated with vehicle cream (32.2 ± 3.0 vs. 31.4 ± 2.5 min, p = 0.97); in contrast, K5-IL-17C mice had accelerated occlusion times compared to littermate controls (15.7 ± 2.1 vs. 26.5 ± 3.5 min, p < 0.01) while carotid artery diameters were similar between all mice. Acanthosis, a surrogate measure of inflammation, was increased in both Aldara-treated and K5-IL-17C mice compared to their respective controls. Monocytosis, defined as elevated SDLN and/or splenic CD11b(+)Ly6C(high) cells, was significantly increased in both Aldara-treated (SDLN: 3.8-fold, p

Safety of a Novel Botanical Extract Formula for Ameliorating Allergic rhinitis. Part II.

PubMed

Amit, A; Joshua, A J; Bagchi, M; Bagchi, D

2005-01-01

Abstract Each year more than 50 million Americans suffer from allergic rhinitis, which is a state of hypersensitivity or hyperimmunity. Basically, allergic rhinitis is symptomatically recognized as the inflammation and irritation of the nasal mucosal membranes; sneezing; stuffy/runny nose; nasal congestion; and itchy; watery, and swollen eyes; and defined as a state of hypersensitivity/ hyperimmunity caused by exposure to a particular allergen (antigen) that results in increased reactivity upon subsequent exposure. A novel polyherbal formulation (Aller-7/NR-A2) was developed for the treatment of allergic rhinitis using a unique combination of extracts from seven medicinal plants, including Phyllanthus emblica, Terminalia chebula, Terminalia bellerica, Albizia lebbeck, Piper nigrum, Zingiber officinale, and Piper longum. Earlier studies in our laboratories have demonstrated potent antihistaminic, anti-inflammatory, antispasmodic, antioxidant, and mast-cell stabilization activities of Aller-7 in addition to its efficacy in a clinical setting. A series of preliminary toxicological evaluations were also conducted in the past, which demonstrated its safety. In this study, we have conducted further safety studies on Aller-7, including acute oral, acute dermal, acute dermal irritation, eye irritation, and 90-day repeated dose toxicity studies. Acute oral toxicity of Aller-7 was found to be greater than 5,000 mg/kg body weight in both male and female rats and no mortality or toxicity was observed at this dose, while the acute dermal toxicity was found to be greater than 2,000 mg/kg body weight. In the acute dermal irritation study, the skin irritancy index was found to be 0.0, which classifies Aller-7 as a nonirritant to rabbit skin. In the acute eye irritation study, Aller-7 was found to have minimal irritancy to eyes of rabbits. In the repeated-dose 90-day oral toxicity study, Aller-7 was administered at dose levels of 100, 300, and 1,000 mg/kg rat body weight for 90

Blocking fatty acid-fueled mROS production within macrophages alleviates acute gouty inflammation.

PubMed

Hall, Christopher J; Sanderson, Leslie E; Lawrence, Lisa M; Pool, Bregina; van der Kroef, Maarten; Ashimbayeva, Elina; Britto, Denver; Harper, Jacquie L; Lieschke, Graham J; Astin, Jonathan W; Crosier, Kathryn E; Dalbeth, Nicola; Crosier, Philip S

2018-05-01

Gout is the most common inflammatory arthritis affecting men. Acute gouty inflammation is triggered by monosodium urate (MSU) crystal deposition in and around joints that activates macrophages into a proinflammatory state, resulting in neutrophil recruitment. A complete understanding of how MSU crystals activate macrophages in vivo has been difficult because of limitations of live imaging this process in traditional animal models. By live imaging the macrophage and neutrophil response to MSU crystals within an intact host (larval zebrafish), we reveal that macrophage activation requires mitochondrial ROS (mROS) generated through fatty acid oxidation. This mitochondrial source of ROS contributes to NF-κB-driven production of IL-1β and TNF-α, which promote neutrophil recruitment. We demonstrate the therapeutic utility of this discovery by showing that this mechanism is conserved in human macrophages and, via pharmacologic blockade, that it contributes to neutrophil recruitment in a mouse model of acute gouty inflammation. To our knowledge, this study is the first to uncover an immunometabolic mechanism of macrophage activation that operates during acute gouty inflammation. Targeting this pathway holds promise in the management of gout and, potentially, other macrophage-driven diseases.

SUPPRESSION OF ALLERGIC UVEITIS BY 6-MERCAPTOPURINE

PubMed Central

Wirostko, E.; Halbert, S. P.

1962-01-01

Experimental uveitis in rabbits was induced by single intraocular antigen injection. Treatment with 6-MP for 14 days suppressed the allergic inflammation and antibody response. A good correlation was demonstrated between the degree of uveitis and the antibody titer. PMID:14001284

Low-Grade Inflammation and Ambulatory Cortisol in Adolescents: Interaction Between Interviewer-Rated Versus Self-Rated Acute Stress and Chronic Stress.

PubMed

Schreier, Hannah M C; Chen, Edith

To determine whether the association between self-rated or interviewer-rated recent acute stress exposures and low-grade inflammation and daily cortisol production in adolescents is moderated by chronic stress ratings. Acute and chronic stress exposures were assessed in 261 adolescents aged 13 to 16 years using a semistructured life stress interview. The negative impact of acute stressors was independently rated by both adolescents (self-rated) and interviewers (interviewer-rated). Markers of inflammation (interleukin (IL)-6, IL-1ra, C-reactive protein) were measured from peripheral blood samples obtained via antecubital venipuncture. Participants collected 4 saliva samples at home on each of 6 consecutive days for the analysis of diurnal salivary cortisol profiles. There were no main effects of acute stressors (self- and interviewer-rated) and chronic family or peer stress on adolescent inflammation markers and cortisol (p values > .10). However, the interaction between interviewer-rated acute stress and chronic family stress was significantly associated with adolescent inflammation markers (IL-6, IL-1ra). Specifically, as chronic family stress increased, the association between acute stressor impact (interviewer-rated) and inflammation markers became more positive (IL-6 (B = .054, SE = .023, p = .022); IL-1ra (B = .030, SE = .014, p = .034)). Interactions between self-rated acute stress and chronic family stress were not associated with any biological measures (p values > .10). Interactions between acute stressor impact (both self- and interviewer-rated) and chronic peer stress were also not significantly associated with any biological measures (p values > .05). Among adolescents, interviewer-based ratings of acute stressor impact may allow for better prediction of health-relevant inflammation markers than adolescents' own ratings.

Low-Grade Inflammation and Ambulatory Cortisol in Adolescents: Interaction between Interviewer-rated versus Self-rated Acute Stress and Chronic Stress

PubMed Central

Schreier, Hannah M. C.; Chen, Edith

2016-01-01

Objective To determine whether the association between self-rated or interviewer-rated recent acute stress exposures and low-grade inflammation and daily cortisol production in adolescents is moderated by chronic stress ratings. Methods Acute and chronic stress exposures were assessed in 261 adolescents aged 13-16 using a semi-structured life stress interview. The negative impact of acute stressors was independently rated by both adolescents (self-rated) and interviewers (interviewer-rated). Markers of inflammation (IL-6, IL-1ra, CRP) were measured from peripheral blood samples obtained via antecubital venipuncture. Participants collected 4 saliva samples at home on each of six consecutive days for the analysis of diurnal salivary cortisol profiles. Results There were no main effects of acute stressors (self- and interviewer-rated) and chronic family or peer stress on adolescent inflammation markers and cortisol (ps > .10). However, the interaction between interviewer-rated acute stress and chronic family stress was significantly associated with adolescent inflammation markers (IL-6, IL-1ra). Specifically, as chronic family stress increased, the association between acute stressor impact (interviewer-rated) and inflammation markers became more positive (IL-6 (B = .054, SE = .023, p = .022); IL-1ra (B = .030, SE = .014, p = .034)). Interactions between self-rated acute stress and chronic family stress were not associated with any biological measures (ps > .10). Interactions between acute stressor impact (both self- and interviewer-rated) and chronic peer stress were also not significantly associated with any biological measures (ps > .05). Conclusions Among adolescents, interviewer-based ratings of acute stressor impact may allow for better prediction of health-relevant inflammation markers than adolescents’ own ratings. PMID:27490853

Effects of acute systemic inflammation on the interplay between sad mood and affective cognition.

PubMed

Benson, Sven; Brinkhoff, Alexandra; Lueg, Larissa; Roderigo, Till; Kribben, Andreas; Wilde, Benjamin; Witzke, Oliver; Engler, Harald; Schedlowski, Manfred; Elsenbruch, Sigrid

2017-12-11

Experimental endotoxemia is a translational model to study inflammatory mechanisms involved in the pathophysiology of mood disorders including depression. Disturbed affective cognition constitutes a core aspect in depression, but has never been studied in the context of inflammation. We combined experimental endotoxemia with an established experimental mood induction procedure to assess the interaction between acute inflammation and sad mood and their effects on affective cognition. In this randomized cross-over study, N = 15 healthy males received endotoxin (0.8 ng/kg lipopolysaccharide iv) on one study day and placebo an otherwise identical study day. The affective Go/Nogo task was conducted after experimental induction of neutral and sad mood. Inflammatory markers were assessed hourly. Endotoxin application induced a transient systemic inflammation, characterized by increased leukocyte counts, TNF-alpha and interleukin-6 plasma concentrations (all p < 0.01, interaction effects). Mood induction led to greater sadness ratings, with highest ratings when sad mood was induced during inflammation (p < 0.05, interaction effect). Based on a 2 (endotoxin vs. placebo) × 2 (sad vs. neutral mood) × 2 (sad vs. happy Go/Nogo target words) factorial design, we observed a significant target × endotoxin condition interaction (p < 0.01) reflecting slower responses to sad targets during endotoxemia. Additionally, we found a valence × mood interaction (p < 0.05), reflecting slower reaction times to sad targets in sad mood. In summary, acute inflammation and sad mood are risk factors for disturbed affective cognition. The results may reflect a mood-congruency effect, with prolonged and sustained processing of mood-congruent information during acute inflammation, which may contribute to depression risk.

Dysregulation of type 2 innate lymphoid cells and TH2 cells impairs pollutant-induced allergic airway responses.

PubMed

De Grove, Katrien C; Provoost, Sharen; Hendriks, Rudi W; McKenzie, Andrew N J; Seys, Leen J M; Kumar, Smitha; Maes, Tania; Brusselle, Guy G; Joos, Guy F

2017-01-01

Although the prominent role of T H 2 cells in type 2 immune responses is well established, the newly identified type 2 innate lymphoid cells (ILC2s) can also contribute to orchestration of allergic responses. Several experimental and epidemiologic studies have provided evidence that allergen-induced airway responses can be further enhanced on exposure to environmental pollutants, such as diesel exhaust particles (DEPs). However, the components and pathways responsible remain incompletely known. We sought to investigate the relative contribution of ILC2 and adaptive T H 2 cell responses in a murine model of DEP-enhanced allergic airway inflammation. Wild-type, Gata-3 +/nlslacZ (Gata-3-haploinsufficient), RAR-related orphan receptor α (RORα) fl/fl IL7R Cre (ILC2-deficient), and recombination-activating gene (Rag) 2 -/- mice were challenged with saline, DEPs, or house dust mite (HDM) or DEP+HDM. Airway hyperresponsiveness, as well as inflammation, and intracellular cytokine expression in ILC2s and T H 2 cells in the bronchoalveolar lavage fluid and lung tissue were assessed. Concomitant DEP+HDM exposure significantly enhanced allergic airway inflammation, as characterized by increased airway eosinophilia, goblet cell metaplasia, accumulation of ILC2s and T H 2 cells, type 2 cytokine production, and airway hyperresponsiveness compared with sole DEPs or HDM. Reduced Gata-3 expression decreased the number of functional ILC2s and T H 2 cells in DEP+HDM-exposed mice, resulting in an impaired DEP-enhanced allergic airway inflammation. Interestingly, although the DEP-enhanced allergic inflammation was marginally reduced in ILC2-deficient mice that received combined DEP+HDM, it was abolished in DEP+HDM-exposed Rag2 -/- mice. These data indicate that dysregulation of ILC2s and T H 2 cells attenuates DEP-enhanced allergic airway inflammation. In addition, a crucial role for the adaptive immune system was shown on concomitant DEP+HDM exposure. Copyright © 2016 American

8-oxoguanine DNA Glycosylase 1-Deficiency Modifies Allergic Airway Inflammation by Regulating STAT6 and IL-4 in Cells and in Mice

PubMed Central

Li, Guoping; Yuan, Kefei; Yan, Chunguang; Fox, John; Gaid, Madeleine; Breitwieser, Wayne; Bansal, Arvind K.; Zeng, Huawei; Gao, Hongwei; Wu, Min

2013-01-01

8-oxoguanine-DNA glycosylase (OGG-1) is a base excision DNA repair enzyme; however, its function in modulating allergic diseases remains undefined. Using OGG-1 knockout (KO) mice, we show that this protein impacts allergic airway inflammation following sensitization and challenge by ovalbumin (OVA). OGG-1 KO mice exhibited less inflammatory cell infiltration and reduced oxidative stress in the lungs after OVA challenge compared to WT mice. The KO phenotype included decreased IL-4, IL-6, IL-10, and IL-17 in lung tissues. In addition, OGG-1 KO mice showed decreased expression and phosphorylation of STAT6 as well as NF-κB. Down-regulation of OGG-1 by siRNA lowered ROS and IL-4 levels but increased INF-γ production in cultured epithelial cells following exposure to house dust mite (HDM) extracts. OGG-1 may affect the levels of oxidative stress and proinflammatory cytokines during asthmatic conditions. OGG-1-deficiency negatively regulates allergen-induced airway inflammatory response. PMID:22100973

Identification of genes differentially regulated by vitamin D deficiency that alter lung pathophysiology and inflammation in allergic airways disease.

PubMed

Foong, Rachel E; Bosco, Anthony; Troy, Niamh M; Gorman, Shelley; Hart, Prue H; Kicic, Anthony; Zosky, Graeme R

2016-09-01

Vitamin D deficiency is associated with asthma risk. Vitamin D deficiency may enhance the inflammatory response, and we have previously shown that airway remodeling and airway hyperresponsiveness is increased in vitamin D-deficient mice. In this study, we hypothesize that vitamin D deficiency would exacerbate house dust mite (HDM)-induced inflammation and alterations in lung structure and function. A BALB/c mouse model of vitamin D deficiency was established by dietary manipulation. Responsiveness to methacholine, airway smooth muscle (ASM) mass, mucus cell metaplasia, lung and airway inflammation, and cytokines in bronchoalveolar lavage (BAL) fluid were assessed. Gene expression patterns in mouse lung samples were profiled by RNA-Seq. HDM exposure increased inflammation and inflammatory cytokines in BAL, baseline airway resistance, tissue elastance, and ASM mass. Vitamin D deficiency enhanced the HDM-induced influx of lymphocytes into BAL, ameliorated the HDM-induced increase in ASM mass, and protected against the HDM-induced increase in baseline airway resistance. RNA-Seq identified nine genes that were differentially regulated by vitamin D deficiency in the lungs of HDM-treated mice. Immunohistochemical staining confirmed that protein expression of midline 1 (MID1) and adrenomedullin was differentially regulated such that they promoted inflammation, while hypoxia-inducible lipid droplet-associated, which is associated with ASM remodeling, was downregulated. Protein expression studies in human bronchial epithelial cells also showed that addition of vitamin D decreased MID1 expression. Differential regulation of these genes by vitamin D deficiency could determine lung inflammation and pathophysiology and suggest that the effect of vitamin D deficiency on HDM-induced allergic airways disease is complex. Copyright © 2016 the American Physiological Society.

The adaptor protein CIKS/Act1 is essential for IL-25-mediated allergic airway inflammation.

PubMed

Claudio, Estefania; Sønder, Søren Ulrik; Saret, Sun; Carvalho, Gabrielle; Ramalingam, Thirumalai R; Wynn, Thomas A; Chariot, Alain; Garcia-Perganeda, Antonio; Leonardi, Antonio; Paun, Andrea; Chen, Amy; Ren, Nina Y; Wang, Hongshan; Siebenlist, Ulrich

2009-02-01

IL-17 is the signature cytokine of recently discovered Th type 17 (Th17) cells, which are prominent in defense against extracellular bacteria and fungi as well as in autoimmune diseases, such as rheumatoid arthritis and experimental autoimmune encephalomyelitis in animal models. IL-25 is a member of the IL-17 family of cytokines, but has been associated with Th2 responses instead and may negatively cross-regulate Th17/IL-17 responses. IL-25 can initiate an allergic asthma-like inflammation in the airways, which includes recruitment of eosinophils, mucus hypersecretion, Th2 cytokine production, and airways hyperreactivity. We demonstrate that these effects of IL-25 are entirely dependent on the adaptor protein CIKS (also known as Act1). Surprisingly, this adaptor is necessary to transmit IL-17 signals as well, despite the very distinct biologic responses that these two cytokines elicit. We identify CD11c(+) macrophage-like lung cells as physiologic relevant targets of IL-25 in vivo.

Cannabinoid receptor 2 augments eosinophil responsiveness and aggravates allergen-induced pulmonary inflammation in mice.

PubMed

Frei, R B; Luschnig, P; Parzmair, G P; Peinhaupt, M; Schranz, S; Fauland, A; Wheelock, C E; Heinemann, A; Sturm, E M

2016-07-01

Accumulation of activated eosinophils in tissue is a hallmark of allergic inflammation. The endocannabinoid 2-arachidonoylglycerol (2-AG) has been proposed to elicit eosinophil migration in a CB2 receptor/Gi/o -dependent manner. However, it has been claimed recently that this process may also involve other mechanisms such as cytokine priming and the metabolism of 2-AG into eicosanoids. Here, we explored the direct contribution of specific CB2 receptor activation to human and mouse eosinophil effector function in vitro and in vivo. In vitro studies including CB2 expression, adhesion and migratory responsiveness, respiratory burst, degranulation, and calcium mobilization were conducted in human peripheral blood eosinophils and mouse bone marrow-derived eosinophils. Allergic airway inflammation was assessed in mouse models of acute OVA-induced asthma and directed eosinophil migration. CB2 expression was significantly higher in eosinophils from symptomatic allergic donors. The selective CB2 receptor agonist JWH-133 induced a moderate migratory response in eosinophils. However, short-term exposure to JWH-133 potently enhanced chemoattractant-induced eosinophil shape change, chemotaxis, CD11b surface expression, and adhesion as well as production of reactive oxygen species. Receptor specificity of the observed effects was confirmed in eosinophils from CB2 knockout mice and by using the selective CB2 antagonist SR144528. Of note, systemic application of JWH-133 clearly primed eosinophil-directed migration in vivo and aggravated both AHR and eosinophil influx into the airways in a CB2 -specific manner. This effect was completely absent in eosinophil-deficient ∆dblGATA mice. Our data indicate that CB2 may directly contribute to the pathogenesis of eosinophil-driven diseases. Moreover, we provide new insights into the molecular mechanisms underlying the CB2 -mediated priming of eosinophils. Hence, antagonism of CB2 receptors may represent a novel pharmacological approach

Ionotropic and metabotropic proton-sensing receptors involved in airway inflammation in allergic asthma.

PubMed

Aoki, Haruka; Mogi, Chihiro; Okajima, Fumikazu

2014-01-01

An acidic microenvironment has been shown to evoke a variety of airway responses, including cough, bronchoconstriction, airway hyperresponsiveness (AHR), infiltration of inflammatory cells in the lung, and stimulation of mucus hyperproduction. Except for the participation of transient receptor potential vanilloid-1 (TRPV1) and acid-sensing ion channels (ASICs) in severe acidic pH (of less than 6.0)-induced cough and bronchoconstriction through sensory neurons, the molecular mechanisms underlying extracellular acidic pH-induced actions in the airways have not been fully understood. Recent studies have revealed that ovarian cancer G protein-coupled receptor 1 (OGR1)-family G protein-coupled receptors, which sense pH of more than 6.0, are expressed in structural cells, such as airway smooth muscle cells and epithelial cells, and in inflammatory and immune cells, such as eosinophils and dendritic cells. They function in a variety of airway responses related to the pathophysiology of inflammatory diseases, including allergic asthma. In the present review, we discuss the roles of ionotropic TRPV1 and ASICs and metabotropic OGR1-family G protein-coupled receptors in the airway inflammation and AHR in asthma and respiratory diseases.

Maintenance of memory-type pathogenic Th2 cells in the pathophysiology of chronic airway inflammation.

PubMed

Hirahara, Kiyoshi; Shinoda, Kenta; Endo, Yusuke; Ichikawa, Tomomi; Nakayama, Toshinori

2018-01-01

Immunological memory is critical for long-standing protection against microorganisms; however, certain antigen-specific memory CD4 + T helper (Th) cells drive immune-related pathology, including chronic allergic inflammation such as asthma. The IL-5-producing memory-type Tpath2 subset is important for the pathogenesis of chronic allergic inflammation. This memory-type pathogenic Th2 cell population (Tpath2) can be detected in various allergic inflammatory lesions. However, how these pathogenic populations are maintained at the local inflammatory site has remained unclear. We performed a series of experiments using mice model for chronic airway inflammation. We also investigated the human samples from patients with eosinophilic chronic rhinosinusitis. We recently reported that inducible bronchus-associated lymphoid tissue (iBALT) was shaped during chronic inflammation in the lung. We also found that memory-type Tpath2 cells are maintained within iBALT. The maintenance of the Tpath2 cells within iBALT is supported by specific cell subpopulations within the lung. Furthermore, ectopic lymphoid structures consisting of memory CD4 + T cells were found in nasal polyps of eosinophilic chronic rhinosinusitis patients, indicating that the persistence of inflammation is controlled by these structures. Thus, the cell components that organize iBALT formation may be therapeutic targets for chronic allergic airway inflammation.

Methodology and potential pitfalls in allergic diseases study designs: measurements for the assessment of the overall severity of atopic dermatitis--the four step severity score (FSSS), SCORAD-related, electronic system, for the simple and rapid evaluation of the skin and mucosal allergic inflammation.

PubMed

Mastrandrea, F; Pecora, S; Scatena, C; Cadario, G

2005-11-01

Medical statistics may contribute to ameliorate research by improving the design of studies and identifying the optimal method for the analysis of results. Sometimes, nevertheless, it could be misemployed flawing the benefit potential. Allergic diseases pathogenesis is recognized to be systemic but global initiatives such as GINA and ARIA documents define allergic asthma and rhinitis as organ diseases; such an asymmetrical view raises a set of known and unknown confounding that could influence the quality of the process of evidence-based decision-making (topic symptomatic therapeutic interventions versus systemic pathogenetic interventions). This article shows the first scoring system for the assessment of atopic dermatitis lesions developed in the allergy-area. A four-step severity score (FSSS) was chosen in agreement with those developed for asthma and rhinitis in global initiatives, to avoid any further differences in evaluating the severity of allergic diseases. FSSS relates each step with the objective signs of the SCORAD and rates the disease course as intermittent or persistent. A devoted electronic program has been also framed to allow a quick and simple contemporary evaluation of the SCORAD Index (Section I) and of the FSSS (Section II); the program furthermore foresees a third section named ESAS (Extra Skin Allergic Signs) (Section III) in which it is possible to check whether organs other than the skin are involved by the allergic inflammation. The limitations potential generated by a misemployment of medical statistics for clinical trials designed to establish benefits rising from specific immunotherapy for allergic diseases have been also discussed extensively.

Supplemental and highly-elevated tocopherol doses differentially regulate allergic inflammation: reversibility of α-tocopherol and γ-tocopherol's effects

PubMed Central

McCary, Christine A.; Abdala-Valencia, Hiam; Berdnikovs, Sergejs; Cook-Mills, Joan M.

2011-01-01

We have reported that supplemental doses of the α- and γ-tocopherol isoforms of vitamin E decrease and increase, respectively, allergic lung inflammation. We have now assessed whether these effects of tocopherols are reversible. For these studies, mice were treated with antigen and supplemental tocopherols in a first phase of treatment followed by a 4 week clearance phase and then the mice received a second phase of antigen and tocopherol treatments. The pro-inflammatory effects of supplemental levels of γ-tocopherol in phase 1 were only partially reversed by supplemental α-tocopherol in phase 2 but were completely reversed by raising α-tocopherol levels 10-fold in phase 2. When γ-tocopherol levels were increased 10-fold (highly-elevated tocopherol) so that the lung tissue γ-tocopherol levels were equal to the lung tissue levels of supplemental α-tocopherol, γ-tocopherol reduced leukocyte numbers in the lung lavage fluid. In contrast to the lung lavage fluid, highly-elevated levels of γ-tocopherol increased inflammation in the lung tissue. These regulatory effects of highly-elevated tocopherols on tissue inflammation and lung lavage fluid were reversible in a second phase of antigen challenge without tocopherols. In summary, the pro-inflammatory effects of supplemental γ-tocopherol on lung inflammation were partially reversed by supplemental levels of α-tocopherol but were completely reversed by highly-elevated-levels of α-tocopherol. Also, highly-elevated levels of γ-tocopherol were inhibitory and reversible in lung lavage but, importantly, were pro-inflammatory in lung tissue sections. These results have implications for future studies with tocopherols and provide a new context in which to review vitamin E studies in the literature. PMID:21317387

Innate lymphoid cells contribute to allergic airway disease exacerbation by obesity.

PubMed

Everaere, Laetitia; Ait-Yahia, Saliha; Molendi-Coste, Olivier; Vorng, Han; Quemener, Sandrine; LeVu, Pauline; Fleury, Sebastien; Bouchaert, Emmanuel; Fan, Ying; Duez, Catherine; de Nadai, Patricia; Staels, Bart; Dombrowicz, David; Tsicopoulos, Anne

2016-11-01

Epidemiologic and clinical observations identify obesity as an important risk factor for asthma exacerbation, but the underlying mechanisms remain poorly understood. Type 2 innate lymphoid cells (ILC2s) and type 3 innate lymphoid cells (ILC3s) have been implicated, respectively, in asthma and adipose tissue homeostasis and in obesity-associated airway hyperresponsiveness (AHR). We sought to determine the potential involvement of innate lymphoid cells (ILCs) in allergic airway disease exacerbation caused by high-fat diet (HFD)-induced obesity. Obesity was induced by means of HFD feeding, and allergic airway inflammation was subsequently induced by means of intranasal administration of house dust mite (HDM) extract. AHR, lung and visceral adipose tissue inflammation, humoral response, cytokines, and innate and adaptive lymphoid populations were analyzed in the presence or absence of ILCs. HFD feeding exacerbated allergic airway disease features, including humoral response, airway and tissue eosinophilia, AHR, and T H 2 and T H 17 pulmonary profiles. Notably, nonsensitized obese mice already exhibited increased lung ILC counts and tissue eosinophil infiltration compared with values in lean mice in the absence of AHR. The numbers of total and cytokine-expressing lung ILC2s and ILC3s further increased in HDM-challenged obese mice compared with those in HDM-challenged lean mice, and this was accompanied by high IL-33 and IL-1β levels and decreased ILC markers in visceral adipose tissue. Furthermore, depletion of ILCs with an anti-CD90 antibody, followed by T-cell reconstitution, led to a profound decrease in allergic airway inflammatory features in obese mice, including T H 2 and T H 17 infiltration. These results indicate that HFD-induced obesity might exacerbate allergic airway inflammation through mechanisms involving ILC2s and ILC3s. Copyright © 2016 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Increase of Frequency and Modulation of Phenotype of Regulatory T Cells by Atorvastatin Is Associated with Decreased Lung Inflammatory Cell Infiltration in a Murine Model of Acute Allergic Asthma

PubMed Central

Blanquiceth, Yurany; Rodríguez-Perea, Ana Lucia; Tabares Guevara, Jorge H.; Correa, Luis Alfonso; Sánchez, María Dulfary; Ramírez-Pineda, José Robinson; Velilla, Paula Andrea

2016-01-01

Regulatory T cells (Tregs) play an important role by controlling allergic inflammation of airways. Recently, it has been shown that statins have immunomodulatory properties, probably mediated by their effects on Tregs. Therefore, we evaluated the in vivo effect of atorvastatin (ATV) on Tregs and its association with the inflammatory process in a model of allergic asthma. BALB/c mice were sensitized with ovalbumin (OVA) and then challenged with intranasal OVA. ATV (40 mg/kg) was delivered by daily intraperitoneal injection for 7 or 15 days before each OVA challenge. ATV treatment for 7 days increased the frequency of Tregs in mediastinal lymph nodes (MLN) and the interleukin (IL)-10 in lungs. After 15 days of treatment, ATV increased the percentage of glucocorticoid-induced tumor necrosis factor receptor-related protein (GITR+) and programmed cell death protein 1 (PD-1+) Tregs in the lung, without enhancing their suppressive activity, but also increased the percentage of conventional T cells expressing GITR+, PD1+, and OX-40 (tumor necrosis factor receptor superfamily member 4). Although no significant changes were observed in the number of inflammatory cells in the bronchoalveolar lavage (BAL), OVA-specific immunoglobulin E in the serum, and type 2 helper (Th2) cytokines in the lungs, there was a significant decrease of peribronchial inflammation that negatively correlated with the Tregs in MLN and the concentration of IL-10 in the lung. These results suggest that ATV has an immunomodulatory role possibly mediated by their effects on Tregs, which could contribute to the control of inflammation during allergic asthma. Further studies are necessary to elucidate the contribution of Treg to immunomodulatory action of statins in the context of allergic asthma. PMID:28066430

Inhibitory effect of putranjivain A on allergic inflammation through suppression of mast cell activation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kim, Hui-Hun; Park, Seung-Bin; Lee, Soyoung

2014-02-01

A great number of people are suffering from allergic inflammatory disease such as asthma, atopic dermatitis, and sinusitis. Therefore discovery of drugs for the treatment of these diseases is an important subject in human health. Putranjivain A (PJA), member of ellagitannin, is known to possess beneficial effects including anti-cancer and anti-viral activities. The aim of the present study was to elucidate whether PJA modulates the allergic inflammatory reaction and to study its possible mechanisms of action using mast cell-based in vitro and in vivo models. The study was performed in anaphylaxis mouse model and cultured mast cells. PJA inhibited themore » expression of pro-inflammatory cytokines in immunoglobulin E-stimulated mast cells. PJA reduced this expression by inhibiting nuclear factor (NF)-κB and nuclear factor of activated T cell. The oral administration of PJA reduced systemic and cutaneous anaphylaxis, the release of serum histamine, and the expression of the histamine H{sub 1} receptor. In addition, PJA attenuated the activation of mast cells. PJA inhibited the release of histamine from various types of mast cells by the suppression of intracellular calcium. The inhibitory activity of PJA on the allergic reaction was similar to that of disodium cromoglycate, a known anti-allergic drug. These results suggest that PJA can facilitate the prevention or treatment of allergic inflammatory diseases mediated by mast cells. - Highlights: • PJA reduced the degranulation of mast cells. • PJA inhibited the production of inflammatory cytokines. • The effect of PJA on allergic reaction was comparable to the DSCG. • PJA might be a candidate for the treatment of allergic inflammatory diseases.« less

Bovine Intestinal Alkaline Phosphatase Reduces Inflammation After Induction of Acute Myocardial Infarction in Mice.

PubMed

Fiechter, Danielle; Kats, Suzanne; Brands, Ruud; van Middelaar, Ben; Pasterkamp, Gerard; de Kleijn, Dominique; Seinen, Willem

2011-10-01

There has been increasing evidence suggesting that lipopolysaccharide or endotoxin may be an important activator of the innate immune system after acute myocardial infarction. Bovine intestinal alkaline phosphatase reduces inflammation in several endotoxin mediated diseases by dephosphorylation of the lipid A moiety of lipopolysaccharide. The aim of this study was to investigate the effect of bovine intestinal alkaline phosphatase on reducing inflammation after acute myocardial infarction. Just before permanent ligation of the left anterior descending coronary (LAD) artery to induce acute myocardial infarction in Balb/c mice, bovine intestinal alkaline phosphatase (bIAP) was administrated intravenously. After 4 hours, mice were sacrificed and the inflammatory response was assessed. Acute myocardial infarction induced the production of different cytokines, which were measured in blood. Treatment with bovine intestinal alkaline phosphatase resulted in a significant reduction of the pro-inflammatory cytokines IL-6, IL-1β and the chymase mouse mast cell protease-1. No difference in the production of the anti-inflammatory cytokine IL-10 was observed between the control group and the bovine intestinal alkaline phosphatase treated group. In a mouse model of permanent LAD coronary artery ligation, bIAP diminishes the pro-inflammatory responses but does not have an effect on the anti-inflammatory response in the acute phase after acute myocardial infarction.

Obeticholic acid protects against carbon tetrachloride-induced acute liver injury and inflammation.

PubMed

Zhang, Da-Gang; Zhang, Cheng; Wang, Jun-Xian; Wang, Bi-Wei; Wang, Hua; Zhang, Zhi-Hui; Chen, Yuan-Hua; Lu, Yan; Tao, Li; Wang, Jian-Qing; Chen, Xi; Xu, De-Xiang

2017-01-01

The farnesoid X receptor (FXR) is a ligand-activated transcription factor that plays important roles in regulating bile acid homeostasis. The aim of the present study was to investigate the effects of obeticholic acid (OCA), a novel synthetic FXR agonist, carbon tetrachloride (CCl 4 )-induced acute liver injury. Mice were intraperitoneally injected with CCl 4 (0.15ml/kg). In CCl 4 +OCA group, mice were orally with OCA (5mg/kg) 48, 24 and 1h before CCl 4 . As expected, hepatic FXR was activated by OCA. Interestingly, OCA pretreatment alleviated CCl 4 -induced elevation of serum ALT and hepatic necrosis. Moreover, OCA pretreatment inhibited CCl 4 -induced hepatocyte apoptosis. Additional experiment showed that OCA inhibits CCl 4 -induced hepatic chemokine gene Mcp-1, Mip-2 and Kc. Moreover, OCA inhibits CCl 4 -induced hepatic pro-inflammatory gene Tnf-α and Il-1β. By contrast, OCA pretreatment elevated hepatic anti-inflammatory gene Il-4. Further analysis showed that OCA pretreatment inhibited hepatic IκB phosphorylation and blocked nuclear translocation of NF-κB p65 and p50 subunits during CCl 4 -induced acute liver injury. In addition, OCA pretreatment inhibited hepatic Akt, ERK and p38 phosphorylation in CCl 4 -induced acute liver injury. These results suggest that OCA protects against CCl 4 -induced acute liver injury and inflammation. Synthetic FXR agonists may be effective antidotes for hepatic inflammation during acute liver injury. Copyright © 2016 Elsevier Inc. All rights reserved.

Urticaria: "You're Probably Just Allergic to Something".

PubMed

Smallwood, Jordan

2016-11-01

Urticaria is a common symptom seen in pediatric patients, and it has multiple allergic and nonallergic causes. Unfortunately, it is far too common that when children present acutely for urticaria, they are told that it is an "allergy." This statement often leads to increased anxiety while the patient waits to be evaluated by an allergist/immunologist. This article discusses the frequency that allergic reactions are involved in urticaria and provides examples of potential nonallergic causes. Additionally, the article discusses approaches to treatment that may be appropriate to initiate in the pediatrician's office or acute setting. This article is intended to provide a broader understanding of urticaria and its management in the outpatient or emergency setting so that we are able to tell our patients more than"you're probably just allergic to something." [Pediatr Ann. 2016;45(11):e399-e402.]. Copyright 2016, SLACK Incorporated.

Extraction, characterization and evaluation of Kaempferia galanga L. (Zingiberaceae) rhizome extracts against acute and chronic inflammation in rats.

PubMed

Jagadish, Puralae Channabasavaiah; Latha, Kotehal Parameshwarappa; Mudgal, Jayesh; Nampurath, Gopalan Kutty

2016-12-24

The rhizomes of an acaulescent perennial herb, Kaempferia galanga Linn (Family: Zingiberaceae), used as traditional ayurvedic herb to get relief from indigestion, swelling, pain, high blood pressure and dyslipidemia. To prepare and characterize various extracts of Kaempferia galanga (K. galanga) for their comparative evaluation for the identification of the most efficacious extract and its possible pharmacological implication in acute and chronic inflammatory paradigm. Dried and powdered rhizome of K. galanga was subjected to alcoholic extraction as well as successive extractions with various solvents. After phytochemical characterization, all the extracts were standardized for the presence of ethyl-p-methoxycinnamate. The extracts, and the isolated compound, were tested against carrageenan-induced acute inflammation in rats. The most promising extract was tested against adjuvant-induced chronic inflammation in rats. Further, local myeloperoxidase (MPO) levels were investigated to establish the possible mechanism of action. Among the extracts, petroleum ether extract (SKG-1) and crude alcoholic extract (KG) had the maximum quantity of ethyl-p-methoxycinnamate. SKG-1 (300mg/kg) was found effective against acute inflammation in rats. Further, SKG-1 (100mg/kg) reversed the inflammation and elevated MPO levels found in the chronic model. The results suggest that among all the extracts of K. galanga, SKG-1 effectively suppresses the progression of acute and chronic inflammation in rats by inhibition of neutrophil infiltration. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Inhibition of neutrophil elastase attenuates airway hyperresponsiveness and inflammation in a mouse model of secondary allergen challenge: neutrophil elastase inhibition attenuates allergic airway responses

PubMed Central

2013-01-01

Background Chronic asthma is often associated with neutrophilic infiltration in the airways. Neutrophils contain elastase, a potent secretagogue in the airways, nonetheless the role for neutrophil elastase as well as neutrophilic inflammation in allergen-induced airway responses is not well defined. In this study, we have investigated the impact of neutrophil elastase inhibition on the development of allergic airway inflammation and airway hyperresponsiveness (AHR) in previously sensitized and challenged mice. Methods BALB/c mice were sensitized and challenged (primary) with ovalbumin (OVA). Six weeks later, a single OVA aerosol (secondary challenge) was delivered and airway inflammation and airway responses were monitored 6 and 48 hrs later. An inhibitor of neutrophil elastase was administered prior to secondary challenge. Results Mice developed a two-phase airway inflammatory response after secondary allergen challenge, one neutrophilic at 6 hr and the other eosinophilic, at 48 hr. PAR-2 expression in the lung tissues was enhanced following secondary challenge, and that PAR-2 intracellular expression on peribronchial lymph node (PBLN) T cells was also increased following allergen challenge of sensitized mice. Inhibition of neutrophil elastase significantly attenuated AHR, goblet cell metaplasia, and inflammatory cell accumulation in the airways following secondary OVA challenge. Levels of IL-4, IL-5 and IL-13, and eotaxin in BAL fluid 6 hr after secondary allergen challenge were significantly suppressed by the treatment. At 48 hr, treatment with the neutrophil elastase inhibitor significantly reduced the levels of IL-13 and TGF-β1 in the BAL fluid. In parallel, in vitro IL-13 production was significantly inhibited in spleen cells from sensitized mice. Conclusion These data indicate that neutrophil elastase plays an important role in the development of allergic airway inflammation and hyperresponsiveness, and would suggest that the neutrophil elastase inhibitor

Chitin elicits CCL2 from airway epithelial cells and induces CCR2-dependent innate allergic inflammation in the lung

PubMed Central

Roy, René M.; Wüthrich, Marcel; Klein, Bruce S.

2012-01-01

Chitin exposure in the lung induces eosinophilia and alternative activation of macrophages, and is correlated with allergic airway disease. However, the mechanism underlying chitin-induced polarization of macrophages is poorly understood. Here, we show that chitin induces alternative activation of macrophages in vivo, but does not do so directly in vitro. We further show that airway epithelial cells bind chitin in vitro and produce CCL2 in response to chitin both in vitro and in vivo. Supernatants of chitin exposed epithelial cells promoted alternative activation of macrophages in vitro, whereas antibody neutralization of CCL2 in the supernate abolished the alternative activation of macrophages. CCL2 acted redundantly in vivo, but mice lacking the CCL2 receptor, CCR2, showed impaired alternative activation of macrophages in response to chitin, as measured by arginase I, CCL17 and CCL22 expression. Furthermore, CCR2KO mice exposed to chitin had diminished ROS products in the lung, blunted eosinophil and monocyte recruitment, and impaired eosinophil functions as measured by expression of CCL5, IL13 and CCL11. Thus, airway epithelial cells secrete CCL2 in response to chitin and CCR2 signaling mediates chitin-induced alternative activation of macrophages and allergic inflammation in vivo. PMID:22851704

Central Role of IL-23 and IL-17 Producing Eosinophils as Immunomodulatory Effector Cells in Acute Pulmonary Aspergillosis and Allergic Asthma.

PubMed

Guerra, Evelyn Santos; Lee, Chrono K; Specht, Charles A; Yadav, Bhawna; Huang, Haibin; Akalin, Ali; Huh, Jun R; Mueller, Christian; Levitz, Stuart M

2017-01-01

Aspergillus fumigatus causes invasive pulmonary disease in immunocompromised hosts and allergic asthma in atopic individuals. We studied the contribution of lung eosinophils to these fungal diseases. By in vivo intracellular cytokine staining and confocal microscopy, we observed that eosinophils act as local sources of IL-23 and IL-17. Remarkably, mice lacking eosinophils had a >95% reduction in the percentage of lung IL-23p19+ cells as well as markedly reduced IL-23 heterodimer in lung lavage fluid. Eosinophils killed A. fumigatus conidia in vivo. Eosinopenic mice had higher mortality rates, decreased recruitment of inflammatory monocytes, and decreased expansion of lung macrophages after challenge with conidia. All of these functions underscore a potential protective role for eosinophils in acute aspergillosis. Given the postulated role for IL-17 in asthma pathogenesis, we assessed whether eosinophils could act as sources of IL-23 and IL-17 in models where mice were sensitized to either A. fumigatus antigens or ovalbumin (OVA). We found IL-23p19+ IL-17AF+ eosinophils in both allergic models. Moreover, close to 95% of IL-23p19+ cells and >90% of IL-17AF+ cells were identified as eosinophils. These data establish a new paradigm in acute and allergic aspergillosis whereby eosinophils act not only as effector cells but also as immunomodulatory cells driving the IL-23/IL-17 axis and contributing to inflammatory cell recruitment.

Allergic manifestations of contact lens wearing.

PubMed

Solomon, Abraham

2016-10-01

Contact lens-induced papillary conjunctivitis (CLPC) is a common ocular allergic disease in contact lens wearers. In its more severe form, it can cause giant papillary conjunctivitis, resulting in contact lens intolerance and the need to discontinue the use of contact lenses. This review presents the pathogenesis, clinical manifestations and management guidelines of this common disorder. Different types of contact lenses are associated with differences in the severity of CLPC. Refitting patients with silicone hydrogel contact lenses or with daily disposable contact lenses may improve the signs and symptoms of CLPC. The recent introduction of the topical immunomodulatory agent tacrolimus in other severe allergic eye diseases may apply in suppressing the allergic inflammation in CLPC as well. CLPC is a common ocular disorder in contact lens wearers, with a significant impact on the quality of vision. It should be promptly recognized by healthcare practitioners and managed by modifications of the types and wearing schedules of contact lenses, as well as novel treatment options with topical immunomodulators.

Obeticholic acid protects against carbon tetrachloride-induced acute liver injury and inflammation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhang, Da-Gang

The farnesoid X receptor (FXR) is a ligand-activated transcription factor that plays important roles in regulating bile acid homeostasis. The aim of the present study was to investigate the effects of obeticholic acid (OCA), a novel synthetic FXR agonist, carbon tetrachloride (CCl{sub 4})-induced acute liver injury. Mice were intraperitoneally injected with CCl{sub 4} (0.15 ml/kg). In CCl{sub 4} + OCA group, mice were orally with OCA (5 mg/kg) 48, 24 and 1 h before CCl{sub 4}. As expected, hepatic FXR was activated by OCA. Interestingly, OCA pretreatment alleviated CCl{sub 4}-induced elevation of serum ALT and hepatic necrosis. Moreover, OCA pretreatmentmore » inhibited CCl{sub 4}-induced hepatocyte apoptosis. Additional experiment showed that OCA inhibits CCl{sub 4}-induced hepatic chemokine gene Mcp-1, Mip-2 and Kc. Moreover, OCA inhibits CCl{sub 4}-induced hepatic pro-inflammatory gene Tnf-α and Il-1β. By contrast, OCA pretreatment elevated hepatic anti-inflammatory gene Il-4. Further analysis showed that OCA pretreatment inhibited hepatic IκB phosphorylation and blocked nuclear translocation of NF-κB p65 and p50 subunits during CCl{sub 4}-induced acute liver injury. In addition, OCA pretreatment inhibited hepatic Akt, ERK and p38 phosphorylation in CCl{sub 4}-induced acute liver injury. These results suggest that OCA protects against CCl{sub 4}-induced acute liver injury and inflammation. Synthetic FXR agonists may be effective antidotes for hepatic inflammation during acute liver injury. - Highlights: • OCA pretreatment activates hepatic FXR. • FXR activation protects against CCl{sub 4}-induced acute liver injury. • FXR activation inhibits hepatocyte apoptosis during CCl{sub 4}-induced liver injury. • FXR activation differentially regulates hepatic inflammatory genes. • Synthetic FXR agonists are effective antidotes for acute liver injury.« less

Flaxseed lignans enriched in secoisolariciresinol diglucoside prevent acute asbestos-induced peritoneal inflammation in mice

PubMed Central

Pietrofesa, Ralph A.; Velalopoulou, Anastasia; Arguiri, Evguenia; Menges, Craig W.; Testa, Joseph R.; Hwang, Wei-Ting; Albelda, Steven M.

2016-01-01

Malignant mesothelioma (MM), linked to asbestos exposure, is a highly lethal form of thoracic cancer with a long latency period, high mortality and poor treatment options. Chronic inflammation and oxidative tissue damage caused by asbestos fibers are linked to MM development. Flaxseed lignans, enriched in secoisolariciresinol diglucoside (SDG), have antioxidant, anti-inflammatory and cancer chemopreventive properties. As a prelude to chronic chemoprevention studies for MM development, we tested the ability of flaxseed lignan component (FLC) to prevent acute asbestos-induced inflammation in MM-prone Nf2+/mu mice. Mice (n = 16–17 per group) were placed on control (CTL) or FLC-supplemented diets initiated 7 days prior to a single intraperitoneal bolus of 400 µg of crocidolite asbestos. Three days post asbestos exposure, mice were evaluated for abdominal inflammation, proinflammatory/profibrogenic cytokine release, WBC gene expression changes and oxidative and nitrosative stress in peritoneal lavage fluid (PLF). Asbestos-exposed mice fed CTL diet developed acute inflammation, with significant (P < 0.0001) elevations in WBCs and proinflammatory/profibrogenic cytokines (IL-1ß, IL-6, TNFα, HMGB1 and active TGFß1) relative to baseline (BL) levels. Alternatively, asbestos-exposed FLC-fed mice had a significant (P < 0.0001) decrease in PLF WBCs and proinflammatory/profibrogenic cytokine levels relative to CTL-fed mice. Importantly, PLF WBC gene expression of cytokines (IL-1ß, IL-6, TNFα, HMGB1 and TGFß1) and cytokine receptors (TNFαR1 and TGFßR1) were also downregulated by FLC. FLC also significantly (P < 0.0001) blunted asbestos-induced nitrosative and oxidative stress. FLC reduces acute asbestos-induced peritoneal inflammation, nitrosative and oxidative stress and may thus prove to be a promising agent in the chemoprevention of MM. PMID:26678224

A "multi-hit" model of neonatal white matter injury: cumulative contributions of chronic placental inflammation, acute fetal inflammation and postnatal inflammatory events.

PubMed

Korzeniewski, Steven J; Romero, Roberto; Cortez, Josepf; Pappas, Athina; Schwartz, Alyse G; Kim, Chong Jai; Kim, Jung-Sun; Kim, Yeon Mee; Yoon, Bo Hyun; Chaiworapongsa, Tinnakorn; Hassan, Sonia S

2014-11-01

We sought to determine whether cumulative evidence of perinatal inflammation was associated with increased risk in a "multi-hit" model of neonatal white matter injury (WMI). This retrospective cohort study included very preterm (gestational ages at delivery <32 weeks) live-born singleton neonates delivered at Hutzel Women's Hospital, Detroit, MI, from 2006 to 2011. Four pathologists blinded to clinical diagnoses and outcomes performed histological examinations according to standardized protocols. Neurosonography was obtained per routine clinical care. The primary indicator of WMI was ventriculomegaly (VE). Neonatal inflammation-initiating illnesses included bacteremia, surgical necrotizing enterocolitis, other infections, and those requiring mechanical ventilation. A total of 425 live-born singleton neonates delivered before the 32nd week of gestation were included. Newborns delivered of pregnancies affected by chronic chorioamnionitis who had histologic evidence of an acute fetal inflammatory response were at increased risk of VE, unlike those without funisitis, relative to referent newborns without either condition, adjusting for gestational age [odds ratio (OR) 4.7; 95% confidence interval (CI) 1.4-15.8 vs. OR 1.3; 95% CI 0.7-2.6]. Similarly, newborns with funisitis who developed neonatal inflammation-initiating illness were at increased risk of VE, unlike those who did not develop such illness, compared to the referent group without either condition [OR 3.6 (95% CI 1.5-8.3) vs. OR 1.7 (95% CI 0.5-5.5)]. The greater the number of these three types of inflammation documented, the higher the risk of VE (P<0.0001). Chronic placental inflammation, acute fetal inflammation, and neonatal inflammation-initiating illness seem to interact in contributing risk information and/or directly damaging the developing brain of newborns delivered very preterm.

Risk of Allergic Rhinitis, Allergic Conjunctivitis, and Eczema in Children Born to Mothers with Gum Inflammation during Pregnancy.

PubMed

Hsieh, Vivian Chia-Rong; Liu, Chin-Chen; Hsiao, Yu-Chen; Wu, Trong-Neng

2016-01-01

Despite links between maternal and child health status, evidence on the association between gum infection in pregnant mothers and childhood allergies is scarce. We aim to evaluate the risk of developing allergy in children born to periodontal mothers in a nationwide study. We conducted a 9-year population-based, retrospective cohort study using Taiwan's National Health Insurance database. A study cohort of 42,217 newborns born to mothers with periodontal disease during pregnancy was identified in 2001 and matched with 42,334 babies born to mothers without any infection (control) by mother's age at delivery and baby sex. With a follow-up period from 2001 to 2010, we observed the incidence of allergic rhinitis (AR), allergic conjunctivitis (AC), and eczema in these children. Cox proportional hazards regression models were performed with premature deaths as competing risk for the estimation of allergic disease risks. Nine-year cumulative incidences were the highest among children born to periodontal mothers; they reached 46.8%, 24.2%, and 40.4% (vs. 39.5%, 18.3% and 34.8% in control) for AR, AC, and eczema, respectively. Our results showed moderately increased risks for the allergies in children born to periodontal mothers relative to their matched non-inflammatory control (adjusted HRs: 1.17, 95% CI: 1.15-1.20; 1.27, 1.24-1.31; 1.14, 1.12-1.17, respectively). Because the impact of food consumption and living environment cannot be considered using insurance data, we attempted to control it by adjusting for parental income and mother's residential area. Overall cumulative incidence and risks of children born to periodontal mothers for AR, AC, and eczema are significantly higher than those born to non-inflammatory mothers. Gum infection in women during pregnancy is an independent risk factor for allergic diseases in children, thus its intergenerational consequences should be considered in gestational care.

The adaptor protein CIKS/Act1 is essential for IL-25-mediated allergic airway inflammation1

PubMed Central

Claudio, Estefania; Sønder, Søren Ulrik; Saret, Sun; Carvalho, Gabrielle; Ramalingam, Thirumalai R; Wynn, Thomas A; Chariot, Alain; Garcia-Perganeda, Antonio; Leonardi, Antonio; Paun, Andrea; Chen, Amy; Ren, Nina Y.; Wang, Hongshan; Siebenlist, Ulrich

2008-01-01

IL-17 is the signature cytokine of recently discovered T helper type 17 (Th17) cells, which are prominent in defense against extracellular bacteria and fungi as well as in autoimmune diseases, such as rheumatoid arthritis and experimental autoimmune encephalomyelitis in animal models. IL-25 is a member of the IL-17 family of cytokines, but has been associated with Th2 responses instead and may negatively cross-regulate Th17/IL-17 responses. IL-25 can initiate an allergic asthma-like inflammation in the airways, which includes recruitment of eosinophils, mucus hypersecretion, Th2 cytokine production and airways hyperreactivity. We demonstrate that these effects of IL-25 are entirely dependent on the adaptor protein CIKS (a.k.a. Act1). Surprisingly, this adaptor is necessary to transmit IL-17 signals as well, despite the very distinct biologic responses these two cytokines elicit. We identify CD11c+ macrophage-like lung cells as physiologic relevant targets of IL-25 in vivo. PMID:19155511

Chronic features of allergic asthma are enhanced in the absence of resistin-like molecule-beta.

PubMed

LeMessurier, Kim S; Palipane, Maneesha; Tiwary, Meenakshi; Gavin, Brian; Samarasinghe, Amali E

2018-05-04

Asthma is characterized by inflammation and architectural changes in the lungs. A number of immune cells and mediators are recognized as initiators of asthma, although therapeutics based on these are not always effective. The multifaceted nature of this syndrome necessitate continued exploration of immunomodulators that may play a role in pathogenesis. We investigated the role of resistin-like molecule-beta (RELM-β), a gut antibacterial, in the development and pathogenesis of Aspergillus-induced allergic airways disease. Age and gender matched C57BL/6J and Retnlb -/- mice rendered allergic to Aspergillus fumigatus were used to measure canonical markers of allergic asthma at early and late time points. Inflammatory cells in airways were similar, although Retnlb -/- mice had reduced tissue inflammation. The absence of RELM-β elevated serum IgA and pro-inflammatory cytokines in the lungs at homeostasis. Markers of chronic disease including goblet cell numbers, Muc genes, airway wall remodelling, and hyperresponsiveness were greater in the absence RELM-β. Specific inflammatory mediators important in antimicrobial defence in allergic asthma were also increased in the absence of RELM-β. These data suggest that while characteristics of allergic asthma develop in the absence of RELM-β, that RELM-β may reduce the development of chronic markers of allergic airways disease.

Anti-inflammatory activities of Aller-7, a novel polyherbal formulation for allergic rhinitis.

PubMed

Pratibha, N; Saxena, V S; Amit, A; D'Souza, P; Bagchi, M; Bagchi, D

2004-01-01

Allergic rhinitis is an immunological disorder and an inflammatory response of nasal mucosal membranes. Allergic rhinitis, a state of hypersensitivity, occurs when the body overreacts to a substance such as pollens or dust. A novel, safe polyherbal formulation (Aller-7/NR-A2) has been developed for the treatment of allergic rhinitis using a unique combination of extracts from seven medicinal plants including Phyllanthus emblica, Terminalia chebula, Terminalia bellerica, Albizia lebbeck, Piper nigrum, Zingiber officinale and Piper longum. Since inflammation is an integral mechanistic component of allergy, the present study aimed to determine the anti-inflammatory activity of Aller-7 in various in vivo models. The efficacy of Aller-7 was investigated in compound 48/80-induced paw edema both in Balb/c mice and Swiss Albino mice, carrageenan-induced paw edema in Wistar Albino rats and Freund's adjuvant-induced arthritis in Wistar Albino rats. The trypsin inhibitory activity of Aller-7 was also determined and compared with ovomucoid. At a dose of 250 mg/kg, Aller-7 demonstrated 62.55% inhibition against compound 48/80-induced paw edema in Balb/c mice, while under the same conditions prednisolone at an oral dose of 14 mg/kg exhibited 44.7% inhibition. Aller-7 significantly inhibited compound 48/80-induced paw edema at all three doses of 175, 225 or 275 mg/kg in Swiss Albino mice, while the most potent effect was observed at 225 mg/kg. Aller-7 (120 mg/kg, p.o.) demonstrated 31.3% inhibition against carrageenan-induced acute inflammation in Wistar Albino rats, while ibuprofen (50 mg/kg, p.o.) exerted 68.1% inhibition. Aller-7 also exhibited a dose-dependent (150-350 mg/kg) anti-inflammatory effect against Freund's adjuvant-induced arthritis in Wistar Albino rats and an approximately 63% inhibitory effect was observed at a dose of 350 mg/kg. The trypsin inhibitory activity of Aller-7 was determined, using ovomucoid as a positive control. Ovomucoid and Aller-7 demonstrated

Bovine Intestinal Alkaline Phosphatase Reduces Inflammation After Induction of Acute Myocardial Infarction in Mice

PubMed Central

Fiechter, Danielle; Kats, Suzanne; Brands, Ruud; van Middelaar, Ben; Pasterkamp, Gerard; de Kleijn, Dominique; Seinen, Willem

2011-01-01

Background There has been increasing evidence suggesting that lipopolysaccharide or endotoxin may be an important activator of the innate immune system after acute myocardial infarction. Bovine intestinal alkaline phosphatase reduces inflammation in several endotoxin mediated diseases by dephosphorylation of the lipid A moiety of lipopolysaccharide. The aim of this study was to investigate the effect of bovine intestinal alkaline phosphatase on reducing inflammation after acute myocardial infarction. Methods Just before permanent ligation of the left anterior descending coronary (LAD) artery to induce acute myocardial infarction in Balb/c mice, bovine intestinal alkaline phosphatase (bIAP) was administrated intravenously. After 4 hours, mice were sacrificed and the inflammatory response was assessed. Acute myocardial infarction induced the production of different cytokines, which were measured in blood. Results Treatment with bovine intestinal alkaline phosphatase resulted in a significant reduction of the pro-inflammatory cytokines IL-6, IL-1β and the chymase mouse mast cell protease-1. No difference in the production of the anti-inflammatory cytokine IL-10 was observed between the control group and the bovine intestinal alkaline phosphatase treated group. Conclusion In a mouse model of permanent LAD coronary artery ligation, bIAP diminishes the pro-inflammatory responses but does not have an effect on the anti-inflammatory response in the acute phase after acute myocardial infarction. PMID:28357012

Neutrophilic inflammation is associated with altered airway hydration in stable asthmatics.

PubMed

Loughlin, Ceila E; Esther, Charles R; Lazarowski, Eduardo R; Alexis, Neil E; Peden, David B

2010-01-01

Airway dehydration is a potential trigger of bronchoconstriction in exercise-induced asthma; however, its role in stable asthma has not been explored. Using sputum percent solids, as an indicator of airway hydration, we sought relationships between airway hydration and other known markers of neutrophilic (TH1) and allergic (TH2) inflammation in stable asthma. Thirty-seven atopic subjects with stable asthma and 15 healthy controls underwent sputum induction. Sputum was analyzed for percent solids, cell counts, cellular and biochemical markers of inflammation and purines. Sputum percent solids was significantly elevated in stable asthmatics vs. controls and positively correlated with markers of neutrophilic/TH1-type inflammation (neutrophils, IL-8 and AMP). Sputum percent solids were not correlated with markers of allergic/TH2-type inflammation. These data suggest a direct relationship between neutrophil inflammation and airway hydration in stable asthmatics. Copyright 2009 Elsevier Ltd. All rights reserved.

Modification of acute and late-phase allergic responses to ovalbumin with lipopolysaccharide.

PubMed

Tulic, Mark K; Holt, Patrick G; Sly, Peter D

2002-10-01

We have previously shown that lipopolysaccharide (LPS) exposure in sensitised animals 18 h after ovalbumin (OVA) challenge inhibits OVA-induced airway hyper-responsiveness (AHR). In the present study, we investigated the effect of LPS on OVA-induced acute and late-phase allergic responses in sensitised rats when challenged with OVA. Rats were sensitised with OVA and 11 days later challenged with 1% OVA in the presence or absence of LPS (0.5-50 microg/ml) given in the same nebulizer. Acute responses to OVA were measured each minute for 30 min after challenge. In a separate group of animals, late-phase responses to OVA were determined at 24 h. At the end of each study, Evans blue dye was injected and animals sacrificed 30 min later. Bronchoalveolar lavage was obtained to monitor inflammatory cell migration and microvascular leakage. OVA challenge in sensitised animals produced an acute response with changes in lung mechanics peaking 10.0 +/- 0.9 min after OVA and returning to baseline within 30 min. This was followed 24 h later by increased responses to methacholine chloride (MCh), inflammatory cell influx and increased Evans blue leakage into the lungs. Presence of 5 or 50 microg/ml LPS in the nebulizer during OVA challenge altered the kinetics of the acute-phase response, with an immediate decrease in lung function (time to peak decreased from 10.3 +/- 1.2 to 1.8 +/- 0.2 and 2.2 +/- 0.3 min, respectively: p < 0.001, n = 6) and a dose-dependent attenuation of late-phase AHR, cellular influx (n = 5, p < 0.001) and Evans blue leakage (n = 5, p < 0.001) at 24 h. In summary, co-administration of OVA with LPS modifies both the acute and late-phase responses to the allergen, inducing an earlier acute change in lung function and a dose-dependent inhibition of late-phase responses to the allergen. Copyright 2002 S. Karger AG, Basel

The central role of hypothalamic inflammation in the acute illness response and cachexia.

PubMed

Burfeind, Kevin G; Michaelis, Katherine A; Marks, Daniel L

2016-06-01

When challenged with a variety of inflammatory threats, multiple systems across the body undergo physiological responses to promote defense and survival. The constellation of fever, anorexia, and fatigue is known as the acute illness response, and represents an adaptive behavioral and physiological reaction to stimuli such as infection. On the other end of the spectrum, cachexia is a deadly and clinically challenging syndrome involving anorexia, fatigue, and muscle wasting. Both of these processes are governed by inflammatory mediators including cytokines, chemokines, and immune cells. Though the effects of cachexia can be partially explained by direct effects of disease processes on wasting tissues, a growing body of evidence shows the central nervous system (CNS) also plays an essential mechanistic role in cachexia. In the context of inflammatory stress, the hypothalamus integrates signals from peripheral systems, which it translates into neuroendocrine perturbations, altered neuronal signaling, and global metabolic derangements. Therefore, we will discuss how hypothalamic inflammation is an essential driver of both the acute illness response and cachexia, and why this organ is uniquely equipped to generate and maintain chronic inflammation. First, we will focus on the role of the hypothalamus in acute responses to dietary and infectious stimuli. Next, we will discuss the role of cytokines in driving homeostatic disequilibrium, resulting in muscle wasting, anorexia, and weight loss. Finally, we will address mechanisms and mediators of chronic hypothalamic inflammation, including endothelial cells, chemokines, and peripheral leukocytes. Copyright © 2015 Elsevier Ltd. All rights reserved.

The effects of acute inflammation on cognitive functioning and emotional processing in humans: A systematic review of experimental studies.

PubMed

Bollen, Jessica; Trick, Leanne; Llewellyn, David; Dickens, Chris

2017-03-01

The cognitive neuropsychological model of depression proposes that negative biases in the processing of emotionally salient information have a central role in the development and maintenance of depression. We have conducted a systematic review to determine whether acute experimental inflammation is associated with changes to cognitive and emotional processing that are thought to cause and maintain depression. We identified experimental studies in which healthy individuals were administered an acute inflammatory challenge (bacterial endotoxin/vaccination) and standardised tests of cognitive function were performed. Fourteen references were identified, reporting findings from 12 independent studies on 345 participants. Methodological quality was rated strong or moderate for 11 studies. Acute experimental inflammation was triggered using a variety of agents (including endotoxin from E. coli, S. typhi, S. abortus Equi and Hepatitis B vaccine) and cognition was assessed over hours to months, using cognitive tests of i) attention/executive functioning, ii) memory and iii) social/emotional processing. Studies found mixed evidence that acute experimental inflammation caused changes to attention/executive functioning (2 of 6 studies showed improvements in attention executive function compared to control), changes in memory (3 of 5 studies; improved reaction time: reduced memory for object proximity: poorer immediate and delayed memory) and changes to social/emotional processing (4 of 5 studies; reduced perception of emotions, increased avoidance of punishment/loss experiences, and increased social disconnectedness). Acute experimental inflammation causes negative biases in social and emotional processing that could explain observed associations between inflammation and depression. Copyright © 2017 Elsevier Inc. All rights reserved.

Experimental extrinsic allergic alveolitis and pulmonary angiitis induced by intratracheal or intravenous challenge with Corynebacterium parvum in sensitized rats.

PubMed Central

Yi, E. S.; Lee, H.; Suh, Y. K.; Tang, W.; Qi, M.; Yin, S.; Remick, D. G.; Ulich, T. R.

1996-01-01

Extrinsic allergic alveolitis and pulmonary sarcoidosis are granulomatous diseases of the lung for which clinical presentation and anatomic site of granuloma formation differ. Extrinsic allergic alveolitis is caused by inhaled antigens, whereas the nature and source of the inciting antigen in sarcoidosis is unknown. To test the hypothesis that the route via which antigen is introduced to the lung contributes to the clinicopathological presentation of pulmonary granulomatous disease, rats immunized with intravenous (i.v.) Corynebacterium parvum were challenged after 2 weeks with either intratracheal (i.t.) or i.v. C. parvum. The granulomatous inflammation elicited by i.t. challenge predominantly involved alveolar spaces and histologically simulated extrinsic allergic alveolitis. In contrast, the inflammation induced by i.v. challenge was characterized by granulomatous angiitis and interstitial inflammation simulating sarcoidosis. Elevations of leukocyte counts and TNF levels in bronchoalveolar fluid, which reflect inflammation in the intra-alveolar compartment, were much more pronounced after i.t. than after i.v. challenge. Tumor necrosis factor, interleukin-6, CC chemokine, CXC chemokine, and adhesion molecule mRNA and protein expression occurred in each model. In conclusion, i.t. or i.v. challenge with C. parvum in sensitized rats caused pulmonary granulomatous inflammation that was histologically similar to human extrinsic allergic alveolitis and sarcoidosis, respectively. Although the soluble and cellular mediators of granulomatous inflammation were qualitatively similar in both disease models, the differing anatomic source of the same antigenic challenge was responsible for differing clinicopathological presentations. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 11 Figure 13 Figure 12 Figure 14 PMID:8863677

Central Role of IL-23 and IL-17 Producing Eosinophils as Immunomodulatory Effector Cells in Acute Pulmonary Aspergillosis and Allergic Asthma

PubMed Central

Guerra, Evelyn Santos; Lee, Chrono K.; Specht, Charles A.; Yadav, Bhawna; Huang, Haibin; Akalin, Ali; Huh, Jun R.; Mueller, Christian

2017-01-01

Aspergillus fumigatus causes invasive pulmonary disease in immunocompromised hosts and allergic asthma in atopic individuals. We studied the contribution of lung eosinophils to these fungal diseases. By in vivo intracellular cytokine staining and confocal microscopy, we observed that eosinophils act as local sources of IL-23 and IL-17. Remarkably, mice lacking eosinophils had a >95% reduction in the percentage of lung IL-23p19+ cells as well as markedly reduced IL-23 heterodimer in lung lavage fluid. Eosinophils killed A. fumigatus conidia in vivo. Eosinopenic mice had higher mortality rates, decreased recruitment of inflammatory monocytes, and decreased expansion of lung macrophages after challenge with conidia. All of these functions underscore a potential protective role for eosinophils in acute aspergillosis. Given the postulated role for IL-17 in asthma pathogenesis, we assessed whether eosinophils could act as sources of IL-23 and IL-17 in models where mice were sensitized to either A. fumigatus antigens or ovalbumin (OVA). We found IL-23p19+ IL-17AF+ eosinophils in both allergic models. Moreover, close to 95% of IL-23p19+ cells and >90% of IL-17AF+ cells were identified as eosinophils. These data establish a new paradigm in acute and allergic aspergillosis whereby eosinophils act not only as effector cells but also as immunomodulatory cells driving the IL-23/IL-17 axis and contributing to inflammatory cell recruitment. PMID:28095479

A ‘Multi-Hit’ Model of Neonatal White Matter Injury: Cumulative Contributions of Chronic Placental Inflammation, Acute Fetal Inflammation and Postnatal Inflammatory Events

PubMed Central

Korzeniewski, SJ; Romero, R; Cortez, J; Pappas, A; Schwartz, AG; Kim, CJ; Kim, JS; Kim, YM; Yoon, BH; Chaiworapongsa, T; Hassan, SS

2018-01-01

Objective We sought to determine whether cumulative evidence of perinatal inflammation was associated with increased risk in a ‘multi-hit’ model of neonatal white matter injury. Methods This retrospective cohort study included very preterm (gestational ages at delivery <32 weeks) liveborn singleton neonates delivered at Hutzel Women’s Hospital, Detroit, MI, from 2006–2011. Four pathologists blinded to clinical diagnoses and outcomes performed histological examinations according to standardized protocols. Neurosonography was obtained per routine clinical care. The primary indicator of WMI was ventriculomegaly (VE). Neonatal inflammation-initiating illnesses included bacteremia, surgical necrotizing enterocolitis, other infections, and those requiring mechanical ventilation. Results A total of 425 liveborn singleton neonates delivered before the 32nd week of gestation were included. Newborns delivered of pregnancies affected by chronic chorioamnionitis who had histologic evidence of an acute fetal inflammatory response were at increased risk of VE, unlike those without funisitis, relative to referent newborns without either condition, adjusting for gestational age [OR 4.7; 95%CI 1.4–15.8 vs. OR 1.3; 95%CI 0.7–2.6]. Similarly, newborns with funisitis who developed neonatal inflammation initiating illness were at increased risk of VE, unlike those who did not develop such illness, compared to the referent group without either condition [OR 3.6; 95%CI 1.5–8.3 vs. OR 1.7; 95%CI 0.5–5.5]. The greater the number of these three types of inflammation documented, the higher the risk of VE (p<0.0001). Conclusion Chronic placental inflammation, acute fetal inflammation and neonatal inflammation-initiating illness seem to interact in contributing risk information and/or directly damaging the developing brain of newborns delivered very preterm. PMID:25205706

Fingerprint of Lung Fluid Ultrafine Particles, a Novel Marker of Acute Lung Inflammation.

PubMed

Bar-Shai, Amir; Alcalay, Yifat; Sagiv, Adi; Rotem, Michal; Feigelson, Sara W; Alon, Ronen; Fireman, Elizabeth

2015-01-01

Acute lung inflammation can be monitored by various biochemical readouts of bronchoalveolar lavage fluid (BALF). To analyze the BALF content of ultrafine particles (UFP; <100 nm) as an inflammatory biomarker in early diagnosis of acute and chronic lung diseases. Mice were exposed to different stress conditions and inflammatory insults (acute lipopolysaccharide inhalation, tobacco smoke and lethal dose of total body irradiation, i.e. 950 rad). After centrifugation, the cellular pellet was assessed while cytokines and ultrafine particles were measured in the soluble fraction of the BALF. A characteristic UFP distribution with a D50 (i.e. the dimension of the 50th UFP percentile) was shared by all tested mouse strains in the BALF of resting lungs. All tested inflammatory insults similarly shifted this size distribution, resulting in a unique UFP fingerprint with an averaged D50 of 58.6 nm, compared with the mean UFP D50 of 23.7 nm for resting BALF (p < 0.0001). This UFP profile was highly reproducible and independent of the intensity or duration of the inflammatory trigger. It returned to baseline after resolution of the inflammation. Neither total body irradiation nor induction of acute cough induced this fingerprint. The UFP fingerprint in the BALF of resting and inflamed lungs can serve as a binary biomarker of healthy and acutely inflamed lungs. This marker can be used as a novel readout for the onset of inflammatory lung diseases and for complete lung recovery from different insults.

Small RNA-seq during acute maximal exercise reveal RNAs involved in vascular inflammation and cardiometabolic health: brief report.

PubMed

Shah, Ravi; Yeri, Ashish; Das, Avash; Courtright-Lim, Amanda; Ziegler, Olivia; Gervino, Ernest; Ocel, Jeffrey; Quintero-Pinzon, Pablo; Wooster, Luke; Bailey, Cole Shields; Tanriverdi, Kahraman; Beaulieu, Lea M; Freedman, Jane E; Ghiran, Ionita; Lewis, Gregory D; Van Keuren-Jensen, Kendall; Das, Saumya

2017-12-01

Exercise improves cardiometabolic and vascular function, although the mechanisms remain unclear. Our objective was to demonstrate the diversity of circulating extracellular RNA (ex-RNA) release during acute exercise in humans and its relevance to exercise-mediated benefits on vascular inflammation. We performed plasma small RNA sequencing in 26 individuals undergoing symptom-limited maximal treadmill exercise, with replication of our top candidate miRNA in a separate cohort of 59 individuals undergoing bicycle ergometry. We found changes in miRNAs and other ex-RNAs with exercise (e.g., Y RNAs and tRNAs) implicated in cardiovascular disease. In two independent cohorts of acute maximal exercise, we identified miR-181b-5p as a key ex-RNA increased in plasma after exercise, with validation in a separate cohort. In a mouse model of acute exercise, we found significant increases in miR-181b-5p expression in skeletal muscle after acute exercise in young (but not older) mice. Previous work revealed a strong role for miR-181b-5p in vascular inflammation in obesity, insulin resistance, sepsis, and cardiovascular disease. We conclude that circulating ex-RNAs were altered in plasma after acute exercise target pathways involved in inflammation, including miR-181b-5p. Further investigation into the role of known (e.g., miRNA) and novel (e.g., Y RNAs) RNAs is warranted to uncover new mechanisms of vascular inflammation on exercise-mediated benefits on health. NEW & NOTEWORTHY How exercise provides benefits to cardiometabolic health remains unclear. We performed RNA sequencing in plasma during exercise to identify the landscape of small noncoding circulating transcriptional changes. Our results suggest a link between inflammation and exercise, providing rich data on circulating noncoding RNAs for future studies by the scientific community. Copyright © 2017 the American Physiological Society.

Resistin-like molecule β regulates innate colonic function: Barrier integrity and inflammation susceptibility

PubMed Central

Hogan, Simon P.; Seidu, Luqman; Blanchard, Carine; Groschwitz, Katherine; Mishra, Anil; Karow, Margaret L.; Ahrens, Richard; Artis, David; Murphy, Andrew J.; Valenzuela, David M.; Yancopoulos, George D.; Rothenberg, Marc E.

2007-01-01

Background: Resistin-like molecule (RELM) β is a cysteine-rich cytokine expressed in the gastrointestinal tract and implicated in insulin resistance and gastrointestinal nematode immunity; however, its function primarily remains an enigma. Objective: We sought to elucidate the function of RELM-β in the gastrointestinal tract. Methods: We generated RELM-β gene-targeted mice and examined colonic epithelial barrier function, gene expression profiles, and susceptibility to acute colonic inflammation. Results: We show that RELM-β is constitutively expressed in the colon by goblet cells and enterocytes and has a role in homeostasis, as assessed by alterations in colon mRNA transcripts and epithelial barrier function in the absence of RELM-β. Using acute colonic inflammatory models, we demonstrate that RELM-β has a central role in the regulation of susceptibility to colonic inflammation. Mechanistic studies identify that RELM-β regulates expression of type III regenerating gene (REG) (REG3β and γ), molecules known to influence nuclear factor κB signaling. Conclusions: These data define a critical role for RELM-β in the maintenance of colonic barrier function and gastrointestinal innate immunity. Clinical implications: These findings identify RELM-β as an important molecule in homeostatic gastrointestinal function and colonic inflammation, and as such, these results have implications for a variety of human inflammatory gastrointestinal conditions, including allergic gastroenteropathies. PMID:16815164

Effects of Ex Vivo y-Tocopherol on Airway Macrophage Function in Healthy and Mild Allergic Asthmatics

EPA Science Inventory

Elevated inflammation and altered immune responses are features found in atopic asthmatic airways. Recent studies indicate y-tocopherol (GT) supplementation can suppress airway inflammation in allergic asthma. We studied the effects of in vitro GT supplementation on receptor-med...

Neutral endopeptidase terminates substance P-induced inflammation in allergic contact dermatitis.

PubMed

Scholzen, T E; Steinhoff, M; Bonaccorsi, P; Klein, R; Amadesi, S; Geppetti, P; Lu, B; Gerard, N P; Olerud, J E; Luger, T A; Bunnett, N W; Grady, E F; Armstrong, C A; Ansel, J C

2001-01-15

Sensory nerve-derived neuropeptides such as substance P demonstrate a number of proinflammatory bioactivities, but less is known about their role in inflammatory skin disease. The cell surface metalloprotease neutral endopeptidase (NEP) is the principal proteolytic substance P-degrading enzyme. This study tests the hypothesis that the absence of NEP results in dysregulated inflammatory skin responses. The effector phase of allergic contact dermatitis (ACD) responses was examined in NEP(-/-) knockout and NEP(+/+) wild-type mice and compared with the irritant contact dermatitis response in these animals. NEP was found to be normally immunolocalized in epidermal keratinocytes and dermal blood vessels. The ACD ear swelling response was 2.5-fold higher in animals lacking NEP and was accompanied by a significant increase in plasma extravasation and infiltration of inflammatory leukocytes. The augmented ACD response in NEP(-/-) animals was abrogated by either administration of a neurokinin receptor 1 antagonist or by repeated pretreatment with topical capsaicin. Similar to NEP(-/-) mice, the acute inhibition of NEP in NEP(+/+) animals resulted in an augmented ACD response. In contrast to the ACD responses, little differences were observed in the irritant contact dermatitis response of NEP(-/-) compared with NEP(+/+) animals after epicutaneous application of the skin irritants croton oil or SDS. Thus, these results indicate that NEP and cutaneous neuropeptides have a significant role in the pathogenesis of ACD.

Risk of Allergic Rhinitis, Allergic Conjunctivitis, and Eczema in Children Born to Mothers with Gum Inflammation during Pregnancy

PubMed Central

Hsieh, Vivian Chia-Rong; Liu, Chin-Chen; Hsiao, Yu-Chen; Wu, Trong-Neng

2016-01-01

Purpose Despite links between maternal and child health status, evidence on the association between gum infection in pregnant mothers and childhood allergies is scarce. We aim to evaluate the risk of developing allergy in children born to periodontal mothers in a nationwide study. Methods We conducted a 9-year population-based, retrospective cohort study using Taiwan’s National Health Insurance database. A study cohort of 42,217 newborns born to mothers with periodontal disease during pregnancy was identified in 2001 and matched with 42,334 babies born to mothers without any infection (control) by mother’s age at delivery and baby sex. With a follow-up period from 2001 to 2010, we observed the incidence of allergic rhinitis (AR), allergic conjunctivitis (AC), and eczema in these children. Cox proportional hazards regression models were performed with premature deaths as competing risk for the estimation of allergic disease risks. Results Nine-year cumulative incidences were the highest among children born to periodontal mothers; they reached 46.8%, 24.2%, and 40.4% (vs. 39.5%, 18.3% and 34.8% in control) for AR, AC, and eczema, respectively. Our results showed moderately increased risks for the allergies in children born to periodontal mothers relative to their matched non-inflammatory control (adjusted HRs: 1.17, 95% CI: 1.15–1.20; 1.27, 1.24–1.31; 1.14, 1.12–1.17, respectively). Because the impact of food consumption and living environment cannot be considered using insurance data, we attempted to control it by adjusting for parental income and mother’s residential area. Conclusions Overall cumulative incidence and risks of children born to periodontal mothers for AR, AC, and eczema are significantly higher than those born to non-inflammatory mothers. Gum infection in women during pregnancy is an independent risk factor for allergic diseases in children, thus its intergenerational consequences should be considered in gestational care. PMID:27224053

The who, where, and when of IgE in allergic airway disease.

PubMed

Dullaers, Melissa; De Bruyne, Ruth; Ramadani, Faruk; Gould, Hannah J; Gevaert, Philippe; Lambrecht, Bart N

2012-03-01

Allergic asthma and allergic rhinitis/conjunctivitis are characterized by a T(H)2-dominated immune response associated with increased serum IgE levels in response to inhaled allergens. Because IgE is a key player in the induction and maintenance of allergic inflammation, it represents a prime target for therapeutic intervention. However, our understanding of IgE biology remains fragmentary. This article puts together our current knowledge on IgE in allergic airway diseases with a special focus on the identity of IgE-secreting cells ("who"), their location ("where"), and the circumstances in which they are induced ("when"). We further consider the therapeutic implications of the insights gained. Copyright © 2011 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.

Allergic sensitization enhances anion current responsiveness of murine trachea to PAR-2 activation.

PubMed

Rievaj, Juraj; Davidson, Courtney; Nadeem, Ahmed; Hollenberg, Morley; Duszyk, Marek; Vliagoftis, Harissios

2012-03-01

Protease-activated receptor 2 (PAR-2) is a G protein-coupled receptor possibly involved in the pathogenesis of asthma. PAR-2 also modulates ion transport in cultured epithelial cells, but these effects in native airways are controversial. The influence of allergic inflammation on PAR-2-induced changes in ion transport has received little attention. Here, we studied immediate changes in transepithelial short circuit current (I (sc)) induced by PAR-2 activation in the tracheas of naive and allergic mice. Activation of PAR-2 with an apically added activation peptide (AP) induced a small increase in I (sc), while a much larger increase was observed following basolateral AP addition. In ovalbumin-sensitized and -challenged animals used as a model of allergic airway inflammation, the effect of basolateral AP addition was enhanced. Responses to basolateral AP in both naive and allergic mice were not decreased by blocking sodium absorption with amiloride or CFTR function with CFTR(inh)172 but were reduced by the cyclooxygenase inhibitor indomethacin and largely blocked (>80%) by niflumic acid, a calcium-activated chloride channels' (CaCC) blocker. Allergic mice also showed an enhanced response to ATP and thapsigargin. There was no change in mRNA expression of Par-2 or of the chloride channels Ano1 (Tmem16a) and Bestrophin 2 in tracheas from allergic mice, while mRNA levels of Bestrophin 1 were increased. In conclusion, basolateral PAR-2 activation in the mouse airways led to increased anion secretion through apical CaCC, which was more pronounced in allergic animals. This could be a protective mechanism aimed at clearing allergens and defending against mucus plugging.

The Effects of Environmental Toxins on Allergic Inflammation

PubMed Central

Yang, San-Nan; Hsieh, Chong-Chao; Kuo, Hsuan-Fu; Lee, Min-Sheng; Huang, Ming-Yii

2014-01-01

The prevalence of asthma and allergic disease has increased worldwide over the last few decades. Many common environmental factors are associated with this increase. Several theories have been proposed to account for this trend, especially those concerning the impact of environmental toxicants. The development of the immune system, particularly in the prenatal period, has far-reaching consequences for health during early childhood, and throughout adult life. One underlying mechanism for the increased levels of allergic responses, secondary to exposure, appears to be an imbalance in the T-helper function caused by exposure to the toxicants. Exposure to environmental endocrine-disrupting chemicals can result in dramatic changes in cytokine production, the activity of the immune system, the overall Th1 and Th2 balance, and in mediators of type 1 hypersensitivity mediators, such as IgE. Passive exposure to tobacco smoke is a common risk factor for wheezing and asthma in children. People living in urban areas and close to roads with a high volume of traffic, and high levels of diesel exhaust fumes, have the highest exposure to environmental compounds, and these people are strongly linked with type 1 hypersensitivity disorders and enhanced Th2 responses. These data are consistent with epidemiological research that has consistently detected increased incidences of allergies and asthma in people living in these locations. During recent decades more than 100,000 new chemicals have been used in common consumer products and are released into the everyday environment. Therefore, in this review, we discuss the environmental effects on allergies of indoor and outside exposure. PMID:25374746

The effects of environmental toxins on allergic inflammation.

PubMed

Yang, San-Nan; Hsieh, Chong-Chao; Kuo, Hsuan-Fu; Lee, Min-Sheng; Huang, Ming-Yii; Kuo, Chang-Hung; Hung, Chih-Hsing

2014-11-01

The prevalence of asthma and allergic disease has increased worldwide over the last few decades. Many common environmental factors are associated with this increase. Several theories have been proposed to account for this trend, especially those concerning the impact of environmental toxicants. The development of the immune system, particularly in the prenatal period, has far-reaching consequences for health during early childhood, and throughout adult life. One underlying mechanism for the increased levels of allergic responses, secondary to exposure, appears to be an imbalance in the T-helper function caused by exposure to the toxicants. Exposure to environmental endocrine-disrupting chemicals can result in dramatic changes in cytokine production, the activity of the immune system, the overall Th1 and Th2 balance, and in mediators of type 1 hypersensitivity mediators, such as IgE. Passive exposure to tobacco smoke is a common risk factor for wheezing and asthma in children. People living in urban areas and close to roads with a high volume of traffic, and high levels of diesel exhaust fumes, have the highest exposure to environmental compounds, and these people are strongly linked with type 1 hypersensitivity disorders and enhanced Th2 responses. These data are consistent with epidemiological research that has consistently detected increased incidences of allergies and asthma in people living in these locations. During recent decades more than 100,000 new chemicals have been used in common consumer products and are released into the everyday environment. Therefore, in this review, we discuss the environmental effects on allergies of indoor and outside exposure.

Adelmidrol, a palmitoylethanolamide analogue, as a new pharmacological treatment for the management of acute and chronic inflammation.

PubMed

Impellizzeri, Daniela; Di Paola, Rosanna; Cordaro, Marika; Gugliandolo, Enrico; Casili, Giovanna; Morittu, Valeria Maria; Britti, Domenico; Esposito, Emanuela; Cuzzocrea, Salvatore

2016-11-01

The aim of study was to examine the anti-inflammatory and analgesic effects of adelmidrol, an analogue of palmitoylethanolamide (PEA), in animal models of acute and chronic inflammation [carrageenan-induced paw edema (CAR) and collagen-induced arthritis (CIA)]. In order to elucidate whether the action of adelmidrol is related to activation of peroxisome proliferator-activated receptors (PPAR-α or PPAR-γ), we investigated the effects of PPAR-γ antagonist, GW9662 on adelmidrol mechanism. CAR induced paw edema, hyperalgesia and the activation of pro-inflammatory NF-κB pathway were markedly reduced by treatment with adelmidrol. GW9662, (administered prior to adelmidrol treatment), antagonized the effect of adelmidrol abolishing its positive action. On the contrary, the genetic absence of PPAR-α receptor did not modify the beneficial results of adelmidrol treatment in the acute model of inflammation. In addition, for the first time, we demonstrated that adelmidrol was able to ameliorate both the clinical signs and the histopathology of the joint and the hind paw during chronic inflammation. In particular, the degree of oxidative damage and proinflammatory cytokines and chemokines production were significantly reduced in adelmidrol-treated mice. Moreover, in CIA model, the effect of GW9662 pre-treatment on adelmidrol mechanism was also confirmed. Thus, in this study, we report that adelmidrol reduces the development of acute and chronic inflammation and could represent a novel therapeutic approach for inflammation and pain. Copyright © 2016 Elsevier Inc. All rights reserved.

Deciphering the complexity of acute inflammation using mathematical models.

PubMed

Vodovotz, Yoram

2006-01-01

Various stresses elicit an acute, complex inflammatory response, leading to healing but sometimes also to organ dysfunction and death. We constructed both equation-based models (EBM) and agent-based models (ABM) of various degrees of granularity--which encompass the dynamics of relevant cells, cytokines, and the resulting global tissue dysfunction--in order to begin to unravel these inflammatory interactions. The EBMs describe and predict various features of septic shock and trauma/hemorrhage (including the response to anthrax, preconditioning phenomena, and irreversible hemorrhage) and were used to simulate anti-inflammatory strategies in clinical trials. The ABMs that describe the interrelationship between inflammation and wound healing yielded insights into intestinal healing in necrotizing enterocolitis, vocal fold healing during phonotrauma, and skin healing in the setting of diabetic foot ulcers. Modeling may help in understanding the complex interactions among the components of inflammation and response to stress, and therefore aid in the development of novel therapies and diagnostics.

Regulation of allergic airway inflammation by adoptive transfer of CD4+ T cells preferentially producing IL-10.

PubMed

Matsuda, Masaya; Doi, Kana; Tsutsumi, Tatsuya; Fujii, Shinya; Kishima, Maki; Nishimura, Kazuma; Kuroda, Ikue; Tanahashi, Yu; Yuasa, Rino; Kinjo, Toshihiko; Kuramoto, Nobuyuki; Mizutani, Nobuaki; Nabe, Takeshi

2017-10-05

Anti-inflammatory pharmacotherapy for asthma has mainly depended on the inhalation of glucocorticoids, which non-specifically suppress immune responses. If the anti-inflammatory cytokine interleukin (IL)-10 can be induced by a specific antigen, asthmatic airway inflammation could be suppressed when individuals are exposed to the antigen. The purpose of this study was to develop cellular immunotherapeutics for atopic diseases using IL-10-producing CD4 + T cells. Spleen cells isolated from ovalbumin (OVA)-sensitized mice were cultured with the antigen, OVA and growth factors, IL-21, IL-27 and TGF-β for 7 days. After the 7-day culture, the CD4 + T cells were purified using a murine CD4 magnetic beads system. When the induced CD4 + T cells were stimulated by OVA in the presence of antigen-presenting cells, IL-10 was preferentially produced in vitro. When CD4 + T cells were adoptively transferred to OVA-sensitized mice followed by intratracheal OVA challenges, IL-10 was preferentially produced in the serum and bronchoalveolar lavage fluid in vivo. IL-10 production coincided with the inhibition of eosinophilic airway inflammation and epithelial mucus plugging. Most of the IL-10-producing CD4 + T cells were negative for Foxp3 and GATA-3, transcription factors of naturally occurring regulatory T cells and Th2 cells, respectively, but double positive for LAG-3 and CD49b, surface markers of inducible regulatory T cells, Tr1 cells. Collectively, most of the induced IL-10-producing CD4 + T cells could be Tr1 cells, which respond to the antigen to produce IL-10, and effectively suppressed allergic airway inflammation. The induced Tr1 cells may be useful for antigen-specific cellular immunotherapy for atopic diseases. Copyright © 2017 Elsevier B.V. All rights reserved.

Fetal inflammation associated with minimal acute morbidity in moderate/late preterm infants.

PubMed

Gisslen, Tate; Alvarez, Manuel; Wells, Casey; Soo, Man-Ting; Lambers, Donna S; Knox, Christine L; Meinzen-Derr, Jareen K; Chougnet, Claire A; Jobe, Alan H; Kallapur, Suhas G

2016-03-23

To determine whether exposure to acute chorioamnionitis and fetal inflammation caused short-term adverse outcomes. This is a prospective observational study: subjects were mothers delivering at 32-36 weeks gestation and their preterm infants at a large urban tertiary level III perinatal unit (N=477 infants). Placentae and fetal membranes were scored for acute histological chorioamnionitis based on the Redline criteria. Fetal inflammation was characterised by histological diagnosis of funisitis (umbilical cord inflammation), increased cord blood cytokines measured by ELISA, and activation of the inflammatory cells infiltrating the placenta and fetal membranes measured by immunohistology. Maternal and infant data were collected. Twenty-four per cent of 32-36-week infants were exposed to histological chorioamnionitis and 6.9% had funisitis. Immunostaining for leucocyte subsets showed selective infiltration of the placenta and fetal membranes with activated neutrophils and macrophages with chorioamnionitis. Interleukin (IL) 6, IL-8 and granulocyte colony-stimulating factor were selectively increased in the cord blood of preterm infants with funisitis. Compared with infants without chorioamnionitis, funisitis was associated with increased ventilation support during resuscitation (43.8% vs 15.4%) and more respiratory distress syndrome postnatally (27.3% vs 10.2%) in univariate analysis. However, these associations disappeared after adjusting for prematurity. Despite fetal exposure to funisitis, increased cord blood cytokines and activated placental inflammatory cells, we could not demonstrate neonatal morbidity specifically attributable to fetal inflammation after adjusting for gestational age in moderate and late preterm infants. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

Educational clinical case series for pediatric allergy and immunology: allergic proctocolitis, food protein-induced enterocolitis syndrome and allergic eosinophilic gastroenteritis with protein-losing gastroenteropathy as manifestations of non-IgE-mediated cow's milk allergy.

PubMed

Maloney, Jennifer; Nowak-Wegrzyn, Anna

2007-06-01

Cow's milk protein allergy is the most common food allergy in infants and young children. It is estimated that up to 50% of pediatric cow's milk allergy is non-IgE-mediated. Allergic proctocolitis is a benign disorder manifesting with blood-streaked stools in otherwise healthy-appearing infants who are breast- or formula-fed. Symptoms resolve within 48-72 h following elimination of dietary cow's milk protein. Most infants tolerate cow's milk by their first birthday. Food protein-induced enterocolitis syndrome presents in young formula-fed infants with chronic emesis, diarrhea, and failure to thrive. Reintroduction of cow's milk protein following a period of avoidance results in profuse, repetitive emesis within 2-3 h following ingestion; 20% of acute exposures may be associated with hypovolemic shock. Treatment of acute reactions is with vigorous hydration. Most children become tolerant with age; attempts of re-introduction of milk must be done under physician supervision and with secure i.v. access. Allergic eosinophilic gastroenteritis affects infants as well as older children and adolescents. Abdominal pain, emesis, diarrhea, failure to thrive, or weight loss are the most common symptoms. A subset of patients may develop protein-losing enteropathy. Fifty percent of affected children are atopic and have evidence of food-specific IgE antibody but skin prick tests and serum food-IgE levels correlate with response to elimination diet poorly. Elemental diet based on the amino-acid formula leads to resolutions of gastrointestinal eosinophilic inflammation typically within 6 wk.

Adam8 Limits the Development of Allergic Airway Inflammation in Mice

PubMed Central

Knolle, Martin D.; Nakajima, Takahiro; Hergrueter, Anja; Gupta, Kushagra; Polverino, Francesca; Craig, Vanessa J.; Fyfe, Susanne E.; Zahid, Muhammad; Permaul, Perdita; Cernadas, Manuela; Montano, Gilbert; Tesfaigzi, Yohannes; Sholl, Lynette; Kobzik, Lester; Israel, Elliot; Owen, Caroline A.

2013-01-01

To determine whether a disintegrin and a metalloproteinase-8 (Adam8) regulates allergic airway inflammation (AAI) and airway hyper-responsiveness (AHR), we compared AAI and AHR in wild type (WT) versus Adam8−/− mice in different genetic backgrounds sensitized and challenged with ovalbumin (OVA) or house dust mite protein extract (HDM). OVA- and HDM-treated Adam8−/− mice had higher lung leukocyte counts, more airway mucus metaplasia, greater lung levels of some TH2 cytokines, and higher methacholine-induced increases in central airway resistance than allergen-treated WT mice. Studies of OVA-treated Adam8 bone marrow chimeric mice confirmed that leukocyte-derived Adam8 predominantly mediated Adam8’s anti-inflammatory activities in murine airways. Airway eosinophils and macrophages both expressed Adam8 in WT mice with AAI. Adam8 limited AAI and AHR in mice by reducing leukocyte survival because: 1) Adam8−/− mice with AAI had fewer apoptotic eosinophils and macrophages in their airways than WT mice with AAI; and 2) Adam8−/− macrophages and eosinophils had reduced rates of apoptosis compared with WT leukocytes when the intrinsic (but not the extrinsic) apoptosis pathway was triggered in the cells in vitro. ADAM8 was robustly expressed by airway granulocytes in lung sections from human asthma patients but, surprisingly, airway macrophages had less ADAM8 staining than airway eosinophils. Thus, ADAM8 has anti-inflammatory activities during AAI in mice by activating the intrinsic apoptosis pathway in myeloid leukocytes. Strategies that increase ADAM8 levels in myeloid leukocytes may have therapeutic efficacy in asthma. PMID:23670189

IgE Immune Complexes Stimulate an Increase in Lung Mast Cell Progenitors in a Mouse Model of Allergic Airway Inflammation

PubMed Central

Dahlin, Joakim S.; Ivarsson, Martin A.; Heyman, Birgitta; Hallgren, Jenny

2011-01-01

Mast cell numbers and allergen specific IgE are increased in the lungs of patients with allergic asthma and this can be reproduced in mouse models. The increased number of mast cells is likely due to recruitment of mast cell progenitors that mature in situ. We hypothesized that formation of IgE immune complexes in the lungs of sensitized mice increase the migration of mast cell progenitors to this organ. To study this, a model of allergic airway inflammation where mice were immunized with ovalbumin (OVA) in alum twice followed by three daily intranasal challenges of either OVA coupled to trinitrophenyl (TNP) alone or as immune complexes with IgE-anti-TNP, was used. Mast cell progenitors were quantified by a limiting dilution assay. IgE immune complex challenge of sensitized mice elicited three times more mast cell progenitors per lung than challenge with the same dose of antigen alone. This dose of antigen challenge alone did not increase the levels of mast cell progenitors compared to unchallenged mice. IgE immune complex challenge of sensitized mice also enhanced the frequency of mast cell progenitors per 106 mononuclear cells by 2.1-fold. The enhancement of lung mast cell progenitors by IgE immune complex challenge was lost in FcRγ deficient mice but not in CD23 deficient mice. Our data show that IgE immune complex challenge enhances the number of mast cell progenitors in the lung through activation of an Fc receptor associated with the FcRγ chain. This most likely takes place via activation of FcεRI, although activation via FcγRIV or a combination of the two receptors cannot be excluded. IgE immune complex-mediated enhancement of lung MCp numbers is a new reason to target IgE in therapies against allergic asthma. PMID:21625525

[Advance in therapy of acute rhinitis--comparison of efficacy and safety of xylometazoline in combination xylometazoline-dexpanthenol in patients with acute rhinitis].

PubMed

Kehrl, W; Sonnemann, U; Dethlefsen, U

2003-04-01

Acute Rhinitis is based on an inflammation of the nasal mucous membrane with nasal discharge and obstruction. Symptomatic treatment includes local application of decongestants as Xylometazoline and epithelia-protective agents as Dexpanthenol. After proving a synergistic effect of Xylometazoline and Dexpanthenol (Nasic) in patients after nasal surgery, this result should be checked in patients with acute non-allergic rhinitis. Randomised verum controlled double-blind parallel-group-comparison of five days treatment with nasal sprays containing the combination of Xylometazolin-Dexpanthenol or Xylometazolin. The assessments of nasal obstruction, rhinorrhea, hyperplasia of nasal concha and redness of the nasal mucous membrane were defined as main-target parameters. 152 outpatients diagnosed with non-allergic, acute rhinitis were included in this study. 151 patients completed the study according to protocol. The superiority of the treatment with Xylometazolin-Dexpanthenol could be proven for the main outcome measures in comparison to Xylometazolin clinically relevant and statistically significant. The result was also validated by the secondary endpoints. The clinically proven efficacy is emphasized by the rhinoscopic findings and safety parameters showing a better tolerability of the combination. Accelerating the wound healing corroborates the superiority of the combination and is due to the epithelia protective effect of Dexpanthenol. These results allow especially under socio-economic points of view the conclusion that shorter treatment time with a diminishing risk of a "rebound effect" will improve compliance.

Prophylactic Bifidobacterium adolescentis ATTCC 15703 supplementation reduces partially allergic airway disease in Balb/c but not in C57BL/6 mice.

PubMed

Casaro, M C; Crisma, A R; Vieira, A T; Silva, G H M; Mendes, E; Ribeiro, W R; Martins, F S; Ferreira, C M

2018-04-25

Allergic asthma is a chronic disease mainly characterised by eosinophil inflammation and airway remodelling. Many studies have shown that the gut microbiota of allergic individuals differs from that of non-allergic individuals. Although high levels of bifidobacteria have been associated with healthy persons, Bifidobacterium adolescentis ATCC 15703, a gut bacteria, has been associated with allergic individuals in some clinical studies. The relationship between B. adolescentis ATCC 15703 and asthma or allergies has not been well elucidated, and its effect may be dependent on the host's genetic profile or disease state. To elucidate this question, we evaluated the role of preventive B. adolescentis ATCC 15703 treatment on experimental allergic airway inflammation in two genetically different mouse strains, Balb/c and C57BL/6 (B6). Balb/c mice display a greater predisposition to develop allergic responses than B6 mice. Oral preventive treatment with B. adolescentis ATCC 15703 modulated experimental allergic airway inflammation, specifically in Balb/c mice, which showed decreased levels of eosinophils in the airway. B6 mice did not exhibit any significant alterations in eosinophils but showed an increased influx of total leukocytes and neutrophils into the airway. The mechanism underlying the beneficial effects of these bacteria in experimental allergic mice may involve products of bacteria metabolism, as dead bacteria did not mimic the ability of live B. adolescentis ATCC 15703 to attenuate the influx of eosinophils into the airway. To conclude, preventive oral B. adolescentis ATCC 15703 treatment can attenuate the major characteristic of allergic asthma, eosinophil airway influx, in Balb/c but not B6 mice. These results suggest that oral treatment with this specific live bacterial strain may have therapeutic potential for the treatment of allergic airway disease, although its effect is mouse-strain-dependent.

Propofol Attenuates Airway Inflammation in a Mast Cell-Dependent Mouse Model of Allergic Asthma by Inhibiting the Toll-like Receptor 4/Reactive Oxygen Species/Nuclear Factor κB Signaling Pathway.

PubMed

Li, Hong-Yi; Meng, Jing-Xia; Liu, Zhen; Liu, Xiao-Wen; Huang, Yu-Guang; Zhao, Jing

2018-06-01

Propofol, an intravenous anesthetic agent widely used in clinical practice, is the preferred anesthetic for asthmatic patients. This study was designed to determine the protective effect and underlying mechanisms of propofol on airway inflammation in a mast cell-dependent mouse model of allergic asthma. Mice were sensitized by ovalbumin (OVA) without alum and challenged with OVA three times. Propofol was given intraperitoneally 0.5 h prior to OVA challenge. The inflammatory cell count and production of cytokines in the bronchoalveolar lavage fluid (BALF) were detected. The changes of lung histology and key molecules of the toll-like receptor 4 (TLR4)/reactive oxygen species (ROS)/NF-κB signaling pathway were also measured. The results showed that propofol significantly decreased the number of eosinophils and the levels of IL-4, IL-5, IL-6, IL-13, and TNF-α in BALF. Furthermore, propofol significantly attenuated airway inflammation, as characterized by fewer infiltrating inflammatory cells and decreased mucus production and goblet cell hyperplasia. Meanwhile, the expression of TLR4, and its downstream signaling adaptor molecules--myeloid differentiation factor 88 (MyD88) and NF-κB, were inhibited by propofol. The hydrogen peroxide and methane dicarboxylic aldehyde levels were decreased by propofol, and the superoxide dismutase activity was increased in propofol treatment group. These findings indicate that propofol may attenuate airway inflammation by inhibiting the TLR4/MyD88/ROS/NF-κB signaling pathway in a mast cell-dependent mouse model of allergic asthma.

Food and Natural Materials Target Mechanisms to Effectively Regulate Allergic Responses.

PubMed

Shin, Hee Soon; Shon, Dong-Hwa

2015-01-01

An immune hypersensitivity disorder called allergy is caused by diverse allergens entering the body via skin contact, injection, ingestion, and/or inhalation. These allergic responses may develop into allergic disorders, including inflammations such as atopic dermatitis, asthma, anaphylaxis, food allergies, and allergic rhinitis. Several drugs have been developed to treat these allergic disorders; however, long-term intake of these drugs could have adverse effects. As an alternative to these medicines, food and natural materials that ameliorate allergic disorder symptoms without producing any side effects can be consumed. Food and natural materials can effectively regulate successive allergic responses in an allergic chain-reaction mechanism in the following ways: [1] Inhibition of allergen permeation via paracellular diffusion into epithelial cells, [2] suppression of type 2 T-helper (Th) cell-related cytokine production by regulating Th1/Th2 balance, [3] inhibition of pathogenic effector CD4(+) T cell differentiation by inducing regulatory T cells (Treg), and [4] inhibition of degranulation in mast cells. The immunomodulatory effects of food and natural materials on each target mechanism were scientifically verified and shown to alleviate allergic disorder symptoms. Furthermore, consumption of certain food and natural materials such as fenugreek, skullcap, chitin/chitosan, and cheonggukjang as anti-allergics have merits such as safety (no adverse side effects), multiple suppressive effects (as a mixture would contain various components that are active against allergic responses), and ease of consumption when required. These merits and anti-allergic properties of food and natural materials help control various allergic disorders.

The dynamics of acute inflammation

NASA Astrophysics Data System (ADS)

Kumar, Rukmini

The acute inflammatory response is the non-specific and immediate reaction of the body to pathogenic organisms, tissue trauma and unregulated cell growth. An imbalance in this response could lead to a condition commonly known as "shock" or "sepsis". This thesis is an attempt to elucidate the dynamics of acute inflammatory response to infection and contribute to its systemic understanding through mathematical modeling and analysis. The models of immunity discussed use Ordinary Differential Equations (ODEs) to model the variation of concentration in time of the various interacting species. Chapter 2 discusses three such models of increasing complexity. Sections 2.1 and 2.2 discuss smaller models that capture the core features of inflammation and offer general predictions concerning the design of the system. Phase-space and bifurcation analyses have been used to examine the behavior at various parameter regimes. Section 2.3 discusses a global physiological model that includes several equations modeling the concentration (or numbers) of cells, cytokines and other mediators. The conclusions drawn from the reduced and detailed models about the qualitative effects of the parameters are very similar and these similarities have also been discussed. In Chapter 3, the specific applications of the biologically detailed model are discussed in greater detail. These include a simulation of anthrax infection and an in silico simulation of a clinical trial. Such simulations are very useful to biologists and could prove to be invaluable tools in drug design. Finally, Chapter 4 discusses the general problem of extinction of populations modeled as continuous variables in ODES is discussed. The average time to extinction and threshold are estimated based on analyzing the equivalent stochastic processes.

Mind-body interactions in the regulation of airway inflammation in asthma: A PET study of acute and chronic stress

PubMed Central

Rosenkranz, Melissa A.; Esnault, Stephane; Christian, Bradley T.; Crisafi, Gina; Gresham, Lauren K.; Higgins, Andrew T.; Moore, Mollie N.; Moore, Sarah M.; Weng, Helen Y.; Salk, Rachel H.; Busse, William W.; Davidson, Richard J.

2016-01-01

Background Psychological stress has long been recognized as a contributing factor to asthma symptom expression and disease progression. Yet, the neural mechanisms that underlie this relationship have been largely unexplored in research addressing the pathophysiology and management of asthma. Studies that have examined the mechanisms of this relationship in the periphery suggest that it is the superimposition of acute stress on top of chronic stress that is of greatest concern for airway inflammation. Methods We compared asthmatic individuals with high and low levels of chronic life stress in their neural and peripheral physiological responses to the Trier Social Stress Test and a matched control task. We used FDG-PET to measure neural activity during performance of the two tasks. We used both circulating and airway-specific markers of asthma-related inflammation to assess the impact of acute stress in these two groups. Results Asthmatics under chronic stress had a larger HPA-axis response to an acute stressor, which failed to show the suppressive effects on inflammatory markers observed in those with low chronic stress. Moreover, our PET data suggest that greater activity in the anterior insula during acute stress may reflect regulation of the effect of stress on inflammation. In contrast, greater activity in the mid-insula and perigenual anterior cingulate seems to reflect greater reactivity and was associated with greater airway inflammation, a more robust alpha amylase response, and a greater stress-induced increase in proinflammatory cytokine mRNA expression in airway cells. Conclusions Acute stress is associated with increases in markers of airway inflammation in asthmatics under chronic stress. This relationship may be mediated by interactions between the insula and anterior cingulate cortex, that determine the salience of environmental cues, as well as descending regulatory influence of inflammatory pathways in the periphery. PMID:27039241

Mind-body interactions in the regulation of airway inflammation in asthma: A PET study of acute and chronic stress.

PubMed

Rosenkranz, Melissa A; Esnault, Stephane; Christian, Bradley T; Crisafi, Gina; Gresham, Lauren K; Higgins, Andrew T; Moore, Mollie N; Moore, Sarah M; Weng, Helen Y; Salk, Rachel H; Busse, William W; Davidson, Richard J

2016-11-01

Psychological stress has long been recognized as a contributing factor to asthma symptom expression and disease progression. Yet, the neural mechanisms that underlie this relationship have been largely unexplored in research addressing the pathophysiology and management of asthma. Studies that have examined the mechanisms of this relationship in the periphery suggest that it is the superimposition of acute stress on top of chronic stress that is of greatest concern for airway inflammation. We compared asthmatic individuals with high and low levels of chronic life stress in their neural and peripheral physiological responses to the Trier Social Stress Test and a matched control task. We used FDG-PET to measure neural activity during performance of the two tasks. We used both circulating and airway-specific markers of asthma-related inflammation to assess the impact of acute stress in these two groups. Asthmatics under chronic stress had a larger HPA-axis response to an acute stressor, which failed to show the suppressive effects on inflammatory markers observed in those with low chronic stress. Moreover, our PET data suggest that greater activity in the anterior insula during acute stress may reflect regulation of the effect of stress on inflammation. In contrast, greater activity in the mid-insula and perigenual anterior cingulate seems to reflect greater reactivity and was associated with greater airway inflammation, a more robust alpha amylase response, and a greater stress-induced increase in proinflammatory cytokine mRNA expression in airway cells. Acute stress is associated with increases in markers of airway inflammation in asthmatics under chronic stress. This relationship may be mediated by interactions between the insula and anterior cingulate cortex, that determine the salience of environmental cues, as well as descending regulatory influence of inflammatory pathways in the periphery. Copyright © 2016 Elsevier Inc. All rights reserved.

Intraepithelial lymphocyte eotaxin-2 expression and perineural mast cell degranulation differentiate allergic/eosinophilic colitis from classic IBD.

PubMed

Torrente, Franco; Barabino, Arrigo; Bellini, Tommaso; Murch, Simon H

2014-09-01

Allergic colitis shows overlap with classic inflammatory bowel disease (IBD). Clinically, allergic colitis is associated with dysmotility and abdominal pain, and mucosal eosinophilia is characteristic. We thus aimed to characterise mucosal changes in children with allergic colitis compared with normal tissue and classic IBD, focusing on potential interaction between eosinophils and mast cells with enteric neurones. A total of 15 children with allergic colitis, 10 with Crohn disease (CD), 10 with ulcerative colitis (UC), and 10 histologically normal controls were studied. Mucosal biopsies were stained for CD3 T cells, Ki-67, eotaxin-1, and eotaxin-2. Eotaxin-2, IgE, and tryptase were localised compared with mucosal nerves, using neuronal markers neurofilament protein, neuron-specific enolase, and nerve growth factor receptor. Overall inflammation was greater in patients with CD and UC than in patients with allergic colitis. CD3 T-cell density was increased in patients with allergic colitis, similar to that in patients with CD but lower than in patients with UC, whereas eosinophil density was higher than in all other groups. Eotaxin-1 and -2 were localised to basolateral crypt epithelium in all specimens, with eotaxin-1+ lamina propria cells found in all of the colitis groups. Eotaxin-2+ intraepithelial lymphocyte (IEL) density was significantly higher in allergic colitis specimens than in all other groups. Mast cell degranulation was strikingly increased in patients with allergic colitis (12/15) compared with that in patients with UC (1/10) and CD (0/1). Tryptase and IgE colocalised on enteric neurons in patients with allergic colitis but rarely in patients with IBD. Eotaxin-2+ IELs may contribute to the periepithelial eosinophil accumulation characteristic of allergic colitis. The colocalisation of IgE and tryptase with mucosal enteric nerves is likely to promote the dysmotility and visceral hyperalgesia classically seen in allergic gastrointestinal inflammation.

Mast Cells Limit the Exacerbation of Chronic Allergic Contact Dermatitis in Response to Repeated Allergen Exposure.

PubMed

Gimenez-Rivera, Vladimir-Andrey; Siebenhaar, Frank; Zimmermann, Carolin; Siiskonen, Hanna; Metz, Martin; Maurer, Marcus

2016-12-01

Allergic contact dermatitis is a chronic T cell-driven inflammatory skin disease that is caused by repeated exposure to contact allergens. Based on murine studies of acute contact hypersensitivity, mast cells (MCs) are believed to play a role in its pathogenesis. The role of MCs in chronic allergic contact dermatitis has not been investigated, in part because of the lack of murine models for chronic contact hypersensitivity. We developed and used a chronic contact hypersensitivity model in wild-type and MC-deficient mice and assessed skin inflammatory responses to identify and characterize the role of MCs in chronic allergic contact dermatitis. Ear swelling chronic contact hypersensitivity responses increased markedly, up to 4-fold, in MC-deficient Kit W-sh/W-sh (Sash) and MCPT5-Cre + iDTR + mice compared with wild-type mice. Local engraftment with MCs protected Sash mice from exacerbated ear swelling after repeated oxazolone challenge. Chronic contact hypersensitivity skin of Sash mice exhibited elevated levels of IFN-γ, IL-17α, and IL-23, as well as increased accumulation of Ag-specific IFN-γ-producing CD8 + tissue-resident memory T (T RM ) cells. The CD8 + T cell mitogen IL-15, which was increased in oxazolone-challenged skin of Sash mice during the accumulation of cutaneous T RM cells, was efficiently degraded by MCs in vitro. MCs protect from the exacerbated allergic skin inflammation induced by repeated allergen challenge, at least in part, via effects on CD8 + T RM cells. MCs may notably influence the course of chronic allergic contact dermatitis. A better understanding of their role and the underlying mechanisms may lead to better approaches for the treatment of this common, disabling, and costly condition. Copyright © 2016 by The American Association of Immunologists, Inc.

Recent Patents and Emerging Therapeutics in the Treatment of Allergic Conjunctivitis

PubMed Central

Mishra, Gyan P.; Tamboli, Viral; Jwala, Jwala; Mitra, Ashim K.

2011-01-01

Ocular allergy is an inflammatory response of the conjunctival mucosa that also affects the cornea and eyelids. Allergic conjunctivitis includes seasonal allergic conjunctivitis (SAC), perennial allergic conjunctivitis (PAC), vernal keratoconjunctivitis (VKC), atopic keratoconjunctivitis (AKC) and giant papillary conjunctivitis (GPC). In general, allergic conditions involve mast cell degranulation that leads to release of inflammatory mediators and activation of enzymatic cascades generating pro-inflammatory mediators. In chronic ocular inflammatory disorders associated with mast cell activation such as VKC and AKC constant inflammatory response is observed due to predominance of inflammatory mediators such as eosinophils and Th2-generated cytokines. Antihistamines, mast-cell stabilizers, non-steroidal anti-inflammatory agents, corticosteroids and immunomodulatory agents are commonly indicated for the treatment of acute and chronic allergic conjunctivitis. In recent years newer drug molecules have been introduced in the treatment of allergic conjunctivitis. This article reviews recent patents and emerging therapeutics in the treatment of allergic conjunctivitis. PMID:21171952

Pro-Resolving lipid mediators and Mechanisms in the resolution of acute inflammation

PubMed Central

Buckley, Christopher D.; Gilroy, Derek W.; Serhan, Charles N.

2014-01-01

SUMMARY Inflammatory responses, like all biological cascades, are shaped by a delicate balance between positive and negative feedback loops. It is now clear that in addition to positive and negative checkpoints, the inflammatory cascade rather unexpectedly boasts an additional checkpoint, a family of chemicals that actively promote resolution and tissue repair without compromising host defence. Indeed the resolution phase of inflammation is just as actively orchestrated and carefully choreographed as its induction and inhibition. In this review we explore the immunological consequences of these omega-3-derived specialized pro-resolving mediators (SPMs) and discuss their place within what is currently understood of the role of the arachidonic acid-derived prostaglandins, lipoxins and their natural C15-epimers. We propose that treatment of inflammation should not be restricted to the use of inhibitors of the acute cascade (antagonism) but broadened to take account of the enormous therapeutic potential of inducers (agonists) of the resolution phase of inflammation. PMID:24656045

Abrogation of Airway Hyperresponsiveness but not Inflammation by Rho kinase Insufficiency

PubMed Central

Kasahara, David I.; Ninin, Fernanda M.C.; Wurmbrand, Allison P.; Liao, James K.; Shore, Stephanie A.

2015-01-01

Background Major features of allergic asthma include airway hyperresponsiveness (AHR), eosinophilic inflammation, and goblet cell metaplasia. Rho kinase (ROCK) is a serine/threonine protein kinase that regulates the actin cytoskeleton. By doing so, it can modulate airway smooth muscle cell contraction and leukocyte migration and proliferation. This study was designed to determine the contributions of the two ROCK isoforms, ROCK1 and ROCK2, to AHR, inflammation and goblet cell metaplasia in a mast-cell dependent model of allergic airways disease. Methods and Results Repeated intranasal challenges with OVA caused AHR, eosinophilic inflammation, and goblet cell hyperplasia in wildtype (WT) mice. OVA-induced AHR was partially or completely abrogated in mice haploinsufficient for ROCK2 (ROCK2+/−) or ROCK1 (ROCK1+/−), respectively. In contrast, there was no effect of ROCK insufficiency on allergic airways inflammation, although both ROCK1 and ROCK2 insufficiency attenuated mast cell degranulation. Goblet cell hyperplasia, as indicated by PAS staining, was not different in ROCK1+/− versus WT mice. However, in ROCK2+/− mice, goblet cell hyperplasia was reduced in medium but not large airways. Maximal acetylcholine-induced force generation was reduced in tracheal rings from ROCK1+/− and ROCK2+/− versus WT mice. The ROCK inhibitor, fasudil, also reduced airway responsiveness in OVA-challenged mice, without affecting inflammatory responses. Conclusion In a mast cell model of allergic airways disease, ROCK1 and ROCK2 both contribute to AHR, likely through direct effects on smooth muscle cell and effects on mast-cell degranulation. In addition, ROCK2 but not ROCK1 plays a role in allergen-induced goblet cell hyperplasia. PMID:25323425

The histone deacetylase inhibitor trichostatin A suppresses murine innate allergic inflammation by blocking group 2 innate lymphoid cell (ILC2) activation

PubMed Central

Toki, Shinji; Goleniewska, Kasia; Reiss, Sara; Zhou, Weisong; Newcomb, Dawn C; Bloodworth, Melissa H; Stier, Matthew T; Boyd, Kelli L; Polosukhin, Vasiliy V; Subramaniam, Sriram; Peebles, R Stokes

2016-01-01

Background Group 2 innate lymphoid cells (ILC2) are an important source of the type 2 cytokines interleukin (IL)-5 and IL-13 that are critical to the allergic airway phenotype. Previous studies reported that histone deacetylase (HDAC) inhibition by trichostatin A (TSA) downregulated adaptive allergic immune responses; however, the effect of HDAC inhibition on the early innate allergic immune response is unknown. Therefore, we investigated the effect of TSA on innate airway inflammation mediated by ILC2 activation. Methods BALB/c mice were challenged intranasally with Alternaria extract, exogenous recombinant mouse IL-33 (rmIL-33) or the respective vehicles for four consecutive days following TSA or vehicle treatment. Bronchoalveolar lavage (BAL) fluids and lungs were harvested 24 h after the last challenge. Results We found that TSA treatment significantly decreased the number of ILC2 expressing IL-5 and IL-13 in the lungs challenged with Alternaria extract or rmIL-33 compared with vehicle treatment (p<0.05). TSA treatment significantly decreased protein expression of IL-5, IL-13, CCL11 and CCL24 in the lung homogenates from Alternaria extract-challenged mice or rmIL-33-challenged mice compared with vehicle treatment (p<0.05). Further, TSA treatment significantly decreased the number of perivascular eosinophils and mucus production in the large airways that are critical components of the asthma phenotype (p<0.05). TSA did not change early IL-33 release in the BAL fluids; however, TSA decreased lung IL-33 expression from epithelial cells 24 h after last Alternaria extract challenge compared with vehicle treatment (p<0.05). Conclusions These results reveal that TSA reduces allergen-induced ILC2 activation and the early innate immune responses to an inhaled protease-containing aeroallergen. PMID:27071418

Quantification of structural changes in acute inflammation by fractal dimension, angular second moment and correlation.

PubMed

Stankovic, Marija; Pantic, Igor; De Luka, Silvio R; Puskas, Nela; Zaletel, Ivan; Milutinovic-Smiljanic, Sanja; Pantic, Senka; Trbovich, Alexander M

2016-03-01

The aim of the study was to examine alteration and possible application of fractal dimension, angular second moment, and correlation for quantification of structural changes in acutely inflamed tissue. Acute inflammation was induced by injection of turpentine oil into the right and left hind limb muscles of mice, whereas control animals received intramuscular saline injection. After 12 h, animals were anesthetised and treated muscles collected. The tissue was stained by hematoxylin and eosin, digital micrographs produced, enabling determination of fractal dimension of the cells, angular second moment and correlation of studied tissue. Histopathological analysis showed presence of inflammatory infiltrate and tissue damage in inflammatory group, whereas tissue structure in control group was preserved, devoid of inflammatory infiltrate. Fractal dimension of the cells, angular second moment and correlation of treated tissue in inflammatory group decreased in comparison to the control group. In this study, we were first to observe and report that fractal dimension of the cells, angular second moment, and correlation were reduced in acutely inflamed tissue, indicating loss of overall complexity of the cells in the tissue, the tissue uniformity and structure regularity. Fractal dimension, angular second moment and correlation could be useful methods for quantification of structural changes in acute inflammation. © 2015 The Authors Journal of Microscopy © 2015 Royal Microscopical Society.

Acidic Chitinase Limits Allergic Inflammation and Promotes Intestinal Nematode Expulsion

USDA-ARS?s Scientific Manuscript database

Acidic mammalian chitinase (AMCase) is stereotypically induced during mammalian immune responses to helminths and allergens—yet, its precise role in immunity and inflammation is unclear. Here we show that in the lung, genetic ablation of AMCase failed to diminish type 2 inflammation against helmint...

Targeting key proximal drivers of type 2 inflammation in disease.

PubMed

Gandhi, Namita A; Bennett, Brandy L; Graham, Neil M H; Pirozzi, Gianluca; Stahl, Neil; Yancopoulos, George D

2016-01-01

Systemic type 2 inflammation encompassing T helper 2 (TH2)-type responses is emerging as a unifying feature of both classically defined allergic diseases, such as asthma, and a range of other inflammatory diseases. Rather than reducing inflammation with broad-acting immunosuppressants or narrowly targeting downstream products of the TH2 pathway, such as immunoglobulin E (IgE), efforts to target the key proximal type 2 cytokines - interleukin-4 (IL-4), IL-5 and IL-13 - represent a promising strategy to achieve therapeutic benefit across multiple diseases. After several initial disappointing clinical results with therapies targeting IL-4, IL-5 or IL-13 in asthma, applying a personalized approach achieved therapeutic benefit in an asthma subtype exhibiting an 'allergic' phenotype. More recently, efficacy was extended into a broad population of people with asthma. This argues that the Type 2 inflammation is broadly relevant across the severe asthma population if the key upstream drivers are properly blocked. Moreover, the simultaneous inhibition of IL-4 and IL-13 has shown significant clinical activity in diseases that are often co-morbid with asthma - atopic dermatitis and chronic sinusitis with nasal polyps - supporting the hypothesis that targeting a central 'driver pathway' could benefit multiple allergic diseases.

Corosolic acid ameliorates acute inflammation through inhibition of IRAK-1 phosphorylation in macrophages

PubMed Central

Kim, Seung-Jae; Cha, Ji-Young; Kang, Hye Suk; Lee, Jae-Ho; Lee, Ji Yoon; Park, Jae-Hyung; Bae, Jae-Hoon; Song, Dae-Kyu; Im, Seung-Soon

2016-01-01

Corosolic acid (CA), a triterpenoid compound isolated from Lagerstroemia speciosa L. (Banaba) leaves, exerts anti-inflammatory effects by regulating phosphorylation of interleukin receptor- associated kinase (IRAK)-2 via the NF-κB cascade. However, the protective effect of CA against endotoxic shock has not been reported. LPS (200 ng/mL, 30 min) induced phosphorylation of IRAK-1 and treatment with CA (10 μM) significantly attenuated this effect. In addition, CA also reduced protein levels of NLRP3 and ASC which are the main components of the inflammasome in BMDMs. LPS-induced inflammasome assembly through activation of IRAK-1 was down-regulated by CA challenge. Treatment with Bay11-7082, an inhibitor of IκB-α, had no effect on CA-mediated inhibition of IRAK-1 activation, indicating that CA-mediated attenuation of IRAK-1 phosphorylation was independent of NF-κB signaling. These results demonstrate that CA ameliorates acute inflammation in mouse BMDMs and CA may be useful as a pharmacological agent to prevent acute inflammation. [BMB Reports 2016; 49(5): 276-281] PMID:26615974

Low triiodothyronine: A new facet of inflammation in acute ischemic stroke.

PubMed

Ma, Lili; Zhu, Dongliang; Jiang, Ying; Liu, Yingying; Ma, Xiaomeng; Liu, Mei; Chen, Xiaohong

2016-07-01

Patients with acute ischemic stroke (AIS) frequently experience low free triiodothyronine (fT3) concentrations. Inflammation is recognized as a key contributor to the pathophysiology of stroke. Previous studies, however, did not simultaneously evaluate fT3 and inflammation biomarkers in AIS patients. Markers of inflammation, including serum concentrations of C-reactive protein (CRP) and albumin, and fT3 were assessed retrospectively in 117 patients. Stroke severity was measured on the National Institutes of Health Stroke Scale (NIHSS). Regression analyses were performed to adjust for confounders. Serum fT3 concentrations were significantly lower in moderate AIS patients than those in mild AIS patients (P<0.001). fT3 concentration also positively correlated with serum albumin concentration (r=0.358, P<0.001) and negatively correlated with log10CRP concentration (r=-0.341, P<0.001), NIHSS score (r=-0.384, P<0.001). Multiple regression analysis showed that CRP, albumin concentrations and NIHSS score were independently correlated with fT3 concentration. Binary logistic regression analysis showed that fT3 concentration was an independent factor correlated with NIHSS score, the area under the receiver operating characteristic curve was 0.712 (95% CI, 0.618-0.805). Low fT3 concentrations may be involved in the pathogenic pathway linking inflammation to stroke severity in AIS patients. Copyright © 2016 Elsevier B.V. All rights reserved.

Human adipose tissue mesenchymal stromal cells and their extracellular vesicles act differentially on lung mechanics and inflammation in experimental allergic asthma.

PubMed

de Castro, Ligia Lins; Xisto, Debora Gonçalves; Kitoko, Jamil Zola; Cruz, Fernanda Ferreira; Olsen, Priscilla Christina; Redondo, Patricia Albuquerque Garcia; Ferreira, Tatiana Paula Teixeira; Weiss, Daniel Jay; Martins, Marco Aurélio; Morales, Marcelo Marcos; Rocco, Patricia Rieken Macedo

2017-06-24

Asthma is a chronic inflammatory disease that can be difficult to treat due to its complex pathophysiology. Most current drugs focus on controlling the inflammatory process, but are unable to revert the changes of tissue remodeling. Human mesenchymal stromal cells (MSCs) are effective at reducing inflammation and tissue remodeling; nevertheless, no study has evaluated the therapeutic effects of extracellular vesicles (EVs) obtained from human adipose tissue-derived MSCs (AD-MSC) on established airway remodeling in experimental allergic asthma. C57BL/6 female mice were sensitized and challenged with ovalbumin (OVA). Control (CTRL) animals received saline solution using the same protocol. One day after the last challenge, each group received saline, 10 5 human AD-MSCs, or EVs (released by 10 5  AD-MSCs). Seven days after treatment, animals were anesthetized for lung function assessment and subsequently euthanized. Bronchoalveolar lavage fluid (BALF), lungs, thymus, and mediastinal lymph nodes were harvested for analysis of inflammation. Collagen fiber content of airways and lung parenchyma were also evaluated. In OVA animals, AD-MSCs and EVs acted differently on static lung elastance and on BALF regulatory T cells, CD3 + CD4 + T cells, and pro-inflammatory mediators (interleukin [IL]-4, IL-5, IL-13, and eotaxin), but similarly reduced eosinophils in lung tissue, collagen fiber content in airways and lung parenchyma, levels of transforming growth factor-β in lung tissue, and CD3 + CD4 + T cell counts in the thymus. No significant changes were observed in total cell count or percentage of CD3 + CD4 + T cells in the mediastinal lymph nodes. In this immunocompetent mouse model of allergic asthma, human AD-MSCs and EVs effectively reduced eosinophil counts in lung tissue and BALF and modulated airway remodeling, but their effects on T cells differed in lung and thymus. EVs may hold promise for asthma; however, further studies are required to elucidate the different

Matrix Metalloproteinase-8 Inactivates Macrophage Inflammatory Protein-1α to Reduce Acute Lung Inflammation and Injury in Mice

PubMed Central

Quintero, Pablo A.; Knolle, Martin D.; Cala, Luisa F.; Zhuang, Yuehong; Owen, Caroline A.

2010-01-01

To determine the role of matrix metalloproteinase-8 (MMP-8) in acute lung injury (ALI), we delivered LPS or bleomycin by the intratracheal route to MMP-8−/− mice versus WT mice or subjected the mice to hyperoxia (95% O2) and measured lung inflammation and injury at intervals. MMP-8−/− mice with ALI had greater increases in lung PMN and macrophage counts, measures of alveolar capillary barrier injury, lung elastance, and mortality than WT mice with ALI. Bronchoalveolar lavage fluid (BALF) from LPS-treated MMP-8−/− mice had more macrophage inflammatory protein-1α (MIP-1α) than BALF from LPS-treated WT mice, but similar levels of other pro- and anti-inflammatory mediators. MIP-1α−/− mice with ALI had less acute lung inflammation and injury than WT mice with ALI, confirming that MIP-1α promotes acute lung inflammation and injury in mice. Genetically deleting MIP-1α in MMP-8−/− mice abrogated the increased lung inflammation and injury and mortality in MMP-8−/− mice with ALI. Soluble MMP-8 cleaved and inactivated MIP-1α in vitro, but membrane-bound MMP-8 on activated PMNs had greater MIP-1α-degrading activity than soluble MMP-8. High levels of membrane-bound MMP-8 were detected on lung PMNs from LPS-treated WT mice, but soluble, active MMP-8 was not detected in BALF samples. Thus, MMP-8 has novel roles in restraining lung inflammation and in limiting alveolar capillary barrier injury during ALI in mice by inactivating MIP-1α. In addition, membrane-bound MMP-8 on activated lung PMNs is likely to be the key bioactive form of the enzyme that limits lung inflammation and alveolar capillary barrier injury during ALI. PMID:20042585

Involvement of prostaglandins and histamine in nickel wire-induced acute inflammation in mice.

PubMed

Hirasawa, Noriyasu; Goi, Yoshiaki; Tanaka, Rina; Ishihara, Kenji; Ohtsu, Hiroshi; Ohuchi, Kazuo

2010-06-15

The irritancy of Nickel (Ni) ions has been well documented clinically. However, the chemical mediators involved in the acute inflammation induced by solid Ni are not fully understood. We used the Ni wire-implantation model in mice and examined roles of prostaglandins and histamine in plasma leakage in the acute phase. The subcutaneous implantation of a Ni wire into the back of mice induced plasma leakage from 8 to 24 h and tissue necrosis around the wire at 3 days, whereas the implantation of an aluminum wire induced no such inflammatory responses. An increase in the mRNA for cyclooxygenase (COX)-2 and HDC in cells around the Ni wire was detected 4 h after the implantation. The leakage of plasma at 8 h was inhibited by indomethacin in a dose-dependent manner. Dexamethasone and the p38 MAP kinase inhibitor SB203580 also inhibited the exudation of plasma consistent with the inhibition of the expression of COX-2 mRNA. Furthermore, plasma leakage was partially but siginificantly reduced in histamine H1 receptor knockout mice and histidine decarboxylase (HDC) knockout mice but not in H2 receptor knockout mice. These results suggested that the Ni ions released from the wire induced the expression of COX-2 and HDC, resulting in an increase in vascular permeability during the acute phase of inflammation. (c) 2009 Wiley Periodicals, Inc.

Acute uriticaria-like lesions in allergen-unexposed cutaneous tissues in a mouse model of late allergic rhinitis

PubMed Central

Hayashi, Toshiharu; Fujii, Taeko

2008-01-01

The mechanisms of distant manifestation after a local allergic reaction are largely unknown. This study examined the development of cutaneous lesions in a mouse model of late allergic rhinitis (LAR). BALB/c mice were sensitized by ovalbumin (OVA) intraperitoneally two times (on days 0 and 10) and challenged by OVA intranasally on day 14. Four days after OVA challenge, nasal and cutaneous lesions including helper T (Th) responses, expression of adhesion molecules and presence of OVA and IgE were examined, and compared with unsensitized and unchallenged (control) mice. Compared with the control group, the LAR group developed LAR characterized by infiltration of lymphocytes and eosinophils, increased IgE values and increased productions of IL-4 and IL-5, but not IFN-γ. A dominant infiltration of eosinophils and increase in mast cells, attachment of eosinophils to endothelium, intense expression of VCAM-1 on endothelium in venules and VLA-4 expression on eosinophils and mast cells were recognized in the cutaneous tissues. There were no differences in the expression of ICAM-1 on vascular endothelium and LFA-1 on infiltrated leucocytes between the two groups. CLA expression on lymphocytes was not detected, and the binding of OVA and IgE on mast cells and eosinophils was found in the cutaneous lesions in the LAR group, but not in the control group. This study suggests that acute uriticaria-like lesions in OVA-unexposed cutaneous tissues may be induced by immediate allergic reaction due to the systemic development of Th2-type response in a mouse model of LAR. PMID:18460071

Association between desloratadine and prednisolone in the treatment of children with acute symptoms of allergic rhinitis: a double-blind, randomized and controlled clinical trial.

PubMed

Wandalsen, Gustavo F; Miranda, Carolina; Ensina, Luis Felipe; Sano, Flavio; Amazonas, Roberto Bleul; Silva, Joyce Macedo da; Solé, Dirceu

A combination of antihistamines and oral corticosteroids is often used to treat acute symptoms of allergic rhinitis. To evaluate safety and efficacy of desloratadine plus prednisolone in the treatment of acute symptoms of children (2-12 years) with allergic rhinitis, and to compare it to dexchlorpheniramine plus betamethasone. Children with moderate/severe persistent allergic rhinitis and symptomatic (nasal symptoms score [0-12]≥6) were allocated in a double-blind, randomized fashion to receive dexchlorpheniramine plus betamethasone (n=105; three daily doses) or desloratadine plus prednisolone (n=105; single dose followed by two of placebo) for 7 days. At the beginning and end of the evaluation, the following were obtained: nasal symptoms score, extra nasal symptoms score, peak nasal inspiratory flow, blood biochemistry, and electrocardiogram. Ninety-six children of the dexchlorpheniramine plus betamethasone group and 98 of the desloratadine plus prednisolone group completed the protocol. The two groups were similar regarding initial and final nasal symptoms scores, extra nasal symptoms scores and peak nasal inspiratory flow. A drop of 76.4% and 79.1% for nasal symptoms score, 86.0% and 79.2% for extra nasal symptoms score, as well as an increase of 25.2% and 24.3% for peak nasal inspiratory flow occurred for those treated with desloratadine plus prednisolone and dexchlorpheniramine plus betamethasone, respectively. There were no significant changes in blood chemistry. Sinus tachycardia was the most frequent electrocardiogram change, but with no clinical significance. Drowsiness was reported significantly more often among those of dexchlorpheniramine plus betamethasone group (17.14%×8.57%, respectively). The desloratadine plus prednisolone combination was able to effectively control acute symptoms of rhinitis in children, improving symptoms and nasal function. Compared to the dexchlorpheniramine plus betamethasone combination, it showed similar clinical action

Transcription and translation of the chemokines RANTES and MCP-1 in nasal polyps and mucosa in allergic and non-allergic rhinopathies.

PubMed

Marcella, Reale; Croce, Adelchi; Moretti, Antonio; Barbacane, Renato C; Di Giocchino, Mario; Conti, Pio

2003-12-15

The pathogenetic findings of rhinopathies show an increase in infiltrating cells including eosinophils. RANTES is a beta chemokine in which the cysteines are adjacent (C-C), and it attracts and activates eosinophil. We hypothesize that RANTES is locally produced within the nasal polyp microenvironment and is responsible for the inflammatory cell recruitment present in nasal polyposis. To test this hypothesis, we evaluated nasal polyps and mucosa from allergic and control, non-allergic patients for RANTES content. The relative levels of RANTES and MCP-1 protein in tissue homogenates were quantified using enzyme-linked immunosorbent assay technology, and quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) tests for RANTES and MCP-1 mRNA expression were performed. The results indicate that RANTES expression and production increase in nasal mucosa (septal and turbinate portions) of allergic patients compared to the same mucosa in non-allergic patients. In allergic patients, RANTES levels of nasal polyp homogenates were nearly 12-fold higher than the RANTES levels in mucosa homogenate. In this study, we hypothesize that the particular anatomic structure and physiologic function of the turbinates are more involved in the pathogenesis of rhinitis and may undergo polypoid degeneration in allergic rhinitis than any other anatomical structure of the nose. Our data suggest that RANTES is more involved than MCP-1 in recruiting inflammatory cells in rhinological disease and may reflect the degree of local inflammation as consequence of the specific chemoattractant properties of RANTES. The level of RANTES in nasal polyps could be important in the development of the pathological state.

Effects of hydrogen sulfide on inflammation in caerulein-induced acute pancreatitis

PubMed Central

2009-01-01

Background Hydrogen sulfide (H2S), a gaseous mediator plays an important role in a wide range of physiological and pathological processes. H2S has been extensively studied for its various roles in cardiovascular and neurological disorders. However, the role of H2S in inflammation is still controversial. The current study was aimed to investigate the therapeutic potential of sodium hydrosulfide (NaHS), an H2S donor in in vivo model of acute pancreatitis in mice. Methods Acute pancreatitis was induced in mice by hourly caerulein injections (50 μg/kg) for 10 hours. Mice were treated with different dosages of NaHS (5 mg/kg, 10 mg/kg or 15 mg/kg) or with vehicle, distilled water (DW). NaHS or DW was administered 1 h before induction of pancreatitis. Mice were sacrificed 1 h after the last caerulein injection. Blood, pancreas and lung tissues were collected and were processed to measure the plasma amylase, myeloperoxidase (MPO) activities in pancreas and lung and chemokines and adhesion molecules in pancreas and lung. Results It was revealed that significant reduction of inflammation, both in pancreas and lung was associated with NaHS 10 mg/kg. Further the anti-inflammatory effects of NaHS 10 mg/kg were associated with reduction of pancreatic and pulmonary inflammatory chemokines and adhesion molecules. NaHS 5 mg/kg did not cause significant improvement on inflammation in pancreas and associated lung injury and NaHS 15 mg/kg did not further enhance the beneficial effects seen with NaHS 10 mg/kg. Conclusion In conclusion, these data provide evidence for anti-inflammatory effects of H2S based on its dosage used. PMID:20040116

Valuing the Economic Costs of Allergic Rhinitis, Acute Bronchitis, and Asthma from Exposure to Indoor Dampness and Mold in the US

PubMed Central

2016-01-01

Two foundational methods for estimating the total economic burden of disease are cost of illness (COI) and willingness to pay (WTP). WTP measures the full cost to society, but WTP estimates are difficult to compute and rarely available. COI methods are more often used but less likely to reflect full costs. This paper attempts to estimate the full economic cost (2014$) of illnesses resulting from exposure to dampness and mold using COI methods and WTP where the data is available. A limited sensitivity analysis of alternative methods and assumptions demonstrates a wide potential range of estimates. In the final estimates, the total annual cost to society attributable to dampness and mold is estimated to be $3.7 (2.3–4.7) billion for allergic rhinitis, $1.9 (1.1–2.3) billion for acute bronchitis, $15.1 (9.4–20.6) billion for asthma morbidity, and $1.7 (0.4–4.5) billion for asthma mortality. The corresponding costs from all causes, not limited to dampness and mold, using the same approach would be $24.8 billion for allergic rhinitis, $13.5 billion for acute bronchitis, $94.5 billion for asthma morbidity, and $10.8 billion for asthma mortality. PMID:27313630

Differential Activation of Airway Eosinophils Induces IL-13 Mediated Allergic Th2 Pulmonary Responses in Mice

PubMed Central

Jacobsen, EA; Doyle, AD; Colbert, DC; Zellner, KR; Protheroe, CA; LeSuer, WE; Lee, NA.; Lee, JJ

2015-01-01

Background Eosinophils are hallmark cells of allergic Th2 respiratory inflammation. However, the relative importance of eosinophil activation and the induction of effector functions such as the expression of IL-13 to allergic Th2 pulmonary disease remain to be defined. Methods Wild type or cytokine deficient (IL-13−/− or IL-4−/−) eosinophils treated with cytokines (GM-CSF, IL-4, IL-33) were adoptively transferred into eosinophil-deficient recipient mice subjected to allergen provocation using established models of respiratory inflammation. Allergen-induced pulmonary changes were assessed. Results In contrast to the transfer of untreated blood eosinophils to the lungs of recipient eosinophildeficient mice, which induced no immune/inflammatory changes either in the lung or lung draining lymph nodes (LDLNs), pretreatment of blood eosinophils with GM-CSF prior to transfer elicited trafficking of these eosinophils to LDLNs. In turn, these LDLN eosinophils elicited the accumulation of dendritic cells and CD4+ T cells to these same LDLNs without inducing pulmonary inflammation. However, exposure of eosinophils to GM-CSF, IL-4 and IL-33 prior to transfer induced not only immune events in the LDLN, but also allergen-mediated increases in airway Th2 cytokine/chemokine levels, the subsequent accumulation of CD4+ T cells as well as alternatively activated (M2) macrophages, and the induction of pulmonary histopathologies. Significantly, this allergic respiratory inflammation was dependent on eosinophil-derived IL-13 whereas IL-4 expression by eosinophils had no significant role. Conclusion The data demonstrate the differential activation of eosinophils as a function of cytokine exposure and suggest that eosinophil-specific IL-13 expression by activated cells is a necessary component of the subsequent allergic Th2 pulmonary pathologies. PMID:26009788

Differential activation of airway eosinophils induces IL-13-mediated allergic Th2 pulmonary responses in mice.

PubMed

Jacobsen, E A; Doyle, A D; Colbert, D C; Zellner, K R; Protheroe, C A; LeSuer, W E; Lee, N A; Lee, J J

2015-09-01

Eosinophils are hallmark cells of allergic Th2 respiratory inflammation. However, the relative importance of eosinophil activation and the induction of effector functions such as the expression of IL-13 to allergic Th2 pulmonary disease remain to be defined. Wild-type or cytokine-deficient (IL-13(-/-) or IL-4(-/-) ) eosinophils treated with cytokines (GM-CSF, IL-4, IL-33) were adoptively transferred into eosinophil-deficient recipient mice subjected to allergen provocation using established models of respiratory inflammation. Allergen-induced pulmonary changes were assessed. In contrast to the transfer of untreated blood eosinophils to the lungs of recipient eosinophil deficient mice, which induced no immune/inflammatory changes either in the lung or in the lung draining lymph nodes (LDLN), pretreatment of blood eosinophils with GM-CSF prior to transfer elicited trafficking of these eosinophils to LDLN. In turn, these LDLN eosinophils elicited the accumulation of dendritic cells and CD4(+) T cells to these same LDLNs without inducing pulmonary inflammation. However, exposure of eosinophils to GM-CSF, IL-4, and IL-33 prior to transfer induced not only immune events in the LDLN, but also allergen-mediated increases in airway Th2 cytokine/chemokine levels, the subsequent accumulation of CD4(+) T cells as well as alternatively activated (M2) macrophages, and the induction of pulmonary histopathologies. Significantly, this allergic respiratory inflammation was dependent on eosinophil-derived IL-13, whereas IL-4 expression by eosinophils had no significant role. The data demonstrate the differential activation of eosinophils as a function of cytokine exposure and suggest that eosinophil-specific IL-13 expression by activated cells is a necessary component of the subsequent allergic Th2 pulmonary pathologies. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Acute phase response, inflammation and metabolic syndrome biomarkers of Libby asbestos exposure

DOE Office of Scientific and Technical Information (OSTI.GOV)

Shannahan, Jonathan H.; Alzate, Oscar; Winnik, Witold M.

Identification of biomarkers assists in the diagnosis of disease and the assessment of health risks from environmental exposures. We hypothesized that rats exposed to Libby amphibole (LA) would present with a unique serum proteomic profile which could help elucidate epidemiologically-relevant biomarkers. In four experiments spanning varied protocols and temporality, healthy (Wistar Kyoto, WKY; and F344) and cardiovascular compromised (CVD) rat models (spontaneously hypertensive, SH; and SH heart failure, SHHF) were intratracheally instilled with saline (control) or LA. Serum biomarkers of cancer, inflammation, metabolic syndrome (MetS), and the acute phase response (APR) were analyzed. All rat strains exhibited acute increases inmore » α-2-macroglobulin, and α1-acid glycoprotein. Among markers of inflammation, lipocalin-2 was induced in WKY, SH and SHHF and osteopontin only in WKY after LA exposure. While rat strain- and age-related changes were apparent in MetS biomarkers, no LA effects were evident. The cancer marker mesothelin was increased only slightly at 1 month in WKY in one of the studies. Quantitative Intact Proteomic profiling of WKY serum at 1 day or 4 weeks after 4 weekly LA instillations indicated no oxidative protein modifications, however APR proteins were significantly increased. Those included serine protease inhibitor, apolipoprotein E, α-2-HS-glycoprotein, t-kininogen 1 and 2, ceruloplasmin, vitamin D binding protein, serum amyloid P, and more 1 day after last LA exposure. All changes were reversible after a short recovery regardless of the acute or long-term exposures. Thus, LA exposure induces an APR and systemic inflammatory biomarkers that could have implications in systemic and pulmonary disease in individuals exposed to LA. -- Highlights: ► Biomarkers of asbestos exposure are required for disease diagnosis. ► Libby amphibole exposure is associated with increased human mortality. ► Libby amphibole increases circulating proteins

Anti-Inflammatory Effects of Licorice and Roasted Licorice Extracts on TPA-Induced Acute Inflammation and Collagen-Induced Arthritis in Mice

PubMed Central

Kim, Ki Rim; Jeong, Chan-Kwon; Park, Kwang-Kyun; Choi, Jong-Hoon; Park, Jung Han Yoon; Lim, Soon Sung; Chung, Won-Yoon

2010-01-01

The anti-inflammatory activity of licorice (LE) and roated licorice (rLE) extracts determined in the murine phorbol ester-induced acute inflammation model and collagen-induced arthritis (CIA) model of human rheumatoid arthritis. rLE possessed greater activity than LE in inhibiting phorbol ester-induced ear edema. Oral administration of LE or rLE reduced clinical arthritis score, paw swelling, and histopathological changes in a murine CIA. LE and rLE decreased the levels of proinflammatory cytokines in serum and matrix metalloproteinase-3 expression in the joints. Cell proliferation and cytokine secretion in response to type II collagen or lipopolysaccharide stimulation were suppressed in spleen cells from LE or rLE-treated CIA mice. Furthermore, LE and rLE treatment prevented oxidative damages in liver and kidney tissues of CIA mice. Taken together, LE and rLE have benefits in protecting against both acute inflammation and chronic inflammatory conditions including rheumatoid arthritis. rLE may inhibit the acute inflammation more potently than LE. PMID:20300198

Therapeutic Targeting of Eosinophil Adhesion and Accumulation in Allergic Conjunctivitis

PubMed Central

Baiula, Monica; Bedini, Andrea; Carbonari, Gioia; Dattoli, Samantha Deianira; Spampinato, Santi

2012-01-01

Considerable evidence indicates that eosinophils are important effectors of ocular allergy. Increased worldwide prevalence of allergic eye pathologies has stimulated the identification of novel drug targets, including eosinophils and adhesion molecules. Accumulation of eosinophils in the eye is a key event in the onset and maintenance of allergic inflammation and is mediated by different adhesion molecules. Antihistamines with multiple mechanisms of action can be effective during the early and late phases of allergic conjunctivitis by blocking the interaction between β1 integrins and vascular cell adhesion molecule (VCAM)-1. Small molecule antagonists that target key elements in the process of eosinophil recruitment have been identified and reinforce the validity of α4β1 integrin as a therapeutic target. Glucocorticoids are among the most effective drugs for ocular allergy, but their use is limited by adverse effects. Novel dissociated glucocorticoids can prevent eosinophil accumulation and induce apoptosis of eosinophils, making them promising candidates for ophthalmic drugs. This article reviews recent understanding of the role of adhesion molecules in eosinophil recruitment in the inflamed conjunctiva along with effective treatments for allergic conjunctivitis. PMID:23271999

S-Nitrosoglutathione Reductase Inhibition Regulates Allergen-Induced Lung Inflammation and Airway Hyperreactivity

PubMed Central

Bassett, David J. P.; Bradley, Matthews O.; Jaffar, Zeina

2013-01-01

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. PMID:23936192

Aeroallergens, allergic rhinitis, and sedating antihistamines: risk factors for traumatic occupational injury and economic impact.

PubMed

Hanrahan, L P; Paramore, L C

2003-10-01

The U.S. workplace injury burden is significant. Our objective was to assess the particular impact of aeroallergen, allergic rhinitis, and antihistamine exposures and side effects on the risk of traumatic work-related injuries, and the associated economic impact. This is an observational case-control study with 1,223 acute traumatic injury cases that are compared to 1,202 chronic back injury controls. Structured telephone interviews were conducted in 1998 and 1999 on Workers' Compensation applicants injured in 1997. Antihistamine use and pollen levels were measured 2 weeks prior to the injury date. Sedating antihistamine exposures elevated acute injury risk (main effect OR: 2.93). A significant increase in traumatic injury risk was observed for combined sedating antihistamine and high pollen exposures among subjects with physician and self-diagnosed allergic rhinitis (OR: 2.41). Direct medical costs associated with this increased risk were estimated at $143 million in 2001. Workers with physician-diagnosed allergic rhinitis have as high a reliance on sedating antihistamines as do self-diagnosed and self-medicating nasal allergy sufferers. High pollen exposures along with sedating antihistamine use may confer significant additional injury risks among allergic rhinitis sufferers. Medical management "best practices" of diagnosed allergic rhinitis should include avoidance of sedating antihistamines to minimize acute, traumatic injury risks. Copyright 2003 Wiley-Liss, Inc.

UP-REGULATION OF IL-6, IL-8 AND CCL2 GENE EXPRESSION AFTER ACUTE INFLAMMATION: CORRELATION TO CLINICAL PAIN

PubMed Central

Wang, Xiao-Min; Hamza, May; Wu, Tai-Xia; Dionne, Raymond A.

2012-01-01

Tissue injury initiates a cascade of inflammatory mediators and hyperalgesic substances including prostaglandins, cytokines and chemokines. Using microarray and qRT-PCR gene expression analyses, the present study evaluated changes in gene expression of a cascade of cytokines following acute inflammation and the correlation between the changes in the gene expression level and pain intensity in the oral surgery clinical model of acute inflammation. Tissue injury resulted in a significant up-regulation in the gene expression of Interleukin-6 (IL-6; 63.3-fold), IL-8 (8.1-fold), chemokine (C-C motif) ligand 2 (CCL2; 8.9-fold), chemokine (C-X-C motif) ligand 1 (CXCL1; 30.5-fold), chemokine (C-X-C motif) ligand 2 (CXCL2; 26-fold) and annexin A1 (ANXA1; 12-fold). The up-regulation of IL-6 gene expression was significantly correlated to the up-regulation on the gene expression of IL-8, CCL2, CXCL1 and CXCL2. Interestingly, the tissue injury induced up-regulation of IL-6 gene expression, IL-8 and CCL2 were positively correlated to pain intensity at 3 hours post-surgery, the onset of acute inflammatory pain. However, ketorolac treatment did not have a significant effect on the gene expression of IL-6, IL-8, CCL2, CXCL2 and ANXA1 at the same time point of acute inflammation. These results demonstrate that up-regulation of IL-6, IL-8 and CCL2 gene expression contributes to the development of acute inflammation and inflammatory pain. The lack of effect for ketorolac on the expression of these gene products may be related to the ceiling analgesic effects of non-steroidal anti-inflammatory drugs. PMID:19233564

[Intrasal corticosteriods prescription to allergic rhinoconjunctivitis and rhinosinusitis during pediatric ages].

PubMed

Sacre Hazouri, José Antonio; de la Torre González, Carlos; López González, Ana Luisa; Alvarez Vega, Ricardo

2007-01-01

The different diseases that affect the upper respiratory tract, like allergic rhinitis, rhinoconjunctivitis, and rhinosinusitis have inflammation as their main pathophysiological component. Affects approximately 25% of the adults and 40% of the children. Intranasal corticosteroids (INSs) are considered the most effective treatment for the management of allergic rhinoconjunctivitis. Unlike antihistamines or antileukotrienes, INSs have a more profound effect on nasal congestion and the related sleep disturbance and daytime somnolence resulting from nasal congestion that affect their everyday quality of life. We review INSs mechanism of action, pharmacological properties of the different INSs, their therapeutic use and give our suggestions for their proper use.

Acute hyperglycaemia and inflammation in patients with ST segment elevation myocardial infarction.

PubMed

Terlecki, Michał; Bednarek, Agnieszka; Kawecka-Jaszcz, Kalina; Czarnecka, Danuta; Bryniarski, Leszek

2013-01-01

Acute hyperglycaemia in patients with acute coronary syndromes (ACS) is associated with increased cardiovascular (CV) risk among both diabetic and non-diabetic patients although the mechanisms underlying this association are not clearly understood. Acute hyperglycaemia in patients with ACS may be associated with increased systemic inflammation. Leukocytes are the major cellular mediators of inflammation and their elevated count is associated with higher CV event rate in ACS patients. Thus, it is possible that there is a relationship between acute hyperglycaemia and high leukocyte count and concomitant presence of these two conditions may contribute to increased CV risk among patients with ST segment elevation myocardial infarction (STEMI). To investigate the relationship between acute hyperglycaemia and high leukocyte count and to evaluate its association with outcomes in patients with STEMI. Glucose level and leukocyte count on admission were measured in 246 patients with STEMI admitted in 2004- -2007 to the First Department of Cardiology and Hypertension at the University Hospital in Cracow who were treated with an early invasive management strategy. Patients were divided into two groups, with acute hyperglycaemia (glycaemia on admission ≥ 7.8 mmol/L) and with normoglycaemia (glycaemia on admission < 7.8 mmol/L). Leukocyte count was defined as high when it was greater than or equal to the median in the overall study group. Acute hyperglycaemia was noted in 136 (55.3%) patients. Median leukocyte count on admission in the overall study group was 10.8 × 103/mm3 (interquartile range: 8.5-13.0). Significantly higher in-hospital mortality (11.8% vs. 1.8%, p = 0.0029) and higher rates of cardiogenic shock (10.3% vs. 0.9%, p = 0.0022), Killip class > 1 heart failure (HF; 44.1% vs. 20.0%, p < 0.0001), atrial fibrillation (11.0% vs. 3.6%, p = 0.0308), ventricular fibrillation (5.9% vs. 0.9%, p = 0.0389), repeated percutaneous coronary angioplasty (5.2% vs. 0.0%, p = 0

Emerging drugs for allergic conjunctivitis.

PubMed

Ridolo, Erminia; Montagni, Marcello; Caminati, Marco; Senna, Gianenrico; Incorvaia, Cristoforo; Canonica, Giorgio Walter

2014-06-01

Allergic conjunctivitis (AC) is a very common disease, especially in association with allergic rhinitis but may also occur in isolated presentation. The treatment of AC has long been based on antihistamines, cromones and topical corticosteroids, but none of these drugs completely abolishes the clinical expression of AC. The development of new drugs for AC is analyzed highlighting the recent insights into the pathophysiological mechanisms of the disease. The major aim of development of drugs for AC is to have agents able to prevent the inflammatory effects of the interaction between the allergen and the specific IgE antibodies on mast cell surface. This may be obtained by blocking the effects of histamine (the main mediator of early allergic response) by H1-receptor antagonists, inhibiting the release of soluble factors able to recruit inflammatory cells (that sustain prolonged inflammation) by mast-cell stabilizers, inhibiting the effects of single mediators, inducing tolerance to the allergen by specific immunotherapy or even acting on factors related to activation and differentiation of T lymphocytes such as the toll-like receptors. AC is an underestimated disease for which there is a search of more effective treatments. The availability of the drugs under current evaluation will allow more refined therapeutic strategies to apply according to the characteristics and the clinical severity of AC.

Conserved gene regulation during acute inflammation between zebrafish and mammals

PubMed Central

Forn-Cuní, G.; Varela, M.; Pereiro, P.; Novoa, B.; Figueras, A.

2017-01-01

Zebrafish (Danio rerio), largely used as a model for studying developmental processes, has also emerged as a valuable system for modelling human inflammatory diseases. However, in a context where even mice have been questioned as a valid model for these analysis, a systematic study evaluating the reproducibility of human and mammalian inflammatory diseases in zebrafish is still lacking. In this report, we characterize the transcriptomic regulation to lipopolysaccharide in adult zebrafish kidney, liver, and muscle tissues using microarrays and demonstrate how the zebrafish genomic responses can effectively reproduce the mammalian inflammatory process induced by acute endotoxin stress. We provide evidence that immune signaling pathways and single gene expression is well conserved throughout evolution and that the zebrafish and mammal acute genomic responses after lipopolysaccharide stimulation are highly correlated despite the differential susceptibility between species to that compound. Therefore, we formally confirm that zebrafish inflammatory models are suited to study the basic mechanisms of inflammation in human inflammatory diseases, with great translational impact potential. PMID:28157230

Differences in inflammation and acute phase response but similar genotoxicity in mice following pulmonary exposure to graphene oxide and reduced graphene oxide

PubMed Central

Bengtson, Stefan; Knudsen, Kristina B.; Kyjovska, Zdenka O.; Berthing, Trine; Skaug, Vidar; Levin, Marcus; Koponen, Ismo K.; Shivayogimath, Abhay; Booth, Timothy J.; Alonso, Beatriz; Pesquera, Amaia; Zurutuza, Amaia; Thomsen, Birthe L.; Troelsen, Jesper T.; Jacobsen, Nicklas R.

2017-01-01

We investigated toxicity of 2–3 layered >1 μm sized graphene oxide (GO) and reduced graphene oxide (rGO) in mice following single intratracheal exposure with respect to pulmonary inflammation, acute phase response (biomarker for risk of cardiovascular disease) and genotoxicity. In addition, we assessed exposure levels of particulate matter emitted during production of graphene in a clean room and in a normal industrial environment using chemical vapour deposition. Toxicity was evaluated at day 1, 3, 28 and 90 days (18, 54 and 162 μg/mouse), except for GO exposed mice at day 28 and 90 where only the lowest dose was evaluated. GO induced a strong acute inflammatory response together with a pulmonary (Serum-Amyloid A, Saa3) and hepatic (Saa1) acute phase response. rGO induced less acute, but a constant and prolonged inflammation up to day 90. Lung histopathology showed particle agglomerates at day 90 without signs of fibrosis. In addition, DNA damage in BAL cells was observed across time points and doses for both GO and rGO. In conclusion, pulmonary exposure to GO and rGO induced inflammation, acute phase response and genotoxicity but no fibrosis. PMID:28570647

Attenuation of acute lung inflammation induced by cigarette smoke in CXCR3 knockout mice.

PubMed

Nie, Li; Xiang, Ruolan; Zhou, Weixun; Lu, Bao; Cheng, Deyun; Gao, Jinming

2008-12-16

CD8+ T cells may participate in cigarette smoke (CS) induced-lung inflammation in mice. CXCL10/IP-10 (IFNgamma-inducible protein 10) and CXCL9/Mig (monokine induced by IFN-gamma) are up-regulated in CS-induced lung injury and may attract T-cell recruitment to the lung. These chemokines together with CXCL11/ITAC (IFN-inducible T-cell alpha chemoattractant) are ligands for the chemokine receptor CXCR3 which is preferentially expressed chiefly in activated CD8+ T cells. The purpose of this investigation was to study the contribution of CXCR3 to acute lung inflammation induced by CS using CXCR3 knockout (KO) mice. Mice (n = 8 per group) were placed in a closed plastic box connected to a smoke generator and were exposed whole body to the tobacco smoke of five cigarettes four times a day for three days. Lung pathological changes, expression of inflammatory mediators in bronchoalveolar lavage (BAL) fluid and lungs at mRNA and protein levels, and lung infiltration of CD8+ T cells were compared between CXCR3-/- mice and wild type (WT) mice. Compared with the WT littermates, CXCR3 KO mice showed less CS-induced lung inflammation as evidenced by less infiltration of inflammatory cells in airways and lung tissue, particularly fewer CD8+ T cells, lower levels of IFNgamma and CXCR3 ligands (particularly CXCL10). Our findings show that CXCR3 is important in promoting CD8+ T cell recruitment and in initiating IFNgamma and CXCL10 release following CS exposure. CXCR3 may represent a promising therapeutic target for acute lung inflammation induced by CS.

Attenuation of acute lung inflammation induced by cigarette smoke in CXCR3 knockout mice

PubMed Central

Nie, Li; Xiang, Ruolan; Zhou, Weixun; Lu, Bao; Cheng, Deyun; Gao, Jinming

2008-01-01

Background CD8+ T cells may participate in cigarette smoke (CS) induced-lung inflammation in mice. CXCL10/IP-10 (IFNγ-inducible protein 10) and CXCL9/Mig (monokine induced by IFN-γ) are up-regulated in CS-induced lung injury and may attract T-cell recruitment to the lung. These chemokines together with CXCL11/ITAC (IFN-inducible T-cell alpha chemoattractant) are ligands for the chemokine receptor CXCR3 which is preferentially expressed chiefly in activated CD8+ T cells. The purpose of this investigation was to study the contribution of CXCR3 to acute lung inflammation induced by CS using CXCR3 knockout (KO) mice. Methods Mice (n = 8 per group) were placed in a closed plastic box connected to a smoke generator and were exposed whole body to the tobacco smoke of five cigarettes four times a day for three days. Lung pathological changes, expression of inflammatory mediators in bronchoalveolar lavage (BAL) fluid and lungs at mRNA and protein levels, and lung infiltration of CD8+ T cells were compared between CXCR3-/- mice and wild type (WT) mice. Results Compared with the WT littermates, CXCR3 KO mice showed less CS-induced lung inflammation as evidenced by less infiltration of inflammatory cells in airways and lung tissue, particularly fewer CD8+ T cells, lower levels of IFNγ and CXCR3 ligands (particularly CXCL10). Conclusion Our findings show that CXCR3 is important in promoting CD8+ T cell recruitment and in initiating IFNγ and CXCL10 release following CS exposure. CXCR3 may represent a promising therapeutic target for acute lung inflammation induced by CS. PMID:19087279

Bromelain limits airway inflammation in an ovalbumin-induced murine model of established asthma.

PubMed

Secor, Eric R; Shah, Sonali J; Guernsey, Linda A; Schramm, Craig M; Thrall, Roger S

2012-01-01

Allergic asthma continues to increase despite new pharmacological advances for both acute treatment and chronic-disease management. Asthma is a multifactorial disease process with genetic, allergic, infectious, environmental, and dietary origins. Researchers are investigating the benefits of lifestyle changes and alternative asthma treatments, including the ability of bromelain to inhibit inflammation. Bromelain is a commonly used, proteolytically active pineapple extract. The present study intended to determine the ability of bromelain to reduce the inflammation of preexisting asthma via an ovalbumin (OVA)-induced murine model of allergic airway disease (AAD). The research team designed a study examining the effects of bromelain in a control group of mice that received phosphate buffered saline (PBS) only and in an intervention group that received bromelain in PBS. Setting The study took place in the Department of Immunology at the University of Connecticut's School of Medicine, Farmington. Intervention The research team sensitized female C57BL/6J mice with intraperitoneal OVA/alum and then challenged them with OVA aerosolization for 10 consecutive days. On day 4, the team began administering daily doses of PBS to the control group (n = 10) and bromelain (6mg/kg) in PBS to the bromelain (intervention) group (n = 10). The primary measures included bronchoalveolar lavage (BAL) cellular differential, cellular phenotype via flow cytometry, and lung histology. Additional outcomes included testing for serum cytokines and immunoglobulin. Bromelain treatment of AAD mice (bromelain group) resulted in significant anti-inflammatory activity as indicated by reduced BAL total leukocytes (P < .05), eosinophils (P < .05), and cellular infiltrates via lung pathology (P < .005), as compared to the control group. In addition, bromelain significantly reduced BAL CD4+ and CD8+ T cells without affecting cell numbers in the spleen or hilar lymph node. The study found decreased

Mast Cells Regulate Epidermal Barrier Function and the Development of Allergic Skin Inflammation.

PubMed

Sehra, Sarita; Serezani, Ana P M; Ocaña, Jesus A; Travers, Jeffrey B; Kaplan, Mark H

2016-07-01

Atopic dermatitis is a chronic inflammatory skin disease characterized by infiltration of eosinophils, T helper cells, and mast cells. The role of mast cells in atopic dermatitis is not completely understood. To define the effects of mast cells on skin biology, we observed that mast cells regulate the homeostatic expression of epidermal differentiation complex and other skin genes. Decreased epidermal differentiation complex gene expression in mice that genetically lack mast cells (Kit(W-sh/W-sh) mice) is associated with increased uptake of protein antigens painted on the skin by dendritic cells (DCs) compared with similarly treated wild-type mice, suggesting a protective role for mast cells in exposure to nominal environmental allergens. To test this further, we crossed Kit(W-sh/W-sh) mice with signal transducer and activator of transcription 6 (i.e., Stat6) VT transgenic mice that develop spontaneous atopic dermatitis-like disease that is dependent on T helper cell 2 cytokines and is associated with high serum concentrations of IgE. We observed that Stat6VT × Kit(W-sh/W-sh) mice developed more frequent and more severe allergic skin inflammation than Stat6VT transgenic mice that had mast cells. Together, these studies suggest that mast cells regulate epidermal barrier function and have a potential protective role in the development of atopic dermatitis-like disease. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Reversal of acute and chronic synovial inflammation by anti-transforming growth factor beta.

PubMed

Wahl, S M; Allen, J B; Costa, G L; Wong, H L; Dasch, J R

1993-01-01

Transforming growth factor beta (TGF-beta) induces leukocyte recruitment and activation, events central to an inflammatory response. In this study, we demonstrate that antagonism of TGF-beta with a neutralizing antibody not only blocks inflammatory cell accumulation, but also tissue pathology in an experimental model of chronic erosive polyarthritis. Intraarticular injection of monoclonal antibody 1D11.16, which inhibits both TGF-beta 1 and TGF-beta 2 bioactivity, into animals receiving an arthropathic dose of bacterial cell walls significantly inhibits arthritis. Inhibition was observed with a single injection of 50 micrograms antibody, and a 1-mg injection blocked acute inflammation > 75% compared with the contralateral joints injected with an irrelevant isotype control antibody (MOPC21) as quantitated by an articular index (AI = 0.93 +/- 0.23 for 1D11.16, and AI = 4.0 +/- 0 on day 4; p < 0.001). Moreover, suppression of the acute arthritis achieved with a single injection of antibody was sustained into the chronic, destructive phase of the disease (on day 18, AI = 0.93 +/- 0.07 vs. AI = 2.6 +/- 0.5; p < 0.01). The decreased inflammatory index associated with anti-TGF-beta treatment was consistent with histopathologic and radiologic evidence of a therapeutic response. These data implicate TGF-beta as a profound agonist not only in the early events responsible for synovial inflammation, but also in the chronicity of streptococcal cell wall fragment-induced inflammation culminating in destructive pathology. Interrupting the cycle of leukocyte recruitment and activation with TGF-beta antagonists may provide a mechanism for resolution of chronic destructive lesions.

Reversal of acute and chronic synovial inflammation by anti- transforming growth factor beta

PubMed Central

1993-01-01

Transforming growth factor beta (TGF-beta) induces leukocyte recruitment and activation, events central to an inflammatory response. In this study, we demonstrate that antagonism of TGF-beta with a neutralizing antibody not only blocks inflammatory cell accumulation, but also tissue pathology in an experimental model of chronic erosive polyarthritis. Intraarticular injection of monoclonal antibody 1D11.16, which inhibits both TGF-beta 1 and TGF-beta 2 bioactivity, into animals receiving an arthropathic dose of bacterial cell walls significantly inhibits arthritis. Inhibition was observed with a single injection of 50 micrograms antibody, and a 1-mg injection blocked acute inflammation > 75% compared with the contralateral joints injected with an irrelevant isotype control antibody (MOPC21) as quantitated by an articular index (AI = 0.93 +/- 0.23 for 1D11.16, and AI = 4.0 +/- 0 on day 4; p < 0.001). Moreover, suppression of the acute arthritis achieved with a single injection of antibody was sustained into the chronic, destructive phase of the disease (on day 18, AI = 0.93 +/- 0.07 vs. AI = 2.6 +/- 0.5; p < 0.01). The decreased inflammatory index associated with anti-TGF-beta treatment was consistent with histopathologic and radiologic evidence of a therapeutic response. These data implicate TGF-beta as a profound agonist not only in the early events responsible for synovial inflammation, but also in the chronicity of streptococcal cell wall fragment-induced inflammation culminating in destructive pathology. Interrupting the cycle of leukocyte recruitment and activation with TGF-beta antagonists may provide a mechanism for resolution of chronic destructive lesions. PMID:8418203

Obese and Allergic Related Asthma Phenotypes Among Children Across the United States.

PubMed

Ross, Mindy K; Romero, Tahmineh; Sim, Myung S; Szilagyi, Peter G

2018-04-19

Pediatric asthma is heterogeneous with phenotypes that reflect differing underlying inflammation and pathophysiology. Little is known about the national prevalence of certain obesity and allergy related asthma phenotypes or associated characteristics. We therefore assessed the national prevalence, risk factors, and parent-reported severity of four asthma phenotypes: not-allergic-not-obese, allergic-not-obese, obese-not-allergic, and allergic-and-obese. We analyzed data from the 2007-2008 National Survey of Children's Health (NSCH) of 10-17 year-olds with parent-reported asthma. We described sociodemographic and health risk factors of each phenotype and then applied logistic and ordinal regression models to identify associated risk factors and level of severity of the phenotypes. Among 4,427 children with asthma in this NSCH cohort, the association between race and phenotype is statistically significant (p<0.0001); white children with asthma were most likely to have allergic-not-obese asthma while black and Hispanic children with asthma were most likely to have the obese-non-allergic phenotype (p<0.001). ADD/ADHD was more likely to be present in allergic-not-obese children (OR 1.50, CI 1.14-1.98, p = 0.004). The phenotype with the highest risk for more severe compared to mild asthma was the obese-and-allergic asthma phenotype (OR 3.34, CI 2.23-5.01, p<0.001). Allergic-not-obese asthma comprised half of our studied asthma phenotypes, while obesity-related asthma (with or without allergic components) comprised one-fifth of asthma phenotypes in this cohort representative of the U.S. Children with both obese and allergic asthma are most likely to have severe asthma. Future management of childhood asthma might consider more tailoring of treatment and management plans based upon different childhood asthma phenotypes.

Helminth-induced regulatory T cells and suppression of allergic responses.

PubMed

Logan, Jayden; Navarro, Severine; Loukas, Alex; Giacomin, Paul

2018-05-28

Infection with helminths has been associated with lower rates of asthma and other allergic diseases. This has been attributed, in part, to the ability of helminths to induce regulatory T cells that suppress inappropriate immune responses to allergens. Recent compelling evidence suggests that helminths may promote regulatory T cell expansion or effector functions through either direct (secretion of excretory/secretory molecules) or indirect mechanisms (regulation of the microbiome). This review will discuss key findings from human immunoepidemiological observations, studies using animal models of disease, and clinical trials with live worm infections, discussing the therapeutic potential for worms and their secreted products for treating allergic inflammation. Crown Copyright © 2018. Published by Elsevier Ltd. All rights reserved.

The role of leukotrienes in airway inflammation.

PubMed

Ogawa, Yoshiko; Calhoun, William J

2006-10-01

Cysteinyl leukotrienes (cysLTs) are a class of closely structurally related lipid molecules, originally described as slow-reacting substance of anaphylaxis, with a myriad of biologic functions. These activities include producing smooth muscle contraction and mucus secretion, recruiting allergic inflammatory cells, modulating cytokine production, influencing neural transmission, and altering structural changes in the airway. Administration of cysLTs to animals and human subjects reproduces many features of allergic inflammation and asthma. Leukotriene (LT) blockers have independent efficacy in asthma and improve pulmonary function when added to inhaled steroids. Conversely, blockade of this pathway both in animals and in human subjects results in important reductions in inflammation and its consequences and might reduce structural changes of remodeling. These data collectively make a compelling case for an important role of cysLTs in airway inflammation and asthma. However, the magnitude of effect of anti-LTs is smaller than that of corticosteroids, and there is more variability in benefit of LT blockade than is seen with inhaled steroids. In addition, adding anti-LTs to inhaled steroids in asthmatic patients does not appear to produce added anti-inflammatory benefit. Genetic polymorphisms and environmental factors, such as tobacco smoke exposure, might underlie some of the heterogeneity of response to LT blockers.

ASEPTIC INFLAMMATION IN THE LUNGS IN ACUTE RADIATION SICKNESS

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ivanov, A.E.

1963-09-01

Inflammation in the lungs of irradiated rabbits at the site of turpentine injection has much in common with the inflammatory changes arising in other tissues and organs during local irradiation or acute radiation sickness. The fact that the inflammatory changes under different conditions of irradiation are similar in type regardless of the character of the inflammatory agent suggests that the phenomenon has a common mechanism. The absence of polymorphonuclear (eosinophtlic) leukocytes from inflammatory foci in irradiated rabbits is due not only to the developing leukopenia, but also to a disturbance of the leukocyte emigration process into the inflammatory focus. Inmore » irradiated rabbits in cortrast to the controls, the normal arrangement of the fibrous structures is preserved in the necrotic lung tissue at the site of turpentine injection. In animals with severe acute radiation sickness induced by external irradiation in sublethal doses, the ability of the organism to respond to introduction of an inflammatory agent by an increase in the number of leukocytes in the blood and by a rise of the body temperature is to some extent preserved. (auth)« less

The plant extract Isatis tinctoria L. extract (ITE) inhibits allergen-induced airway inflammation and hyperreactivity in mice.

PubMed

Brattström, A; Schapowal, A; Kamal, M A; Maillet, I; Ryffel, B; Moser, R

2010-07-01

The herbal Isatis tinctoria extract (ITE) inhibits the inducible isoform of cyclooxygenase (COX-2) as well as lipoxygenase (5-LOX) and therefore possesses anti-inflammatory properties. The extract might also be useful in allergic airway diseases which are characterized by chronic inflammation. ITE obtained from leaves by supercritical carbon dioxide extraction was investigated in ovalbumin (OVA) immunised BALB/c mice given intranasally together with antigen challenge in the murine model of allergic airway disease (asthma) with the analysis of the inflammatory and immune parameters in the lung. ITE given with the antigen challenge inhibited in a dose related manner the allergic response. ITE diminished airway hyperresponsiveness (AHR) and eosinophil recruitment into the bronchoalveolar lavage (BAL) fluid upon allergen challenge, but had no effect in the saline control mice. Eosinophil recruitment was further assessed in the lung by eosinophil peroxidase (EPO) activity at a dose of 30 microg ITE per mouse. Microscopic investigations revealed less inflammation, eosinophil recruitment and mucus hyperproduction in the lung in a dose related manner. Diminution of AHR and inflammation was associated with reduced IL-4, IL-5, and RANTES production in the BAL fluid at the 30 microg ITE dose, while OVA specific IgE and eotaxin serum levels remained unchanged. ITE, which has been reported inhibiting COX-2 and 5-LOX, reduced allergic airway inflammation and AHR by inhibiting the production of the Th2 cytokines IL-4 and IL-5, and RANTES. (c) 2009 Elsevier GmbH. All rights reserved.

Mast cells and histamine are triggering the NF-κB-mediated reactions of adult and aged perilymphatic mesenteric tissues to acute inflammation

PubMed Central

Nizamutdinova, Irina Tsoy; Dusio, Giuseppina F.; Gasheva, Olga Yu.; Skoog, Hunter; Tobin, Richard; Peddaboina, Chander; Meininger, Cynthia J.; Zawieja, David C.; Newell-Rogers, M. Karen; Gashev, Anatoliy A.

2016-01-01

This study aimed to establish mechanistic links between the aging-associated changes in the functional status of mast cells and the altered responses of mesenteric tissue and mesenteric lymphatic vessels (MLVs) to acute inflammation. We used an in vivo model of acute peritoneal inflammation induced by lipopolysaccharide treatment of adult (9-month) and aged (24-month) F-344 rats. We analyzed contractility of isolated MLVs, mast cell activation, activation of nuclear factor-κB (NF-κB) without and with stabilization of mast cells by cromolyn or blockade of all types of histamine receptors and production of 27 major pro-inflammatory cytokines in adult and aged perilymphatic mesenteric tissues and blood. We found that the reactivity of aged contracting lymphatic vessels to LPS-induced acute inflammation was abolished and that activated mast cells trigger NF-κB signaling in the mesentery through release of histamine. The aging-associated basal activation of mesenteric mast cells limits acute inflammatory NF-κB activation in aged mesentery. We conclude that proper functioning of the mast cell/histamine/NF-κB axis is necessary for reactions of the lymphatic vessels to acute inflammatory stimuli as well as for interaction and trafficking of immune cells near and within the collecting lymphatics. PMID:27875806

Melatonin attenuates inflammation of acute pulpitis subjected to dental pulp injury

PubMed Central

Li, Ji-Guo; Lin, Jia-Ji; Wang, Zhao-Ling; Cai, Wen-Ke; Wang, Pei-Na; Jia, Qian; Zhang, An-Sheng; Wu, Gao-Yi; Zhu, Guo-Xiong; Ni, Long-Xing

2015-01-01

Acute pulpitis (AP), one of the most common diseases in the endodontics, usually causes severe pain to the patients, which makes the search for therapeutic target of AP essential in clinic. Toll-like receptor 4 (TLR4) signaling is widely involved in the mechanism of pulp inflammation, while melatonin has been reported to have an inhibition for a various kinds of inflammation. We hereby studied whether melatonin can regulate the expression of TLR4/NF-ĸB signaling in the pulp tissue of AP and in human dental pulp cells (HDPCs). Two left dental pulps of the adult rat were drilled open to establish the AP model, and the serum levels of melatonin and pro-inflammatory cytokines, including interleukin 1β (IL-1β), interleukin 18 (IL-18) and tumor necrosis factor α (TNF-α), were assessed at 1, 3 and 5 d post injury. At the same time points, the expression of TLR4 signaling in the pulp was explored by quantitative real-time PCR and immunohistochemistry. The AP rats were administered an abdominal injection of melatonin to assess whether melatonin rescued AP and TLR4/NF-ĸB signaling. Dental pulp injury led to an approximately five-day period acute pulp inflammation and necrosis in the pulp and a significant up-regulation of IL-1β, IL-18 and TNF-α in the serum. ELISA results showed that the level of melatonin in the serum decreased due to AP, while an abdominal injection of melatonin suppressed the increase in serum cytokines and the percentage of necrosis at the 5 d of the injured pulp. Consistent with the inflammation in AP rats, TLR4, NF-ĸB, TNF-α and IL-1β in the pulp were increased post AP compared with the baseline expression. And melatonin showed an inhibition on TLR4/NF-ĸB signaling as well as IL-1β and TNF-α production in the pulp of AP rats. Furthermore, melatonin could also regulate the expression of TLR4/NF-ĸB signaling in LPS-stimulated HDPCs. These data suggested that dental pulp injury induced AP and reduced the serum level of melatonin and that

Association of rheumatoid arthritis with allergic diseases: A nationwide population-based cohort study.

PubMed

Lai, Ning-Sheng; Tsai, Tzung-Yi; Koo, Malcolm; Lu, Ming-Chi

2015-01-01

Low-grade inflammation conditions, e.g., type 2 diabetes, have been shown to be associated with an increased risk of rheumatoid arthritis (RA). However, the association between other chronic inflammatory conditions, e.g., asthma, allergic rhinitis, and atopic dermatitis, is still unclear. To investigate the risk of RA in patients with allergic diseases, including asthma, allergic rhinitis, and atopic dermatitis, by using a nationwide health claims database. The Taiwan National Health Insurance Research Database was used to assemble a cohort of 170,570 patients ages 20 years old and older diagnosed with allergic diseases, including asthma, allergic rhinitis, or atopic dermatitis. A comparison cohort of 170,238 patients was constructed from the same data base, with frequency matching for sex, 10-year age group, and year of insurance enrollment. Cox proportional hazards regression analyses were conducted to assess the association between the allergic diseases and incident RA. Asthma (adjusted hazard ratio [AHR] 1.67, [95% confidence interval {CI}], 1.32-2.62) and allergic rhinitis (AHR 1.62 [95% CI, 1.33-1.98]) were significantly associated with the incident RA. These associations remained significant even after excluding patients who had concurrent diagnoses of asthma and allergic rhinitis. Patients with more than one allergic disease had an increased risk of developing RA (AHR 1.98 [95% CI, 1.50-2.62]). Subgroup analysis further indicated that middle-aged and elderly female patients with more than one allergic disease exhibited a high risk of developing RA. Significant associations between common allergic diseases and incident RA was found in this population-based cohort study. Our findings provided support to the hypothesis that allergic diseases and RA might share a similar underlying etiologic pathway related to chronic inflammatory responses.

Cannabidiol improves lung function and inflammation in mice submitted to LPS-induced acute lung injury.

PubMed

Ribeiro, A; Almeida, V I; Costola-de-Souza, C; Ferraz-de-Paula, V; Pinheiro, M L; Vitoretti, L B; Gimenes-Junior, J A; Akamine, A T; Crippa, J A; Tavares-de-Lima, W; Palermo-Neto, J

2015-02-01

We have previously shown that the prophylactic treatment with cannabidiol (CBD) reduces inflammation in a model of acute lung injury (ALI). In this work we analyzed the effects of the therapeutic treatment with CBD in mice subjected to the model of lipopolysaccharide (LPS)-induced ALI on pulmonary mechanics and inflammation. CBD (20 and 80 mg/kg) was administered (i.p.) to mice 6 h after LPS-induced lung inflammation. One day (24 h) after the induction of inflammation the assessment of pulmonary mechanics and inflammation were analyzed. The results show that CBD decreased total lung resistance and elastance, leukocyte migration into the lungs, myeloperoxidase activity in the lung tissue, protein concentration and production of pro-inflammatory cytokines (TNF and IL-6) and chemokines (MCP-1 and MIP-2) in the bronchoalveolar lavage supernatant. Thus, we conclude that CBD administered therapeutically, i.e. during an ongoing inflammatory process, has a potent anti-inflammatory effect and also improves the lung function in mice submitted to LPS-induced ALI. Therefore the present and previous data suggest that in the future cannabidiol might become a useful therapeutic tool for the attenuation and treatment of inflammatory lung diseases.

Eosinophils contribute to the resolution of lung-allergic responses following repeated allergen challenge.

PubMed

Takeda, Katsuyuki; Shiraishi, Yoshiki; Ashino, Shigeru; Han, Junyan; Jia, Yi; Wang, Meiqin; Lee, Nancy A; Lee, James J; Gelfand, Erwin W

2015-02-01

Eosinophils accumulate at the site of allergic inflammation and are critical effector cells in allergic diseases. Recent studies have also suggested a role for eosinophils in the resolution of inflammation. To determine the role of eosinophils in the resolution phase of the response to repeated allergen challenge. Eosinophil-deficient (PHIL) and wild-type (WT) littermates were sensitized and challenged to ovalbumin (OVA) 7 or 11 times. Airway inflammation, airway hyperresponsiveness (AHR) to inhaled methacholine, bronchoalveolar lavage (BAL) cytokine levels, and lung histology were monitored. Intracellular cytokine levels in BAL leukocytes were analyzed by flow cytometry. Groups of OVA-sensitized PHIL mice received bone marrow from WT or IL-10(-/-) donors 30 days before the OVA challenge. PHIL and WT mice developed similar levels of AHR and numbers of leukocytes and cytokine levels in BAL fluid after OVA sensitization and 7 airway challenges; no eosinophils were detected in the PHIL mice. Unlike WT mice, sensitized PHIL mice maintained AHR, lung inflammation, and increased levels of IL-4, IL-5, and IL-13 in BAL fluid after 11 challenges whereas IL-10 and TGF-β levels were decreased. Restoration of eosinophil numbers after injection of bone marrow from WT but not IL-10-deficient mice restored levels of IL-10 and TGF-β in BAL fluid as well as suppressed AHR and inflammation. Intracellular staining of BAL leukocytes revealed the capacity of eosinophils to produce IL-10. After repeated allergen challenge, eosinophils appeared not essential for the development of AHR and lung inflammation but contributed to the resolution of AHR and inflammation by producing IL-10. Copyright © 2014 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Fecal markers of inflammation, protein loss, and microbial changes in dogs with the acute hemorrhagic diarrhea syndrome (AHDS).

PubMed

Heilmann, Romy M; Guard, Melissa M; Steiner, Jörg M; Suchodolski, Jan S; Unterer, Stefan

2017-09-01

Idiopathic acute hemorrhagic diarrhea syndrome (AHDS) is characterized by acute onset of bloody diarrhea, severe dehydration, and increased vascular and intestinal mucosal permeability. Markers of gastrointestinal inflammation, protein loss, and changes in the intestinal microbiota have not been studied extensively in dogs with AHDS. For 3 consecutive days, feces were collected from dogs with AHDS, and assayed for calprotectin and S100A12 (both markers of inflammation), α 1 -proteinase inhibitor (a marker of gastrointestinal protein loss), and the presence of selected species of bacteria. Concentrations of all assayed markers were significantly greater than the institutional reference intervals at the time of presentation, and all decreased significantly by Day 3 of treatment. Abundances of selected bacterial groups (Ruminococcaceae, Faecalibacterium spp., Bifidobacterium spp., and Proteobacteria) at the time of diagnosis were consistent with an intestinal bacterial dysbiosis. No differences in the abundance of bacterial groups over time was seen, except for a mild but significant decrease in Ruminococcaceae at Day 3. These results suggest that canine AHDS is associated with a significant but transient gastrointestinal loss of protein and intestinal inflammation. The intestinal bacterial dysbiosis appears to outlast the protein loss and inflammation. © Veterinary Emergency and Critical Care Society 2017.

Exposure to particulate hexavalent chromium exacerbates allergic asthma pathology

DOE Office of Scientific and Technical Information (OSTI.GOV)

Schneider, Brent C.; Department of Pharmacology and Physiology, The George Washington University, Washington, DC 20037; Constant, Stephanie L.

Airborne hexavalent chromate, Cr(VI), has been identified by the Environmental Protection Agency as a possible health threat in urban areas, due to the carcinogenic potential of some of its forms. Particulate chromates are produced in many different industrial settings, with high levels of aerosolized forms historically documented. Along with an increased risk of lung cancer, a high incidence of allergic asthma has been reported in workers exposed to certain inhaled particulate Cr(VI) compounds. However, a direct causal association between Cr(VI) and allergic asthma has not been established. We recently showed that inhaled particulate Cr(VI) induces an innate neutrophilic inflammatory responsemore » in BALB/c mice. In the current studies we investigated how the inflammation induced by inhaled particulate Cr(VI) might alter the pathology of an allergic asthmatic response. We used a well-established mouse model of allergic asthma. Groups of ovalbumin protein (OVA)-primed mice were challenged either with OVA alone, or with a combination of OVA and particulate zinc chromate, and various parameters associated with asthmatic responses were measured. Co-exposure to particulate Cr(VI) and OVA mediated a mixed form of asthma in which both eosinophils and neutrophils are present in airways, tissue pathology is markedly exacerbated, and airway hyperresponsiveness is significantly increased. Taken together these findings suggest that inhalation of particulate forms of Cr(VI) may augment the severity of ongoing allergic asthma, as well as alter its phenotype. Such findings may have implications for asthmatics in settings in which airborne particulate Cr(VI) compounds are present at high levels. -- Highlights: ► Allergic asthma correlated with exposure to certain inhaled particulate chromates. ► Direct causal association between Cr(VI) and allergic asthma not established. ► Cr exacerbated pathology and airway hyperresponsiveness in an OVA-challenged mouse. �

Mangifera indica L. extract (Vimang) and mangiferin reduce the airway inflammation and Th2 cytokines in murine model of allergic asthma.

PubMed

Rivera, Dagmar García; Hernández, Ivones; Merino, Nelson; Luque, Yilian; Álvarez, Alina; Martín, Yanet; Amador, Aylin; Nuevas, Lauro; Delgado, René

2011-10-01

The aim was to study the effects of Mangifera indica extract and its major component mangiferin on lung inflammation response and Th2 cytokine production using a murine experimental model of allergic asthma. BALB/c mice were intraperitoneally sensitized with 10 µg of ovoalbumin (OVA) adsorbed on aluminium hydroxide on days 0, 7 and 14. Seven days after the last injection, the mice were challenged with 2% aerosolized OVA inhalation for 30 min beginning on day 21 and continuing until day 24. To evaluate the protective effect, mice were orally treated with M. indica extract (50, 100 or 250 mg/kg) or mangiferin (50 mg/kg) from days 0 to 24. Anti-OVA immunoglobulin E, interleukin (IL)-4 and IL-5 were determined by ELISA and lungs were analysed by histology. M. indica extract and mangiferin produced a marked reduction of airway inflammation around vessels and bronchi, inhibition of IL-4 and IL-5 cytokines in bronchoalveolar lavage fluid and lymphocyte culture supernatant, IgE levels and lymphocyte proliferation. This is the first pre-clinical report of the anti-inflammatory properties of M. indica extract and mangiferin in experimental asthma and it could be an important part of pre-clinical requirement necessary for its use to complement the treatment of this complex disease. © 2011 The Authors. JPP © 2011 Royal Pharmaceutical Society.

Acute inflammation induces segmental, bilateral, supraspinally mediated opioid release in the rat spinal cord, as measured by μ-opioid receptor internalization

PubMed Central

Chen, Wenling; Marvizón, Juan Carlos G.

2009-01-01

The objective of this study was to measure opioid release in the spinal cord during acute and long-term inflammation using μ-opioid receptor (MOR) internalization. In particular, we determined whether opioid release occurs in the segments receiving the noxious signals or in the entire spinal cord, and whether it involves supraspinal signals. Internalization of neurokinin 1 receptors (NK1Rs) was measured to track the intensity of the noxious stimulus. Rats received peptidase inhibitors intrathecally to protect opioids from degradation. Acute inflammation of the hindpaw with formalin induced moderate MOR internalization in the L5 segment bilaterally, whereas NK1R internalization occurred only ipsilaterally. MOR internalization was restricted to the lumbar spinal cord, regardless of whether the peptidase inhibitors were injected in a lumbar or thoracic site. Formalin-induced MOR internalization was substantially reduced by isoflurane anesthesia. It was also markedly reduced by a lidocaine block of the cervical-thoracic spinal cord (which did not affect the evoked NK1R internalization) indicating that spinal opioid release is mediated supraspinally. In the absence of peptidase inhibitors, formalin and hindpaw clamp induced a small amount of MOR internalization, which was significantly higher than in controls. To study spinal opioid release during chronic inflammation, we injected Complete Freund's Adjuvant (CFA) in the hindpaw and peptidase inhibitors intrathecally. Two days later, no MOR or NK1R internalization was detected. Furthermore, CFA inflammation decreased MOR internalization induced by clamping the inflamed hindpaw. These results show that acute inflammation, but not chronic inflammation, induce segmental opioid release in the spinal cord that involves supraspinal signals. PMID:19298846

Acute inflammation induces segmental, bilateral, supraspinally mediated opioid release in the rat spinal cord, as measured by mu-opioid receptor internalization.

PubMed

Chen, W; Marvizón, J C G

2009-06-16

The objective of this study was to measure opioid release in the spinal cord during acute and long-term inflammation using mu-opioid receptor (MOR) internalization. In particular, we determined whether opioid release occurs in the segments receiving the noxious signals or in the entire spinal cord, and whether it involves supraspinal signals. Internalization of neurokinin 1 receptors (NK1Rs) was measured to track the intensity of the noxious stimulus. Rats received peptidase inhibitors intrathecally to protect opioids from degradation. Acute inflammation of the hind paw with formalin induced moderate MOR internalization in the L5 segment bilaterally, whereas NK1R internalization occurred only ipsilaterally. MOR internalization was restricted to the lumbar spinal cord, regardless of whether the peptidase inhibitors were injected in a lumbar or thoracic site. Formalin-induced MOR internalization was substantially reduced by isoflurane anesthesia. It was also markedly reduced by a lidocaine block of the cervical-thoracic spinal cord (which did not affect the evoked NK1R internalization) indicating that spinal opioid release is mediated supraspinally. In the absence of peptidase inhibitors, formalin and hind paw clamp induced a small amount of MOR internalization, which was significantly higher than in controls. To study spinal opioid release during chronic inflammation, we injected complete Freund's adjuvant (CFA) in the hind paw and peptidase inhibitors intrathecally. Two days later, no MOR or NK1R internalization was detected. Furthermore, CFA inflammation decreased MOR internalization induced by clamping the inflamed hind paw. These results show that acute inflammation, but not chronic inflammation, induces segmental opioid release in the spinal cord that involves supraspinal signals.

DIESEL PARTICLE INSTILLATION ENHANCES INFLAMMATORY AND NEUROTROPHIN RESPONSES IN THE LUNGS OF ALLERGIC BALB/C MICE

EPA Science Inventory

Neurotrophins, including nerve growth factor (NGF) partially mediate many features of allergic airways disease including airways resistance and inflammation. Antibody blockade of NGF attenuates airways resistance associated with the allergen-specific airways responses in mice. ...

Budesonide suppresses pulmonary antibacterial host defense by down-regulating cathelicidin-related antimicrobial peptide in allergic inflammation mice and in lung epithelial cells

PubMed Central

2013-01-01

Background Glucocorticoids are widely regarded as the most effective treatment for asthma. However, the direct impact of glucocorticoids on the innate immune system and antibacterial host defense during asthma remain unclear. Understanding the mechanisms underlying this process is critical to the clinical application of glucocorticoids for asthma therapy. After sensitization and challenge with ovalbumin (OVA), BALB/c mice were treated with inhaled budesonide and infected with Pseudomonas aeruginosa (P. aeruginosa). The number of viable bacteria in enflamed lungs was evaluated, and levels of interleukin-4 (IL-4) and interferon-γ (IFN-γ) in serum were measured. A lung epithelial cell line was pretreated with budesonide. Levels of cathelicidin-related antimicrobial peptide (CRAMP) were measured by immunohistochemistry and western blot analysis. Intracellular bacteria were observed in lung epithelial cells. Results Inhaled budesonide enhanced lung infection in allergic mice exposed to P. aeruginosa and increased the number of viable bacteria in lung tissue. Higher levels of IL-4 and lower levels of IFN-γ were observed in the serum. Budesonide decreased the expression of CRAMP, increased the number of internalized P. aeruginosa in OVA-challenged mice and in lung epithelial cell lines. These data indicate that inhaled budesonide can suppress pulmonary antibacterial host defense by down-regulating CRAMP in allergic inflammation mice and in cells in vitro. Conclusions Inhaled budesonide suppressed pulmonary antibacterial host defense in an asthmatic mouse model and in lung epithelium cells in vitro. This effect was dependent on the down-regulation of CRAMP. PMID:23387852

Compartmental and temporal dynamics of chronic inflammation and airway remodelling in a chronic asthma mouse model.

PubMed

Alrifai, Mohammed; Marsh, Leigh M; Dicke, Tanja; Kılıç, Ayse; Conrad, Melanie L; Renz, Harald; Garn, Holger

2014-01-01

Allergic asthma is associated with chronic airway inflammation and progressive airway remodelling. However, the dynamics of the development of these features and their spontaneous and pharmacological reversibility are still poorly understood. We have therefore investigated the dynamics of airway remodelling and repair in an experimental asthma model and studied how pharmacological intervention affects these processes. Using BALB/c mice, the kinetics of chronic asthma progression and resolution were characterised in absence and presence of inhaled corticosteroid (ICS) treatment. Airway inflammation and remodelling was assessed by the analysis of bronchoalveolar and peribronichal inflammatory cell infiltrate, goblet cell hyperplasia, collagen deposition and smooth muscle thickening. Chronic allergen exposure resulted in early (goblet cell hyperplasia) and late remodelling (collagen deposition and smooth muscle thickening). After four weeks of allergen cessation eosinophilic inflammation, goblet cell hyperplasia and collagen deposition were resolved, full resolution of lymphocyte inflammation and smooth muscle thickening was only observed after eight weeks. ICS therapy when started before the full establishment of chronic asthma reduced the development of lung inflammation, decreased goblet cell hyperplasia and collagen deposition, but did not affect smooth muscle thickening. These effects of ICS on airway remodelling were maintained for a further four weeks even when therapy was discontinued. Utilising a chronic model of experimental asthma we have shown that repeated allergen exposure induces reversible airway remodelling and inflammation in mice. Therapeutic intervention with ICS was partially effective in inhibiting the transition from acute to chronic asthma by reducing airway inflammation and remodelling but was ineffective in preventing smooth muscle hypertrophy.

Allergic rhinitis: continuous or on demand antihistamine therapy?

PubMed

Montoro, J; Sastre, J; Jáuregui, I; Bartra, J; Dávila, I; del Cuvillo, A; Ferrer, M; Mullol, J; Valero, A

2007-01-01

Allergic rhinitis is an inflammatory disease of the nasal mucosa, caused by an IgE-mediated reaction after exposure to the allergen to which the patient is sensitized. Histamine is the most important preformed mediator released in the early stage of the allergic reaction, and also contributes to the late phase of the latter, exhibiting proinflammatory effects. Minimal persistent inflammation is a physiopathological phenomenon induced by the presence of an inflammatory cell infiltrate, together with ICAM-1 expression in the epithelial cells of the mucosa exposed to the allergen to which they are sensitized, in the absence of clinical symptoms. This molecule is considered to be an allergic inflammatory marker. The priming effect first described by Connell in 1968 consists of the reduction in the allergen concentration required to elicit a nasal hyper-response when performing a daily nasal exposure test. This implies that with natural exposure to inhaled allergens, small amounts of environmental allergen will maintain the patient symptoms, and thus of course minimal persistent inflammation. Considering the above, it is questionable whether antihistamines should be administered on a continuous basis or upon demand. The antihistamines, and fundamentally the second-generation drugs, have been shown to exert an antiinflammatory effect, and this effect is greater when the drug is administered continuously than when administered upon demand. Likewise, a reduction in treatment cost and an improvement in quality of life among patients treated on a continuous basis has been documented. However, no studies have been specifically designed to clarify the indication of treatment on a continuous basis or upon demand, as occurs in the GINA. As a result, the individualization of treatment according to the concrete characteristics of each patient seems to be the best approach, at least for the time being.

Black-spot poison ivy dermatitis. An acute irritant contact dermatitis superimposed upon an allergic contact dermatitis.

PubMed

Hurwitz, R M; Rivera, H P; Guin, J D

1984-08-01

A black spot in the epidermis over a blister of poison ivy dermatitis is an uncommon finding. Four patients with the phenomenon are described. Histologic and histochemical studies were made on biopsy material and the blackish deposit on the skin surface was compared with black deposits in and on leaves of the species of poison ivy. This examination revealed a yellow, amorphous substance on the stratum corneum of the lesions and a similar substance in and on leaves of the poison ivy plant, Toxicodendron radicans ssp. negundo. Associated with the pigmentary deposits there were distinct changes of acute irritant contact dermatitis superimposed upon allergic contact dermatitis. Our findings support the view that the black material is the oleoresin of the plant, and that this substance behaves both as an irritant and an allergen.

Restoring conjunctival tolerance by topical nuclear factor-κB inhibitors reduces preservative-facilitated allergic conjunctivitis in mice.

PubMed

Guzmán, Mauricio; Sabbione, Florencia; Gabelloni, María Laura; Vanzulli, Silvia; Trevani, Analía Silvina; Giordano, Mirta Nilda; Galletti, Jeremías Gastón

2014-09-04

To evaluate the role of nuclear factor-κB (NF-κB) activation in eye drop preservative toxicity and the effect of topical NF-κB inhibitors on preservative-facilitated allergic conjunctivitis. Balb/c mice were instilled ovalbumin (OVA) combined with benzalkonium chloride (BAK) and/or NF-κB inhibitors in both eyes. After immunization, T-cell responses and antigen-induced ocular inflammation were evaluated. Nuclear factor-κB activation and associated inflammatory changes also were assessed in murine eyes and in an epithelial cell line after BAK exposure. Benzalkonium chloride promoted allergic inflammation and leukocyte infiltration of the conjunctiva. Topical NF-κB inhibitors blocked the disruptive effect of BAK on conjunctival immunological tolerance and ameliorated subsequent ocular allergic reactions. In line with these findings, BAK induced NF-κB activation and the secretion of IL-6 and granulocyte-monocyte colony-stimulating factor in an epithelial cell line and in the conjunctiva of instilled mice. In addition, BAK favored major histocompatibility complex (MHC) II expression in cultured epithelial cells in an NF-κB-dependent fashion after interaction with T cells. Benzalkonium chloride triggers conjunctival epithelial NF-κB activation, which seems to mediate some of its immune side effects, such as proinflammatory cytokine release and increased MHC II expression. Breakdown of conjunctival tolerance by BAK favors allergic inflammation, and this effect can be prevented in mice by topical NF-κB inhibitors. These results suggest a new pharmacological target for preservative toxicity and highlight the importance of conjunctival tolerance in ocular surface homeostasis. Copyright 2014 The Association for Research in Vision and Ophthalmology, Inc.

A review of the pathophysiology, diagnosis, and management of allergic reactions in the dental office.

PubMed

Rochford, Christopher; Milles, Maano

2011-02-01

Since more than 50 million people in the United States have allergies, knowledge of the management of allergic reactions in the dental office is extremely important. Appropriate care may range from a simple referral to a primary care physician to lifesaving measures implemented during acute anaphylactic reactions. The authors present a basic review of the pathophysiology of allergic reactions and provide information detailing the diagnosis and management of allergic reactions that may be encountered in the dental office. Utilizing this information, the dental practitioner and ancillary staff will have a thorough understanding of allergic reactions and be prepared to successfully identify and treat these reactions.

Regulatory B-cell induction by helminths: implications for allergic disease.

PubMed

Hussaarts, Leonie; van der Vlugt, Luciën E P M; Yazdanbakhsh, Maria; Smits, Hermelijn H

2011-10-01

Chronic helminth infections are often associated with a reduced prevalence of inflammatory disorders, including allergic diseases. Helminths influence the host immune system by downregulating T-cell responses; the cytokine IL-10 appears to play a central role in this process. Over the last decade, evidence has emerged toward a new regulatory cell type: IL-10-producing B cells, capable of regulating immunity and therefore termed regulatory B cells. Initially, regulatory B cells have been described in autoimmunity models where they dampen inflammation, but recently they were also found in several helminth infection models. Importantly, regulatory B cells have recently been identified in humans, and it has been suggested that patients suffering from autoimmunity have an impaired regulatory B-cell function. As such, it is of therapeutic interest to study the conditions in which IL-10-producing B cells can be induced. Chronic helminth infections appear to hold promise in this context as emerging evidence suggests that helminth-induced regulatory B cells strongly suppress allergic inflammation. In this review, we will discuss the conditions under which regulatory B cells are present, leading to a state of tolerance, as well as the conditions where their absence or functional impairment leads to exacerbated disease. We will summarize their phenotypic characteristics and their mechanisms of action and elaborate on possible mechanisms whereby regulatory B cells can be induced or expanded, as this may open novel avenues for the treatment of inflammatory diseases, such as allergic asthma. Copyright © 2011 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.

The Intestinal Microbiota Contributes to the Ability of Helminths to Modulate Allergic Inflammation

PubMed Central

Zaiss, Mario M.; Rapin, Alexis; Lebon, Luc; Dubey, Lalit Kumar; Mosconi, Ilaria; Sarter, Kerstin; Piersigilli, Alessandra; Menin, Laure; Walker, Alan W.; Rougemont, Jacques; Paerewijck, Oonagh; Geldhof, Peter; McCoy, Kathleen D.; Macpherson, Andrew J.; Croese, John; Giacomin, Paul R.; Loukas, Alex; Junt, Tobias; Marsland, Benjamin J.; Harris, Nicola L.

2015-01-01

Summary Intestinal helminths are potent regulators of their host’s immune system and can ameliorate inflammatory diseases such as allergic asthma. In the present study we have assessed whether this anti-inflammatory activity was purely intrinsic to helminths, or whether it also involved crosstalk with the local microbiota. We report that chronic infection with the murine helminth Heligmosomoides polygyrus bakeri (Hpb) altered the intestinal habitat, allowing increased short chain fatty acid (SCFA) production. Transfer of the Hpb-modified microbiota alone was sufficient to mediate protection against allergic asthma. The helminth-induced anti-inflammatory cytokine secretion and regulatory T cell suppressor activity that mediated the protection required the G protein-coupled receptor (GPR)-41. A similar alteration in the metabolic potential of intestinal bacterial communities was observed with diverse parasitic and host species, suggesting that this represents an evolutionary conserved mechanism of host-microbe-helminth interactions. PMID:26522986

Allergic Asthmatics Show Divergent Lipid Mediator Profiles from Healthy Controls Both at Baseline and following Birch Pollen Provocation

PubMed Central

Lundström, Susanna L.; Yang, Jun; Källberg, Henrik J.; Thunberg, Sarah; Gafvelin, Guro; Haeggström, Jesper Z.; Grönneberg, Reidar; Grunewald, Johan; van Hage, Marianne; Hammock, Bruce D.; Eklund, Anders; Wheelock, Åsa M.; Wheelock, Craig E.

2012-01-01

Background Asthma is a respiratory tract disorder characterized by airway hyper-reactivity and chronic inflammation. Allergic asthma is associated with the production of allergen-specific IgE and expansion of allergen-specific T-cell populations. Progression of allergic inflammation is driven by T-helper type 2 (Th2) mediators and is associated with alterations in the levels of lipid mediators. Objectives Responses of the respiratory system to birch allergen provocation in allergic asthmatics were investigated. Eicosanoids and other oxylipins were quantified in the bronchoalveolar lumen to provide a measure of shifts in lipid mediators associated with allergen challenge in allergic asthmatics. Methods Eighty-seven lipid mediators representing the cyclooxygenase (COX), lipoxygenase (LOX) and cytochrome P450 (CYP) metabolic pathways were screened via LC-MS/MS following off-line extraction of bronchoalveolar lavage fluid (BALF). Multivariate statistics using OPLS were employed to interrogate acquired oxylipin data in combination with immunological markers. Results Thirty-two oxylipins were quantified, with baseline asthmatics possessing a different oxylipin profile relative to healthy individuals that became more distinct following allergen provocation. The most prominent differences included 15-LOX-derived ω-3 and ω-6 oxylipins. Shared-and-Unique-Structures (SUS)-plot modeling showed a correlation (R2 = 0.7) between OPLS models for baseline asthmatics (R2Y[cum] = 0.87, Q2[cum] = 0.51) and allergen-provoked asthmatics (R2Y[cum] = 0.95, Q2[cum] = 0.73), with the majority of quantified lipid mediators and cytokines contributing equally to both groups. Unique structures for allergen provocation included leukotrienes (LTB4 and 6-trans-LTB4), CYP-derivatives of linoleic acid (epoxides/diols), and IL-10. Conclusions Differences in asthmatic relative to healthy profiles suggest a role for 15-LOX products of both ω-6 and ω-3 origin in allergic

Masticatory changes in oral breath secondary to allergic rhinitis: integrative review.

PubMed

Bezerra, Luciana Ângelo; Silva, Hilton Justino da; Melo, Ana Carolina Cardoso de; Moraes, Klyvia Juliana Rocha de; Cunha, Renata Andrade da; Cunha, Daniele Andrade da; Medeiros, Décio

2014-04-01

Introduction The III Brazilian Consensus on Rhinitis (2012) defines allergic rhinitis as a nasal mucosa inflammation, mediated by immunoglobulin E, after exposure to allergens. The classic signs and symptoms of allergic rhinitis are nasal obstruction, watery rhinorrhea, sneezing, and nasal itching, often reversible either spontaneously or with treatment, and mouth breathing (breathing predominantly through the mouth, regardless of the cause, due to a nasal breathing impairment) in some cases. Objective To evaluate the literature on masticatory changes in children with mouth breathing due to allergic rhinitis. Methods We conducted a search of the past 10 years, at Bireme and MEDLINE databases, for articles that covered masticatory changes in children with mouth breathing secondary to allergic rhinitis. Results We found 1,986 articles, including 15 repeated in databases, but only two articles met the inclusion criteria fully. Discussion We found few studies to answer the question raised in this review, and those studies have some methodological limitations. Most articles claimed no have statistically significant differences in masticatory changes in this population. Conclusion A better controlled study (isolating diseases, exposure time), with a larger sample (sample calculation appropriate), would be necessary to examine such changes.

Masticatory Changes in Oral Breath Secondary to Allergic Rhinitis: Integrative Review

PubMed Central

Bezerra, Luciana Ângelo; Silva, Hilton Justino da; Melo, Ana Carolina Cardoso de; Moraes, Klyvia Juliana Rocha de; Cunha, Renata Andrade da; Cunha, Daniele Andrade da; Medeiros, Décio

2013-01-01

Introduction The III Brazilian Consensus on Rhinitis (2012) defines allergic rhinitis as a nasal mucosa inflammation, mediated by immunoglobulin E, after exposure to allergens. The classic signs and symptoms of allergic rhinitis are nasal obstruction, watery rhinorrhea, sneezing, and nasal itching, often reversible either spontaneously or with treatment, and mouth breathing (breathing predominantly through the mouth, regardless of the cause, due to a nasal breathing impairment) in some cases. Objective To evaluate the literature on masticatory changes in children with mouth breathing due to allergic rhinitis. Methods We conducted a search of the past 10 years, at Bireme and MEDLINE databases, for articles that covered masticatory changes in children with mouth breathing secondary to allergic rhinitis. Results We found 1,986 articles, including 15 repeated in databases, but only two articles met the inclusion criteria fully. Discussion We found few studies to answer the question raised in this review, and those studies have some methodological limitations. Most articles claimed no have statistically significant differences in masticatory changes in this population. Conclusion A better controlled study (isolating diseases, exposure time), with a larger sample (sample calculation appropriate), would be necessary to examine such changes. PMID:25992077

Allergic colitis in infants related to cow's milk: clinical characteristics, pathologic changes, and immunologic findings.

PubMed

Yu, Man-Chun; Tsai, Chia-Lun; Yang, Yao-Jong; Yang, Sing-San; Wang, Li-Hui; Lee, Chung-Ta; Jan, Ren-Long; Wang, Jiu-Yao

2013-02-01

Allergic colitis (AC) is an inflammatory condition characterized by eosinophils infiltrating the colonic wall. It can be a benign and/or severe illness among gastrointestinal diseases in infants. We report five infants who, since January 2009, in whom AC under fibrotic endoscopic examinations has been diagnosed. The criterion for histopathologic diagnosis of AC in this study was five or more eosinophils per high-power field. Patients' clinical symptoms, pathologic findings, and immunologic studies, such as specific antibodies against component of cow's milk protein, were compared with those of allergic children without AC and those of nonatopic control children. Histopathologic examinations of biopsy specimens revealed acute inflammation with characteristic eosinophilic infiltration of lamina propria (5-15 eosinophils per high-power field) in all five patients. They all had strongly positive skin prick tests against milk protein, which were not correlated with in vitro allergen-specific immunoglobulin (Ig) E levels. In contrast, there were significantly higher levels of IgE antibodies, and lower specific IgG4 and IgA levels to components and whole milk proteins in AC, as compared to control children without AC. Endoscopic biopsy specimens of intestine confirm the diagnosis of AC. However, allergen skin prick test and IgE antibody to milk protein components also provide helpful diagnostic tools for this rare disease in children. Copyright © 2012. Published by Elsevier B.V.

Local injections of corticotropin releasing factor reduce doxorubicin-induced acute inflammation in the eyelid.

PubMed

McLoon, L K; Wirtschafter, J

1997-04-01

Doxorubicin chemomyectomy is an effective alternative treatment option for patients with blepharospasm and hemifacial spasm. One side effect of the use of doxorubicin in localized injections is the development of acute inflammation and skin injury at the injection site. Corticotropin releasing factor (CRF) was reported to reduce inflammation after acute inflammatory injuries due to other causes and at other sites. This study was performed to assess the potential of CRF to prevent the development of skin injury and eyelid soreness after local doxorubicin injection. Rabbits received lower eyelid injections of either 75 or 150 micrograms CRF followed by injection of either 0.5, 1, or 2 mg doxorubicin or doxorubicin alone. Eyelids were assessed for changes in acute inflammation by immunohistochemical localization of macrophages and monocytes using anti-CD11, an antibody specific for these cell types. Short-term alterations in vascular permeability were assessed using an Evans blue assay. Additional eyelids were followed daily for changes in the skin over the injection site to determine day of onset of skin injury and the total duration of skin injury. After 1 month, the eyelids were processed histologically for morphometric analysis of muscle fiber loss. Monkey eyelids also were examined for the effect of CRF and doxorubicin injections. Doxorubicin alone produced an acute inflammatory reaction in the treated eyelids, with a large influx of macrophages and monocytes throughout the connective tissue at 1 and 2 days. Corticotropin releasing factor pretreatment significantly reduced this influx of inflammatory cells into the connective tissue. Doxorubicin produced a large increase in vascular permeability in the treated eyelids, with resultant edema. Corticotropin releasing factor did not alter this change in vascular permeability, indicating that CRF appears to have a specific effect on migration of inflammatory cells rather than just a generalized effect on vascular

Allergic-like reactions to asparaginase: Atypical allergies without asparaginase inactivation.

PubMed

Kloos, Robin Q H; Pieters, Rob; Escherich, Gabriele; van der Sluis, Inge M

2016-11-01

Asparaginase is an important component of pediatric acute lymphoblastic leukemia (ALL) therapy. Unfortunately, this treatment is hampered by hypersensitivity reactions. In general, allergies - regardless of severity - cause complete inactivation of the drug. However, we report atypical allergic reactions without inactivation of asparaginase, here called allergic-like reactions. Patients with an allergic-like reaction, who were treated according to the Dutch Childhood Oncology Group ALL-11 or the CoALL 08-09 protocol, were described. The reactions were identified by continual measurement of asparaginase activity levels. Characteristics, including timing of occurrence, symptoms, grade, and the presence of antiasparaginase antibodies, were compared to those of real allergies. Fourteen allergic-like reactions occurred in nine patients. Five reactions were to PEGasparaginase and nine to Erwinia asparaginase. Allergic-like reactions occurred relatively late after the start of infusion compared to real allergies. Antibodies were absent in all but one patient with an allergic-like reaction, while they were detected in all patients with a real allergy. Symptoms and grade did not differ between the groups. Asparaginase was continued with the same formulation in six patients of whom four finished treatment with adequate activity levels. In conclusion, allergic-like reactions occur relatively late after the start of infusion and without antibodies. Despite these clinical differences, allergic-like reactions can only be distinguished from real allergies by continually measuring asparaginase activity levels. If clinically tolerated, formulations should not be switched in case of allergic-like reactions. Moreover, failure to recognize these reactions may lead to a less favorable prognosis if asparaginase therapy is terminated unnecessarily. © 2016 Wiley Periodicals, Inc.

Salivary Markers of Inflammation in Response to Acute Stress

PubMed Central

Slavish, Danica C.; Graham-Engeland, Jennifer E.; Smyth, Joshua M.; Engeland, Christopher G.

2014-01-01

There is burgeoning interest in the ability to detect inflammatory markers in response to stress within naturally occurring social contexts and/or across multiple time points per day within individuals. Salivary collection is a less invasive process than current methods of blood collection and enables intensive naturalistic methodologies, such as those involving extensive repeated measures per day over time. Yet the reliability and validity of saliva-based to blood-based inflammatory biomarkers in response to stress remains unclear. We review and synthesize the published studies that have examined salivary markers of inflammation following exposure to an acute laboratory stressor. Results from each study are reviewed by analyte (IL-1β, TNF-α, IL-6, IL-2, IL-4, IL-10, IL-12, CRP) and stress type (social-cognitive and exercise-physical), after which methodological issues and limitations are addressed. Although the literature is limited, several inflammatory markers (including IL-1β, TNF-α, and IL-6) have been reliably determined from saliva and have increased significantly in response to stress across multiple studies, with effect sizes ranging from very small to very large. Although CRP from saliva has been associated with CRP in circulating blood more consistently than other biomarkers have been associated with their counterparts in blood, evidence demonstrating it reliably responds to acute stress is absent. Although the current literature is presently too limited to allow broad assertion that inflammatory biomarkers determined from saliva are valuable for examining acute stress responses, this review suggests that specific targets may be valid and highlights specific areas of need for future research. PMID:25205395

Allergic rhinitis

MedlinePlus

... allergic to, such as dust, animal dander, or pollen. Symptoms can also occur when you eat a ... article focuses on allergic rhinitis due to plant pollens. This type of allergic rhinitis is commonly called ...

Modified immunoglobulin G glycosylation pattern during turpentine-induced acute inflammation in rats.

PubMed

Canellada, Andrea; Margni, Ricardo A

2002-01-01

Alterations in the pattern of protein glycosylation have been described during inflammation. In chronic parasitic and tumoral diseases we have reported an increase in the proportion of serum Immunoglobulin G (IgG) molecules possessing an altered Fab glycosylation pattern designated asymmetric antibodies. The alteration results in augmented concanavalin A affinity and functional univalence of the antibody. In addition, Fc agalactosylation has been described as occurring in chronically autoimmune diseases. Therefore, the aim of this paper was to evaluate by analyzing sera whether during an acute inflammatory response in rats produced by subcutaneous inoculation of turpentine oil, there was an alteration in the synthesis and glycosylation of IgG (as revealed by concanavalin A binding). We found that during acute inflammation there was a decrease in the synthesis of IgG which was not affected by prior oral administration of dexamethasone; however, the turpentine-induced increase in IgG binding to concanavalin A was found to be inhibited upon prior administration of the anti-inflammatory agent. As with turpentine, the corticoid used induced an increase in the interleukin-6 levels detected in sera by ELISA. Although we have described an improvement in asymmetric antibody synthesis by low dose of interleukin-6 previously, here we found no correlation between the observed glycosylation pattern of IgG and interleukin-6 concentration assessed in sera of treated rats, probably due to a different dexamethasone mediated pathway.

Exposure to Particulate Hexavalent Chromium Exacerbates Allergic Asthma Pathology

PubMed Central

Schneider, Brent C.; Constant, Stephanie L.; Patierno, Steven R.; Jurjus, Rosalyn A.; Ceryak, Susan M.

2011-01-01

Airborne hexavalent chromate, Cr(VI), has been identified by the Environmental Protection Agency as a possible health threat in urban areas, due to the carcinogenic potential of some of its forms. Particulate chromates are produced in many different industrial settings, with high levels of aerosolized forms historically documented. Along with an increased risk of lung cancer, a high incidence of allergic asthma has been reported in workers exposed to certain inhaled particulate Cr(VI) compounds. However, a direct causal association between Cr(VI) and allergic asthma has not been established. We recently showed that inhaled particulate Cr(VI) induces an innate neutrophilic inflammatory response in BALB/c mice. In the current studies we investigated how the inflammation induced by inhaled particulate Cr(VI) might alter the pathology of an allergic asthmatic response. We used a well-established mouse model of allergic asthma. Groups of ovalbumin protein (OVA)-primed mice were challenged either with OVA alone, or with a combination of OVA and particulate zinc chromate, and various parameters associated with asthmatic responses were measured. Co-exposure to particulate Cr(VI) and OVA mediated a mixed form of asthma in which both eosinophils and neutrophils are present in airways, tissue pathology is markedly exacerbated, and airway hyperresponsiveness is significantly increased. Taken together these findings suggest that inhalation of particulate forms of Cr(VI) may augment the severity of ongoing allergic asthma, as well as alter its phenotype. Such findings may have implications for asthmatics in settings in which airborne particulate Cr(VI) compounds are present at high levels. PMID:22178736

The Intestinal Microbiota Contributes to the Ability of Helminths to Modulate Allergic Inflammation.

PubMed

Zaiss, Mario M; Rapin, Alexis; Lebon, Luc; Dubey, Lalit Kumar; Mosconi, Ilaria; Sarter, Kerstin; Piersigilli, Alessandra; Menin, Laure; Walker, Alan W; Rougemont, Jacques; Paerewijck, Oonagh; Geldhof, Peter; McCoy, Kathleen D; Macpherson, Andrew J; Croese, John; Giacomin, Paul R; Loukas, Alex; Junt, Tobias; Marsland, Benjamin J; Harris, Nicola L

2015-11-17

Intestinal helminths are potent regulators of their host's immune system and can ameliorate inflammatory diseases such as allergic asthma. In the present study we have assessed whether this anti-inflammatory activity was purely intrinsic to helminths, or whether it also involved crosstalk with the local microbiota. We report that chronic infection with the murine helminth Heligmosomoides polygyrus bakeri (Hpb) altered the intestinal habitat, allowing increased short chain fatty acid (SCFA) production. Transfer of the Hpb-modified microbiota alone was sufficient to mediate protection against allergic asthma. The helminth-induced anti-inflammatory cytokine secretion and regulatory T cell suppressor activity that mediated the protection required the G protein-coupled receptor (GPR)-41. A similar alteration in the metabolic potential of intestinal bacterial communities was observed with diverse parasitic and host species, suggesting that this represents an evolutionary conserved mechanism of host-microbe-helminth interactions. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

EFFECT OF SHORT TERM DIESEL EXHAUST EXPOSURE ON NASAL RESPONSES TO INFLUENZA IN ALLERGIC RHINITICS.

EPA Science Inventory

Introduction: Recently published data suggest that diesel exhaust (DE) has special impact on allergic inflammation, suppressing Th1 and augmenting Th2 responses to allergen via oxidant stress effects on airway cells. Exposures to particulate air pollutants including DE are also a...

Circuit resistance training attenuates acute exertion-induced reductions in arterial function but not inflammation in obese women.

PubMed

Franklin, Nina C; Robinson, Austin T; Bian, Jing-Tan; Ali, Mohamed M; Norkeviciute, Edita; McGinty, Patrick; Phillips, Shane A

2015-06-01

Cardiovascular disease (CVD) is a leading cause of preventable death among young women in the United States. Habitual resistance exercise training is known to have beneficial effects on endothelial function and CVD risk factors, including obesity; however, previous studies show that acute resistance exercise impairs endothelial function in obese adults who are sedentary, a response that may be linked to inflammation. We sought to determine if circuit-based resistance training (CRT) attenuates acute resistance exercise-induced reductions in endothelial function in a population of young, obese, sedentary women and whether or not inflammation plays a role in this response. Eighteen obese [body mass index (BMI) 30.0-40.0 kg · m(-2)] young premenopausal women were randomly assigned to either a CRT group or a no-exercise control group (CON). Conduit artery endothelial function was assessed using brachial artery flow-mediated dilation (FMD) determined by ultrasound before and after a single bout of strenuous weightlifting (SWL). In addition, circulating inflammatory mediators (tumor necrosis factor-α and C-reactive protein), blood pressure, fasting blood lipids, glucose, waist circumference, body composition, and aerobic capacity were assessed. Among participants randomized to the CRT group, 8 weeks of training led to considerable increases in FMD after SWL (P=0.001) compared to the CON group. However, no significant differences between the groups were observed in circulating inflammatory mediators, blood pressure, fasting blood lipids, or other physical and physiological characteristics. This study shows that CRT alleviates acute exertion-induced reductions in endothelial function among obese sedentary women in the absence of changes in inflammation.

Acute cardiovascular toxicity of sterilizers, PHMG, and PGH: severe inflammation in human cells and heart failure in zebrafish.

PubMed

Kim, Jae-Yong; Kim, Hak Hyeon; Cho, Kyung-Hyun

2013-06-01

In 2011, dozens of children and pregnant women in Korea died by exposure to sterilizer for household humidifier, such as Oxy(®) and Cefu(®). Until now, however, it remains unknown how the sterilizer affect the human health to cause the acute deaths. To find its toxicity for organ, we investigated the putative toxicity of the sterilizer in the cardiovascular system. The sterilizers, polyhexamethylene guanidine phosphate (PHMG, Cefu(®)), and oligo-[2-(2-ethoxy)-ethoxyethyl)-guanidinium-chloride (PGH, Oxy(®)) were treated to human lipoproteins, macrophages, and dermal fibroblast cells. The PGH and PHMG at normal dosages caused severe atherogenic process in human macrophages, cytotoxic effect, and aging in human dermal cell. Zebrafish embryos, which were exposed to the sterilizer, showed early death with acute inflammation and attenuated developmental speed. All zebrafish exposed to the working concentration of PHMG (final 0.3 %) and PGH (final 10 mM) died within 70 min and displayed acute increases in serum triacylglycerol level and fatty liver induction. The dead zebrafish showed severe accumulation of fibrous collagen in the bulbous artery of the heart with elevation of reactive oxygen species. In conclusion, the sterilizers showed acute toxic effect in blood circulation system, causing by severe inflammation, atherogenesis, and aging, with embryo toxicity.

Decreased expression of indolamine 2,3-dioxygenase in childhood allergic asthma and its inverse correlation with fractional concentration of exhaled nitric oxide.

PubMed

Hu, Ying; Chen, Zhiqiang; Jin, Ling; Wang, Mei; Liao, Wei

2017-11-01

The tryptophan metabolic pathway mediated by indolamine 2,3-dioxygenase (IDO), a tryptophan-degrading enzyme, plays an important role in controlling the development of allergic inflammation. The fractional concentration of exhaled nitric oxide (FeNO) is closely associated with the allergic state and is extensively used for the clinical evaluation of airway allergic inflammation. Clinical trials have rarely assessed the expression of IDO in childhood allergic asthma and its correlation with FeNO. To evaluate the IDO level in children with childhood allergic asthma and the relation between IDO levels and FeNO. Thirty children older than 5 years who were diagnosed the first time with allergic asthma were selected from the pediatric outpatient department. Another 30 healthy children were selected as controls. The subjects were evaluated by complete medical history, pulmonary function test results, skin prick test reaction, FeNO concentration test result, eosinophil count, and a disease severity score. Peripheral venous blood and induced sputum were obtained to measure the concentrations of IDO metabolites (ie, tryptophan and kynurenine). The IDO levels in the peripheral blood and induced sputum were significantly lower in patients with childhood allergic asthma than in children in the control group. The IDO level was negatively correlated with FeNO but was not significantly correlated with age, sex, blood eosinophil count, or disease severity scale. The expression of IDO was significantly lower in childhood allergic asthma, particularly in children with high FeNO levels. There was no significant relation between IDO levels and asthma severity. Chinese Clinical Trial Register (www.chictr.org.cn) Identifier: ChiCTR-COC-15006080. Copyright © 2017 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

D-tryptophan from probiotic bacteria influences the gut microbiome and allergic airway disease.

PubMed

Kepert, Inge; Fonseca, Juliano; Müller, Constanze; Milger, Katrin; Hochwind, Kerstin; Kostric, Matea; Fedoseeva, Maria; Ohnmacht, Caspar; Dehmel, Stefan; Nathan, Petra; Bartel, Sabine; Eickelberg, Oliver; Schloter, Michael; Hartmann, Anton; Schmitt-Kopplin, Philippe; Krauss-Etschmann, Susanne

2017-05-01

Chronic immune diseases, such as asthma, are highly prevalent. Currently available pharmaceuticals improve symptoms but cannot cure the disease. This prompted demands for alternatives to pharmaceuticals, such as probiotics, for the prevention of allergic disease. However, clinical trials have produced inconsistent results. This is at least partly explained by the highly complex crosstalk among probiotic bacteria, the host's microbiota, and immune cells. The identification of a bioactive substance from probiotic bacteria could circumvent this difficulty. We sought to identify and characterize a bioactive probiotic metabolite for potential prevention of allergic airway disease. Probiotic supernatants were screened for their ability to concordantly decrease the constitutive CCL17 secretion of a human Hodgkin lymphoma cell line and prevent upregulation of costimulatory molecules of LPS-stimulated human dendritic cells. Supernatants from 13 of 37 tested probiotic strains showed immunoactivity. Bioassay-guided chromatographic fractionation of 2 supernatants according to polarity, followed by total ion chromatography and mass spectrometry, yielded C 11 H 12 N 2 O 2 as the molecular formula of a bioactive substance. Proton nuclear magnetic resonance and enantiomeric separation identified D-tryptophan. In contrast, L-tryptophan and 11 other D-amino acids were inactive. Feeding D-tryptophan to mice before experimental asthma induction increased numbers of lung and gut regulatory T cells, decreased lung T H 2 responses, and ameliorated allergic airway inflammation and hyperresponsiveness. Allergic airway inflammation reduced gut microbial diversity, which was increased by D-tryptophan. D-tryptophan is a newly identified product from probiotic bacteria. Our findings support the concept that defined bacterial products can be exploited in novel preventative strategies for chronic immune diseases. Copyright © 2016. Published by Elsevier Inc.

Trefoil factor-2 reverses airway remodeling changes in allergic airways disease.

PubMed

Royce, Simon G; Lim, Clarice; Muljadi, Ruth C; Samuel, Chrishan S; Ververis, Katherine; Karagiannis, Tom C; Giraud, Andrew S; Tang, Mimi L K

2013-01-01

Trefoil factor 2 (TFF2) is a small peptide with an important role in mucosal repair. TFF2 is up-regulated in asthma, suggesting a role in asthma pathogenesis. Given its known biological role in promoting epithelial repair, TFF2 might be expected to exert a protective function in limiting the progression of airway remodeling in asthma. The contribution of TFF2 to airway remodeling in asthma was investigated by examining the expression of TFF2 in the airway and lung, and evaluating the effects of recombinant TFF2 treatment on established airway remodeling in a murine model of chronic allergic airways disease (AAD). BALB/c mice were sensitized and challenged with ovalbumin (OVA) or saline for 9 weeks, whereas mice with established OVA-induced AAD were treated with TFF2 or vehicle control (intranasally for 14 d). Effects on airway remodeling, airway inflammation, and airway hyperresponsiveness were then assessed, whereas TFF2 expression was determined by immunohistochemistry. TFF2 expression was significantly increased in the airways of mice with AAD, compared with expression levels in control mice. TFF2 treatment resulted in reduced epithelial thickening, subepithelial collagen deposition, goblet-cell metaplasia, bronchial epithelium apoptosis, and airway hyperresponsiveness (all P < 0.05, versus vehicle control), but TFF2 treatment did not influence airway inflammation. The increased expression of endogenous TFF2 in response to chronic allergic inflammation is insufficient to prevent the progression of airway inflammation and remodeling in a murine model of chronic AAD. However, exogenous TFF2 treatment is effective in reversing aspects of established airway remodeling. TFF2 has potential as a novel treatment for airway remodeling in asthma.

Central autonomic network mediates cardiovascular responses to acute inflammation: Relevance to increased cardiovascular risk in depression?

PubMed Central

Harrison, Neil A.; Cooper, Ella; Voon, Valerie; Miles, Ken; Critchley, Hugo D.

2013-01-01

Inflammation is a risk factor for both depression and cardiovascular disease. Depressed mood is also a cardiovascular risk factor. To date, research into mechanisms through which inflammation impacts cardiovascular health rarely takes into account central effects on autonomic cardiovascular control, instead emphasizing direct effects of peripheral inflammatory responses on endothelial reactivity and myocardial function. However, brain responses to inflammation engage neural systems for motivational and homeostatic control and are expressed through depressed mood state and changes in autonomic cardiovascular regulation. Here we combined an inflammatory challenge, known to evoke an acute reduction in mood, with neuroimaging to identify the functional brain substrates underlying potentially detrimental changes in autonomic cardiovascular control. We first demonstrated that alterations in the balance of low to high frequency (LF/HF) changes in heart rate variability (a measure of baroreflex sensitivity) could account for some of the inflammation-evoked changes in diastolic blood pressure, indicating a central (rather than solely local endothelial) origin. Accompanying alterations in regional brain metabolism (measured using 18FDG-PET) were analysed to localise central mechanisms of inflammation-induced changes in cardiovascular state: three discrete regions previously implicated in stressor-evoked blood pressure reactivity, the dorsal anterior and posterior cingulate and pons, strongly mediated the relationship between inflammation and blood pressure. Moreover, activity changes within each region predicted the inflammation-induced shift in LF/HF balance. These data are consistent with a centrally-driven component originating within brain areas supporting stressor evoked blood pressure reactivity. Together our findings highlight mechanisms binding psychological and physiological well-being and their perturbation by peripheral inflammation. PMID:23416033

Circulating Cell-Free DNA Differentiates Severity of Inflammation.

PubMed

Frank, Mayu O

2016-10-01

As the U.S. population ages, the incidence of chronic disease will rise. Chronic diseases have been linked to chronic inflammation. The purpose of this review is to summarize the literature on cell-free DNA (cfDNA) in relation to inflammation. PubMed, EMBASE, and Web of Science were searched. Inclusion criteria were noninterventional studies on acute and chronic inflammation, autoimmunity, and infection published in English after 2000, conducted in humans using the fluorescence method of quantifying DNA. Of the 442 articles retrieved, 83 were identified for full-text review and 13 remained after application of inclusion criteria. Of the reviewed studies, three involved acute inflammation, six involved chronic inflammation, and four involved infection. Healthy controls with interpretable results were included in six studies, three of which used the Quant-iT high-sensitivity DNA kit and found cfDNA quantities near 800 ng/ml, while the other three used other fluorescence methods and found quantities below 100 ng/ml. All 13 studies compared groups, and all but 1 found statistically significant differences between them. Among studies using the Quant-iT reagent, levels were higher in infection than in chronic inflammation. Among studies that used other reagents, levels increased from chronic to acute inflammation to severe infection. CfDNA levels were associated with mortality and with clinical outcomes in acute inflammation and infection. Most studies assessed cfDNA's correlation with other inflammation biomarkers and found inconclusive results. There appears to be an association between inflammation and cfDNA. Further research is necessary before cfDNA can be used clinically as a measure of inflammation. © The Author(s) 2016.

Th2 Allergic Immune Response to Inhaled Fungal Antigens is Modulated By TLR-4-Independent Bacterial Products

PubMed Central

Allard, Jenna B.; Rinaldi, Lisa; Wargo, Matt; Allen, Gilman; Akira, Shizuo; Uematsu, Satoshi; Poynter, Matthew E.; Hogan, Deborah A.; Rincon, Mercedes; Whittaker, Laurie A.

2009-01-01

SUMMARY Allergic airway disease is characterized by eosinophilic inflammation, mucus hypersecretion and increased airway resistance. Fungal antigens are ubiquitous within the environment and are well know triggers of allergic disease. Bacterial products are also frequently encountered within the environment and may alter the immune response to certain antigens. The consequence of simultaneous exposure to bacterial and fungal products on the lung adaptive immune response has not been explored. Here we show that oropharyngeal aspiration of fungal lysates (Candida albicans, Aspergillus fumigatus) promotes airway eosinophilia, secretion of Th2 cytokines and mucus cell metaplasia. In contrast, oropharyngeal exposure to bacterial lysates (Pseudomonas aeruginosa) promotes airway inflammation characterized by neutrophils, Th1 cytokine secretion and no mucus production. More importantly, administration of bacterial lysates together with fungal lysates deviates the adaptive immune response to a Th1 type associated with neutrophilia and diminished mucus production. The immunomodulatory effect that bacterial lysates have on the response to fungi is TLR4-independent but MyD88 dependent. Thus, different types of microbial products within the airway can alter the host's adaptive immune response, and potentially impact the development of allergic airway disease to environmental fungal antigens. PMID:19224641

Oxidative stress and inflammation: liver responses and adaptations to acute and regular exercise.

PubMed

Pillon Barcelos, Rômulo; Freire Royes, Luiz Fernando; Gonzalez-Gallego, Javier; Bresciani, Guilherme

2017-02-01

The liver is remarkably important during exercise outcomes due to its contribution to detoxification, synthesis, and release of biomolecules, and energy supply to the exercising muscles. Recently, liver has been also shown to play an important role in redox status and inflammatory modulation during exercise. However, while several studies have described the adaptations of skeletal muscles to acute and chronic exercise, hepatic changes are still scarcely investigated. Indeed, acute intense exercise challenges the liver with increased reactive oxygen species (ROS) and inflammation onset, whereas regular training induces hepatic antioxidant and anti-inflammatory improvements. Acute and regular exercise protocols in combination with antioxidant and anti-inflammatory supplementation have been also tested to verify hepatic adaptations to exercise. Although positive results have been reported in some acute models, several studies have shown an increased exercise-related stress upon liver. A similar trend has been observed during training: while synergistic effects of training and antioxidant/anti-inflammatory supplementations have been occasionally found, others reported a blunting of relevant adaptations to exercise, following the patterns described in skeletal muscles. This review discusses current data regarding liver responses and adaptation to acute and regular exercise protocols alone or combined with antioxidant and anti-inflammatory supplementation. The understanding of the mechanisms behind these modulations is of interest for both exercise-related health and performance outcomes.

Circuit Resistance Training Attenuates Acute Exertion-Induced Reductions in Arterial Function but Not Inflammation in Obese Women

PubMed Central

Franklin, Nina C.; Robinson, Austin T.; Bian, Jing-Tan; Ali, Mohamed M.; Norkeviciute, Edita; McGinty, Patrick

2015-01-01

Abstract Background: Cardiovascular disease (CVD) is a leading cause of preventable death among young women in the United States. Habitual resistance exercise training is known to have beneficial effects on endothelial function and CVD risk factors, including obesity; however, previous studies show that acute resistance exercise impairs endothelial function in obese adults who are sedentary, a response that may be linked to inflammation. We sought to determine if circuit-based resistance training (CRT) attenuates acute resistance exercise-induced reductions in endothelial function in a population of young, obese, sedentary women and whether or not inflammation plays a role in this response. Methods: Eighteen obese [body mass index (BMI) 30.0–40.0 kg·m−2] young premenopausal women were randomly assigned to either a CRT group or a no-exercise control group (CON). Conduit artery endothelial function was assessed using brachial artery flow-mediated dilation (FMD) determined by ultrasound before and after a single bout of strenuous weightlifting (SWL). In addition, circulating inflammatory mediators (tumor necrosis factor-α and C-reactive protein), blood pressure, fasting blood lipids, glucose, waist circumference, body composition, and aerobic capacity were assessed. Results: Among participants randomized to the CRT group, 8 weeks of training led to considerable increases in FMD after SWL (P=0.001) compared to the CON group. However, no significant differences between the groups were observed in circulating inflammatory mediators, blood pressure, fasting blood lipids, or other physical and physiological characteristics. Conclusions: This study shows that CRT alleviates acute exertion-induced reductions in endothelial function among obese sedentary women in the absence of changes in inflammation. PMID:25844686

DO ACUTE PHASE PROTEINS REFLECT SEVERITY OF INFLAMMATION IN RAT MODELS OF POLLUTANT-INDUCED LUNG INJURY?

EPA Science Inventory

Title: DO ACUTE PHASE PROTEINS REFLECT THE SEVERITY OF INFLAMMATION IN RAT MODELS OF POLLUTANT-INDUCED LUNG INJURY?

M. C. Schladweiler, BS 1, P. S. Gilmour, PhD 2, D. L. Andrews, BS 1, D. L. Costa, ScD 1, A. D. Ledbetter, BS 1, K. E. Pinkerton, PhD 3 and U. P. Kodavanti, ...

Fisetin, a bioactive flavonol, attenuates allergic airway inflammation through negative regulation of NF-κB.

PubMed

Goh, Fera Y; Upton, Nadine; Guan, Shouping; Cheng, Chang; Shanmugam, Muthu K; Sethi, Gautam; Leung, Bernard P; Wong, W S Fred

2012-03-15

Persistent activation of nuclear factor-κB (NF-κB) has been associated with the development of asthma. Fisetin (3,7,3',4'-tetrahydroxyflavone), a naturally occurring bioactive flavonol, has been shown to inhibit NF-κB activity. We hypothesized that fisetin may attenuate allergic asthma via negative regulation of the NF-κB activity. Female BALB/c mice sensitized and challenged with ovalbumin developed airway inflammation. Bronchoalveolar lavage fluid was assessed for total and differential cell counts, and cytokine and chemokine levels. Lung tissues were examined for cell infiltration and mucus hypersecretion, and the expression of inflammatory biomarkers. Airway hyperresponsiveness was monitored by direct airway resistance analysis. Fisetin dose-dependently inhibited ovalbumin-induced increases in total cell count, eosinophil count, and IL-4, IL-5 and IL-13 levels recovered in bronchoalveolar lavage fluid. It attenuated ovalbumin-induced lung tissue eosinophilia and airway mucus production, mRNA expression of adhesion molecules, chitinase, IL-17, IL-33, Muc5ac and inducible nitric oxide synthase in lung tissues, and airway hyperresponsiveness to methacholine. Fisetin blocked NF-κB subunit p65 nuclear translocation and DNA-binding activity in the nuclear extracts from lung tissues of ovalbumin-challenged mice. In normal human bronchial epithelial cells, fisetin repressed TNF-α-induced NF-κB-dependent reporter gene expression. Our findings implicate a potential therapeutic value of fisetin in the treatment of asthma through negative regulation of NF-κB pathway. Copyright © 2012 Elsevier B.V. All rights reserved.

Severe Vitamin E deficiency modulates airway allergic inflammatory responses in the murine asthma model

PubMed Central

LIM, YUNSOOK; VASU, VIHAS T.; VALACCHI, GIUSEPPE; LEONARD, SCOTT; AUNG, HNIN HNIN; SCHOCK, BETTINA C.; KENYON, NICHOLAS J.; LI, CHIN-SHANG; TRABER, MARET G.; CROSS, CARROLL E.

2009-01-01

Allergic asthma is a complex immunologically mediated disease associated with increased oxidative stress and altered antioxidant defenses. It was hypothesized that α-tocopherol (α-T) decreases oxidative stress and therefore its absence may influence allergic inflammatory process, a pathobiology known to be accompanied by oxidative stress. Therefore, selected parameters of allergic asthma sensitization and inflammation were evaluated following ovalbumin sensitization and re-challenge of α-T transfer protein (TTP) knock-out mice (TTP–/–) that have greatly reduced lung α-T levels (e.g. < 5%) compared to their litter mate controls (TTP+/+). Results showed that severe α-T deficiency result in a blunted lung expression of IL-5 mRNA and IL-5 protein and plasma IgE levels compared with TTP+/+ mice following immune sensitization and rechallenge, although lung lavage eosinophil levels were comparable in both genomic strains. It is concluded that the initial stimulation of immune responses by the TTP–/– mice were generally blunted compared to the TTP+/+ mice, thus diminishing some aspects of subsequent allergic inflammatory processes. PMID:18404538

Nickel (Ni) allergic patients with complications to Ni containing joint replacement show preferential IL-17 type reactivity to Ni.

PubMed

Summer, Burkhard; Paul, Carina; Mazoochian, Farhad; Rau, Christoph; Thomsen, Marc; Banke, Ingo; Gollwitzer, Hans; Dietrich, Karin-Almut; Mayer-Wagner, Susanne; Ruzicka, Thomas; Thomas, Peter

2010-07-01

Some nickel (Ni) allergic patients develop complications following Ni-containing arthroplasty. In the peri-implant tissue of such patients, we had observed lymphocyte dominated inflammation together with IFN-gamma and IL-17 expression. To determine whether Ni stimulation of peripheral blood mononuclear cells (PBMCs) of such patients would lead to a different cytokine pattern as compared to Ni-allergic patients with symptom-free arthroplasty. Based on history and patch testing in 15 Ni-allergic patients (five without implant, five with symptom-free arthroplasty, five with complicated arthroplasty) and five non-allergic individuals, lymphocyte transformation test (LTT) was performed using PBMC. In parallel in vitro cytokine response to Ni was assessed by real-time reverse transcriptase-polymerase chain reaction (RT-PCR). All 15 Ni-allergic individuals showed enhanced LTT reactivity to Ni (mean SI = 8.42 +/- 1.8) compared to the non-allergic control group. Predominant IFN-gamma expression to Ni was found both in the five allergic patients without arthroplasty and also in the five allergic, symptom-free arthroplasty patients. In contrast, in the five Ni-allergic patients with arthroplasty-linked complications a predominant, significant IL-17 expression to Ni was seen but not in patients with symptom-free arthroplasty. The predominant IL-17 type response to Ni may characterize a subgroup of Ni-allergic patients prone to develop lymphocytic peri-implant hyper-reactivity.

Inflammation and Rupture of a Congenital Pericardial Cyst Manifesting Itself as an Acute Chest Pain Syndrome.

PubMed

Aertker, Robert A; Cheong, Benjamin Y C; Lufschanowski, Roberto

2016-12-01

We present the case of a 63-year-old woman with a remote history of supraventricular tachycardia and hyperlipidemia, who presented with recurrent episodes of acute-onset chest pain. An electrocardiogram showed no evidence of acute coronary syndrome. A chest radiograph revealed a prominent right-sided heart border. A suspected congenital pericardial cyst was identified on a computed tomographic chest scan, and stranding was noted around the cyst. The patient was treated with nonsteroidal anti-inflammatory drugs, and the pain initially abated. Another flare-up was treated similarly. Cardiac magnetic resonance imaging was then performed after symptoms had resolved, and no evidence of the cyst was seen. The suspected cause of the patient's chest pain was acute inflammation of a congenital pericardial cyst with subsequent rupture and resolution of symptoms.

Evaluation of orally administered robenacoxib versus ketoprofen for treatment of acute pain and inflammation associated with musculoskeletal disorders in cats.

PubMed

Giraudel, Jerome M; Gruet, Philippe; Alexander, Debbie G; Seewald, Wolfgang; King, Jonathan N

2010-07-01

To evaluate the efficacy and tolerability of oral administration of robenacoxib for treatment of acute pain and inflammation associated with musculoskeletal disorders in cats. 155 cats requiring relief of signs of pain and inflammation associated with acute musculoskeletal disorders. The study was a multicenter, prospective, randomized, masked, noninferiority field trial. Cats were allocated randomly to 1 of 3 treatment groups: group 1 (1.0 to 2.4 mg of robenacoxib/kg, q 24 h), group 2 (1.0 to 2.4 mg of robenacoxib/kg, q 12 h [daily dosage, 2.0 to 4.8 mg/kg]), and group 3 (ketoprofen [mean dosage, 1 mg/kg, q 24 h]). All cats were administered tablets PO for 5 or 6 days. The primary efficacy endpoint was the investigator global assessment score, which was the sum of scores of signs of pain, inflammation, and mobility assessed in a masked manner by veterinary investigators at baseline, day 2, and day 4 or 5. Cat owners monitored in a nonmasked manner secondary responses by observation of cats' activity, behavior, appetite, and interactions. Safety was assessed by monitoring adverse events, clinical signs, and hematologic and plasma biochemical variables (before and after treatment). No significant differences were detected among the 3 treatment groups for any primary or secondary efficacy endpoints or for tolerability variables. Robenacoxib tablets administered once daily were significantly more palatable than ketoprofen tablets. Robenacoxib tablets administered once daily had noninferior efficacy and tolerability, and superior palatability, compared with the active control drug, ketoprofen, for the treatment of signs of acute pain and inflammation associated with musculoskeletal disorders in cats.

Modeling TH 2 responses and airway inflammation to understand fundamental mechanisms regulating the pathogenesis of asthma.

PubMed

Foster, Paul S; Maltby, Steven; Rosenberg, Helene F; Tay, Hock L; Hogan, Simon P; Collison, Adam M; Yang, Ming; Kaiko, Gerard E; Hansbro, Philip M; Kumar, Rakesh K; Mattes, Joerg

2017-07-01

In this review, we highlight experiments conducted in our laboratories that have elucidated functional roles for CD4 + T-helper type-2 lymphocytes (T H 2 cells), their associated cytokines, and eosinophils in the regulation of hallmark features of allergic asthma. Notably, we consider the complexity of type-2 responses and studies that have explored integrated signaling among classical T H 2 cytokines (IL-4, IL-5, and IL-13), which together with CCL11 (eotaxin-1) regulate critical aspects of eosinophil recruitment, allergic inflammation, and airway hyper-responsiveness (AHR). Among our most important findings, we have provided evidence that the initiation of T H 2 responses is regulated by airway epithelial cell-derived factors, including TRAIL and MID1, which promote T H 2 cell development via STAT6-dependent pathways. Further, we highlight studies demonstrating that microRNAs are key regulators of allergic inflammation and potential targets for anti-inflammatory therapy. On the background of T H 2 inflammation, we have demonstrated that innate immune cells (notably, airway macrophages) play essential roles in the generation of steroid-resistant inflammation and AHR secondary to allergen- and pathogen-induced exacerbations. Our work clearly indicates that understanding the diversity and spatiotemporal role of the inflammatory response and its interactions with resident airway cells is critical to advancing knowledge on asthma pathogenesis and the development of new therapeutic approaches. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Role of Type 2 Innate Lymphoid Cells in Allergic Diseases.

PubMed

Cosmi, Lorenzo; Liotta, Francesco; Maggi, Laura; Annunziato, Francesco

2017-09-11

The adaptive immune response orchestrated by type 2 T helper (Th2) lymphocytes, strictly cooperates with the innate response of group 2 innate lymphoid cells (ILC2), in the protection from helminths infection, as well as in the pathogenesis of allergic disease. The aim of this review is to explore the pathogenic role of ILC2 in different type 2-mediated disorders. Recent studies have shown that epithelial cell-derived cytokines and their responding cells, ILC2, play a pathogenic role in bronchial asthma, chronic rhinosinusitis, and atopic dermatitis. The growing evidences of the contribution of ILC2 in the induction and maintenance of allergic inflammation in such disease suggest the possibility to target them in therapy. Biological therapies blocking ILC2 activation or neutralizing their effector cytokines are currently under evaluation to be used in patients with type 2-dominated diseases.

Difference in the breast milk proteome between allergic and non-allergic mothers.

PubMed

Hettinga, Kasper A; Reina, Fabiola M; Boeren, Sjef; Zhang, Lina; Koppelman, Gerard H; Postma, Dirkje S; Vervoort, Jacques J M; Wijga, Alet H

2015-01-01

Breastfeeding has been linked to a reduction in the prevalence of allergy and asthma. However, studies on this relationship vary in outcome, which may partly be related to differences in breast milk composition. In particular breast milk composition may differ between allergic and non-allergic mothers. Important components that may be involved are breast milk proteins, as these are known to regulate immune development in the newborn. The objective of this study was therefore to explore differences in the proteins of breast milk from 20 allergic and non-allergic mothers. The results from this comparison may then be used to generate hypotheses on proteins associated with allergy in their offspring. Milk samples from allergic and non-allergic mothers were obtained from the PIAMA project, a prospective birth cohort study on incidence, risk factors, and prevention of asthma and inhalant allergy. Non-targeted proteomics technology, based on liquid chromatography and mass spectrometry, was used to compare breast milk from allergic and non-allergic mothers. Nineteen proteins, out of a total of 364 proteins identified in both groups, differed significantly in concentration between the breast milk of allergic and non-allergic mothers. Protease inhibitors and apolipoproteins were present in much higher concentrations in breast milk of allergic than non-allergic mothers. These proteins have been suggested to be linked to allergy and asthma. The non-targeted milk proteomic analysis employed has provided new targets for future studies on the relation between breast milk composition and allergy.

Changing glucocorticoid action: 11β-Hydroxysteroid dehydrogenase type 1 in acute and chronic inflammation

PubMed Central

Chapman, Karen E.; Coutinho, Agnes E.; Zhang, Zhenguang; Kipari, Tiina; Savill, John S.; Seckl, Jonathan R.

2013-01-01

Since the discovery of cortisone in the 1940s and its early success in treatment of rheumatoid arthritis, glucocorticoids have remained the mainstay of anti-inflammatory therapies. However, cortisone itself is intrinsically inert. To be effective, it requires conversion to cortisol, the active glucocorticoid, by the enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). Despite the identification of 11β-HSD in liver in 1953 (which we now know to be 11β-HSD1), its physiological role has been little explored until recently. Over the past decade, however, it has become apparent that 11β-HSD1 plays an important role in shaping endogenous glucocorticoid action. Acute inflammation is more severe with 11β-HSD1-deficiency or inhibition, yet in some inflammatory settings such as obesity or diabetes, 11β-HSD1-deficiency/inhibition is beneficial, reducing inflammation. Current evidence suggests both beneficial and detrimental effects may result from 11β-HSD1 inhibition in chronic inflammatory disease. Here we review recent evidence pertaining to the role of 11β-HSD1 in inflammation. This article is part of a Special Issue entitled ‘CSR 2013’. PMID:23435016

Rupatadine inhibits inflammatory mediator release from human laboratory of allergic diseases 2 cultured mast cells stimulated by platelet-activating factor.

PubMed

Alevizos, Michail; Karagkouni, Anna; Vasiadi, Magdalini; Sismanopoulos, Nikolaos; Makris, Michael; Kalogeromitros, Dimitrios; Theoharides, Theoharis C

2013-12-01

Mast cells are involved in allergy and inflammation by the secretion of multiple mediators, including histamine, cytokines, and platelet-activating factor (PAF), in response to different triggers, including emotional stress. PAF has been associated with allergic inflammation, but there are no clinically available PAF inhibitors. To investigate whether PAF could stimulate human mast cell mediator release and whether rupatadine (RUP), a dual histamine-1 and PAF receptor antagonist, could inhibit the effect of PAF on human mast cells. Laboratory of allergic diseases 2 cultured mast cells were stimulated with PAF (0.001, 0.01, and 0.1 μmol/L) and substance P (1 μmol/L) with or without pretreatment with RUP (2.5 and 25 μmol/L), which was added 10 minutes before stimulation. Release of β-hexosaminidase was measured in supernatant fluid by spectrophotoscopy, and histamine, interleukin-8, and tumor necrosis factor were measured by enzyme-linked immunosorbent assay. PAF stimulated a statistically significant release of histamine, interleukin-8, and tumor necrosis factor (0.001-0.1 μmol/L) that was comparable to that stimulated by substance P. Pretreatment with RUP (25 μmol/L) for 10 minutes inhibited this effect. In contrast, pretreatment of laboratory of allergic diseases 2 cells with diphenhydramine (25 μmol/L) did not inhibit mediator release, suggesting that the effect of RUP was not due to its antihistaminic effect. PAF stimulates human mast cell release of proinflammatory mediators that is inhibited by RUP. This action endows RUP with additional properties in treating allergic inflammation. Copyright © 2013 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Host DNA released by NETosis promotes rhinovirus-induced type 2 allergic asthma exacerbation

PubMed Central

Toussaint, Marie; Jackson, David J; Swieboda, Dawid; Guedán, Anabel; Tsourouktsoglou, Theodora-Dorita; Ching, Yee Man; Radermecker, Coraline; Makrinioti, Heidi; Aniscenko, Julia; Edwards, Michael R; Solari, Roberto; Farnir, Frédéric; Papayannopoulos, Venizelos; Bureau, Fabrice; Marichal, Thomas; Johnston, Sebastian L

2018-01-01

Respiratory viral infections represent the most common cause of allergic asthma exacerbations. Amplification of type 2 immune response is strongly implicated in asthma exacerbation, but how virus infection boosts type 2 responses is poorly understood. We report a significant correlation between release of host double stranded DNA (dsDNA) following rhinovirus infection and exacerbation of type 2 allergic inflammation in humans. In a mouse model of allergic airway hypersensitivity, we show that rhinovirus infection triggers dsDNA release associated with neutrophil extracellular traps (NETs) formation (NETosis). We further demonstrate that inhibiting NETosis by blocking neutrophil elastase, or degrading NETs with DNase protects mice from type 2 immunopathology. Furthermore, injection of mouse genomic DNA alone is sufficient to recapitulate many features of rhinovirus-induced type 2 immune responses and asthma pathology. Thus, NETosis and its associated extracellular dsDNA contribute to the pathogenesis and may represent potential therapeutic targets of rhinovirus-induced asthma exacerbations. PMID:28459437

Innate immunity and effector and regulatory mechanisms involved in allergic contact dermatitis*

PubMed Central

Silvestre, Marilene Chaves; Sato, Maria Notomi; dos Reis, Vitor Manoel Silva

2018-01-01

Skin's innate immunity is the initial activator of immune response mechanisms, influencing the development of adaptive immunity. Some contact allergens are detected by Toll-like receptors (TLRs) and inflammasome NLR3. Keratinocytes participate in innate immunity and, in addition to functioning as an anatomical barrier, secrete cytokines, such as TNF, IL-1β, and IL-18, contributing to the development of Allergic Contact Dermatitis. Dendritic cells recognize and process antigenic peptides into T cells. Neutrophils cause pro-inflammatory reactions, mast cells induce migration/maturation of skin DCs, the natural killer cells have natural cytotoxic capacity, the γδ T cells favor contact with hapten during the sensitization phase, and the innate lymphoid cells act in the early stages by secreting cytokines, as well as act in inflammation and tissue homeostasis. The antigen-specific inflammation is mediated by T cells, and each subtype of T cells (Th1/Tc1, Th2/Tc2, and Th17/Tc17) activates resident skin cells, thus contributing to inflammation. Skin's regulatory T cells have a strong ability to inhibit the proliferation of hapten-specific T cells, acting at the end of the Allergic Contact Dermatitis response and in the control of systemic immune responses. In this review, we report how cutaneous innate immunity is the first line of defense and focus its role in the activation of the adaptive immune response, with effector response induction and its regulation. PMID:29723367

Innate immunity and effector and regulatory mechanisms involved in allergic contact dermatitis.

PubMed

Silvestre, Marilene Chaves; Sato, Maria Notomi; Reis, Vitor Manoel Silva Dos

2018-03-01

Skin's innate immunity is the initial activator of immune response mechanisms, influencing the development of adaptive immunity. Some contact allergens are detected by Toll-like receptors (TLRs) and inflammasome NLR3. Keratinocytes participate in innate immunity and, in addition to functioning as an anatomical barrier, secrete cytokines, such as TNF, IL-1β, and IL-18, contributing to the development of Allergic Contact Dermatitis. Dendritic cells recognize and process antigenic peptides into T cells. Neutrophils cause pro-inflammatory reactions, mast cells induce migration/maturation of skin DCs, the natural killer cells have natural cytotoxic capacity, the γδ T cells favor contact with hapten during the sensitization phase, and the innate lymphoid cells act in the early stages by secreting cytokines, as well as act in inflammation and tissue homeostasis. The antigen-specific inflammation is mediated by T cells, and each subtype of T cells (Th1/Tc1, Th2/Tc2, and Th17/Tc17) activates resident skin cells, thus contributing to inflammation. Skin's regulatory T cells have a strong ability to inhibit the proliferation of hapten-specific T cells, acting at the end of the Allergic Contact Dermatitis response and in the control of systemic immune responses. In this review, we report how cutaneous innate immunity is the first line of defense and focus its role in the activation of the adaptive immune response, with effector response induction and its regulation.

The expression and activation of the AIM2 inflammasome correlates with inflammation and disease severity in patients with acute pancreatitis.

PubMed

Algaba-Chueca, Francisco; de-Madaria, Enrique; Lozano-Ruiz, Beatriz; Martínez-Cardona, Claudia; Quesada-Vázquez, Noé; Bachiller, Victoria; Tarín, Fabián; Such, José; Francés, Rubén; Zapater, Pedro; González-Navajas, José M

Acute pancreatitis is an inflammatory disorder of the pancreas that is responsible for significant morbidity and mortality. The inflammasome pathway has acquired significant relevance in the pathogenesis of many inflammatory disorders, but its role in patients with acute pancreatitis still awaits clarification. We performed a prospective study in which 27 patients with acute pancreatitis and 16 healthy controls were included. We isolated peripheral blood mononuclear cells (PBMCs) and we assessed the expression and activation of different inflammasomes as well as their association with the clinical course of the disease. Our results show that PBMCs from patients with acute pancreatitis have elevated expression of several components of the inflammasome complex, including the inflammasome-forming receptor absent in melanoma 2 (AIM2), early during the onset of the disease. Activation of the AIM2 or NLRP3 inflammasomes in PBMCs from patients with acute pancreatitis results in exacerbated IL-1β and IL-18 production compared with PBMCs from healthy controls. Furthermore, both AIM2 mRNA expression and AIM2-mediated production of IL-1β by PBMCs correlated with increased systemic inflammation in these patients. Last, AIM2 expression was further increased in those patients that developed transient or persistent organ failure (moderate or severe acute pancreatitis). Our data demonstrates that AIM2 inflammasome expression and activation is increased early during the course of acute pancreatitis, and suggests that AIM2 activation may affect systemic inflammation and organ failure in these patients. Copyright © 2017 IAP and EPC. Published by Elsevier B.V. All rights reserved.

Risk factors associated with allergic and non-allergic asthma in adolescents.

PubMed

Janson, Christer; Kalm-Stephens, Pia; Foucard, Tony; Alving, Kjell; Nordvall, S Lennart

2007-07-01

Risk factors for asthma have been investigated in a large number of studies in adults and children, with little progress in the primary and secondary prevention of asthma. The aim of this investigation was to investigate risk factors associated with allergic and non-allergic asthma in adolescents. In this study, 959 schoolchildren (13-14 years old) answered a questionnaire and performed exhaled nitric oxide (NO) measurements. All children (n = 238) with reported asthma, asthma-related symptoms and/or increased NO levels were invited to a clinical follow-up which included a physician evaluation and skin-prick testing. Asthma was diagnosed in 96 adolescents, whereof half had allergic and half non-allergic asthma. Children with both allergic and non-allergic asthma had a significantly higher body mass index (BMI) (20.8 and 20.7 vs. 19.8 kg/m(2)) (p < 0.05) and a higher prevalence of parental asthma (30% and 32% vs. 16%) (p < 0.05). Early-life infection (otitis and croup) [adjusted odds ratio (OR) (95% confidence interval (CI)): 1.99 (1.02-3.88) and 2.80 (1.44-5.42), respectively], pets during the first year of life [2.17 (1.16-4.04)], window pane condensation [2.45 (1.11-5.40)] and unsatisfactory school cleaning [(2.50 (1.28-4.89)] was associated with non-allergic but not with allergic asthma. This study indicates the importance of distinguishing between subtypes of asthma when assessing the effect of different risk factors. While the risk of both allergic and non-allergic asthma increased with increasing BMI, associations between early-life and current environmental exposure were primarily found in relation to non-allergic asthma.

Pitavastatin is a potent anti-inflammatory agent in the rat paw model of acute inflammation.

PubMed

Qadir, Farida; Alam, Syed Mahboob; Siddiqi, Abeer Qamar; Kamran, Afshan

2014-11-01

Statins are used extensively as anti-hyperlipidemic agents. In addition to curtailing cholesterol synthesis they have been found to have multiple actions unrelated to cholesterol lowering "the pleiotropic effects," which includes inhibition of inflammation. We aimed at investigating the effect of pitavastatin a 3rd generation statin, in suppressing acute inflammation in rat paw edema model. Male Sprague-Dawley rats were randomly assigned to one of five groups (n=8): Control, indomethacin and pitavastatin (0.2mg/kg, 0.4mg/kg, 0.8mg/kg) treated. 1hour following treatment, inflammation was induced by sub-planter injection of egg albumin into the hind paw. Anti-inflammatory effect was evaluated by measurement of edema formation every half hour for three hours, assessment of polymorphonuclear leukocyte (PMNL) infiltration and measurement of tissue damage in skin biopsies. Ascending doses of pitavastatin were found to attenuate these parameters. The lowest dose of pitavastatin (0.2mg/kg) was found to significantly reduce edema volume, PMNL infiltration and tissue damage. The efficacy of the smallest dose was found comparable to indomethacin.

Intratracheal IL-6 protects against lung inflammation in direct, but not indirect, causes of acute lung injury in mice.

PubMed

Bhargava, Rhea; Janssen, William; Altmann, Christopher; Andrés-Hernando, Ana; Okamura, Kayo; Vandivier, R William; Ahuja, Nilesh; Faubel, Sarah

2013-01-01

Serum and bronchoalveolar fluid IL-6 are increased in patients with acute respiratory distress syndrome (ARDS) and predict prolonged mechanical ventilation and poor outcomes, although the role of intra-alveolar IL-6 in indirect lung injury is unknown. We investigated the role of endogenous and exogenous intra-alveolar IL-6 in AKI-mediated lung injury (indirect lung injury), intraperitoneal (IP) endotoxin administration (indirect lung injury) and, for comparison, intratracheal (IT) endotoxin administration (direct lung injury) with the hypothesis that IL-6 would exert a pro-inflammatory effect in these causes of acute lung inflammation. Bronchoalveolar cytokines (IL-6, CXCL1, TNF-α, IL-1β, and IL-10), BAL fluid neutrophils, lung inflammation (lung cytokines, MPO activity [a biochemical marker of neutrophil infiltration]), and serum cytokines were determined in adult male C57Bl/6 mice with no intervention or 4 hours after ischemic AKI (22 minutes of renal pedicle clamping), IP endotoxin (10 µg), or IT endotoxin (80 µg) with and without intratracheal (IT) IL-6 (25 ng or 200 ng) treatment. Lung inflammation was similar after AKI, IP endotoxin, and IT endotoxin. BAL fluid IL-6 was markedly increased after IT endotoxin, and not increased after AKI or IP endotoxin. Unexpectedly, IT IL-6 exerted an anti-inflammatory effect in healthy mice characterized by reduced BAL fluid cytokines. IT IL-6 also exerted an anti-inflammatory effect in IT endotoxin characterized by reduced BAL fluid cytokines and lung inflammation; IT IL-6 had no effect on lung inflammation in AKI or IP endotoxin. IL-6 exerts an anti-inflammatory effect in direct lung injury from IT endotoxin, yet has no role in the pathogenesis or treatment of indirect lung injury from AKI or IP endotoxin. Since intra-alveolar inflammation is important in the pathogenesis of direct, but not indirect, causes of lung inflammation, IT anti-inflammatory treatments may have a role in direct, but not indirect, causes of ARDS.

Therapeutic Effects of Fermented Red Ginseng in Allergic Rhinitis: A Randomized, Double-Blind, Placebo-Controlled Study

PubMed Central

Jung, Jae-Woo; Ji, Geun-Eog; Park, Myeong-Soo; Song, Woo-Jung; Kim, Min-Hye; Kwon, Jae-Woo; Kim, Tae-Whan; Park, Heung-Woo; Cho, Sang-Heon; Min, Kyung-Up

2011-01-01

Purpose Allergic rhinitis is clinically defined as a disorder of the nose induced by IgE mediated inflammation after allergen exposure of the nasal mucosa. Many reports have stated that Panax ginseng and fermented red ginseng have anti-inflammatory effects, especially against Th2-type inflammation. This study was conducted to evaluate the therapeutic effects of fermented red ginseng in allergic rhinitis. Methods In this 4-week, double-blind, placebo-controlled study, 59 patients with persistent perennial allergic rhinitis were randomly divided into two groups: those receiving fermented red ginseng tablets (experimental group) and those receiving placebo (control group). The primary efficacy variable was the total nasal symptom score (TNSS; rhinorrhea, sneezing, itchy nose, and nasal congestion). Secondary efficacy variables were the Rhinitis Quality of Life (RQoL) score and skin reactivity to inhalant allergens, as determined by the skin prick test. Results There was no significant difference in the TNSS score and TNSS duration score between the experimental and placebo groups in weeks 1, 2, 3, or 4. For nasal congestion, fermented red ginseng was significantly effective (P<0.005), while placebo caused no change. The activity and emotion of RQoL improved markedly secondary to treatment with fermented red ginseng (P<0.05), while placebo caused no change. Additionally, fermented red ginseng reduced skin reactivity to sensitized perennial allergens (P<0.05). Fermented red ginseng was well tolerated. Conclusions Fermented red ginseng improved nasal congestion symptoms and RQoL in patients with perennial allergic rhinitis. PMID:21461249

Assessment of sensitization to insect aeroallergens among patients with allergic rhinitis in Yazd City, Iran.

PubMed

Bemanian, Mohammad Hassan; Alizadeh Korkinejad, Narges; Shirkhoda, Shima; Nabavi, Mohammad; Pourpak, Zahra

2012-09-01

The frequency of allergic diseases such as allergic rhinitis is considerable in general population. Insect aeroallergens are important allergens which can induce airway inflammation. The aim of this study was to determine the prevalence of sensitization to insect aeroallergens in allergic rhinitis patients in Yazd as a desert city in Iran.A cross-sectional study was undertaken on 95 allergic rhinitis patients who were referred to allergy clinic of Yazd city. Skin prick tests (SPT) by standard extracts of three insect aeroallergens including Mosquito, Corn moth, Cockroach and two species of mites as common aeroallergens in allergic rhinitis (Dermatophagoid Farina, Dermatophagoid Peteronysinus) were done.SPT results showed that the most common insect aeroallergens were: mosquito (32.6%) followed by corn moth (26.3%) and cockroach (13.7%).The prevalence of SPT positive response to Dermatophagoid Peteronysinus, Dermatophagoid Farina were 8.4% and 7.4%, respectively. These results demonstrated that sensitization to insect aeroallergens was significantly more common compared to mites in patients with allergic rhinitis in Yazd city, a city surrounded by deserts. High prevalence of skin reactivity to mosquito and corn moth as insect aeroallergens in Yazd city with hot and dry climate in contrast to humid regions such as north of Iran, where mites are more frequent, indicates differences in the prevalence of aeroallergen reactivity in various areas with different climates. Our study could highlight the importance of insect aeroallergens for clinicians for better diagnosis and management of patients with allergic rhinitis.

Dietary, nondigestible oligosaccharides and Bifidobacterium breve M-16V suppress allergic inflammation in intestine via targeting dendritic cell maturation.

PubMed

de Kivit, Sander; Kostadinova, Atanaska I; Kerperien, JoAnn; Morgan, Mary E; Muruzabal, Veronica Ayechu; Hofman, Gerard A; Knippels, Leon M J; Kraneveld, Aletta D; Garssen, Johan; Willemsen, Linette E M

2017-07-01

Dietary intervention with short-chain galacto-oligosaccharides (scGOS), long-chain fructo-oligosaccharides (lcFOS) and Bifidobacterium breve M-16V ( Bb ) (GF/ Bb ) suppresses food allergic symptoms in mice, potentially via intestinal epithelial cell (IEC)-derived galectin-9. Furthermore, in vitro studies showed galacto- and fructo-oligosaccharides (GF) to enhance the immunomodulatory capacity of a TLR9 ligand representing bacterial CpG DNA when exposed to IEC. In this study, we investigated whether GF/ Bb modulates dendritic cells (DCs) and subsequent Th2 and regulatory T cell (T reg ) frequency in the small intestinal lamina propria (SI-LP). BALB/c mice were fed GF/ Bb during oral OVA sensitization. DC and T cell phenotype were determined in SI-LP mononuclear cells using flow cytometry. Murine bone marrow-derived DCs (BMDCs) were exposed to recombinant galectin-9 or human monocyte-derived DCs (moDCs) and were cultured in IEC-conditioned medium from GF and TLR9 ligand-exposed HT-29 cells. GF/ Bb reduced allergic symptoms and enhanced serum galectin-9 levels, while suppressing activation, restoring phagocytic capacity, and normalizing CD103 expression of SI-LP DCs of OVA-allergic mice. In vitro, galectin-9 suppressed LPS-induced activation markers and cytokine secretion by BMDCs, and IEC-conditioned medium suppressed moDC activation in a galectin-9-dependent manner. Besides suppression of SI-LP DC activation, dietary GF/ Bb also lowered the frequency of activated Th2 cells, while enhancing T reg in the SI-LP of OVA-allergic mice compared to the control diet. Dietary intervention with GF/ Bb enhances galectin-9 and suppresses allergic symptoms of OVA-allergic mice in association with reduced intestinal DC and Th2 activation and increased T reg frequency in these mice. © Society for Leukocyte Biology.

Histopathological effects of intranasal phototherapy and nasal corticosteroids in allergic rhinitis in a rabbit model.

PubMed

Yurttas, Veysel; Şereflican, Murat; Erkoçoğlu, Mustafa; Terzi, Elçin Hakan; Kükner, Aysel; Oral, Mesut

2015-08-01

Allergic rhinitis is one of the most common health problems and has a major effect on quality of life. Although new-generation antihistamines and nasal steroids are the main treatment options, complete resolution cannot be obtained in some patients. Besides common side effects such as nasal irritation and epistaxis, the use of these drugs is controversial in some patients, such as pregnant or breastfeeding women. These findings highlight the need for new treatment options. Although phototherapy has been successfully used in the treatment of atopic dermatitis, which is an IgE-mediated disease and shares several common pathogenic features with allergic rhinitis, there are limited studies about its role in the treatment of allergic rhinitis. In this study, we aimed to evaluate and compare the histopathological effects of intranasal phototherapy (Rhinolight) and nasal corticosteroid treatment on the nasal mucosa in allergic rhinitis in a rabbit model and we found that both treatment options significantly reduced inflammation in the nasal mucosa without increasing apoptosis of mucosal cells. Copyright © 2015 Elsevier B.V. All rights reserved.

Self-Assembling Nanoparticles Containing Dexamethasone as a Novel Therapy in Allergic Airways Inflammation

PubMed Central

Kenyon, Nicholas J.; Bratt, Jennifer M.; Lee, Joyce; Luo, Juntao; Franzi, Lisa M.; Zeki, Amir A.; Lam, Kit S.

2013-01-01

Nanocarriers can deliver a wide variety of drugs, target them to sites of interest, and protect them from degradation and inactivation by the body. They have the capacity to improve drug action and decrease undesirable systemic effects. We have previously developed a well-defined non-toxic PEG-dendritic block telodendrimer for successful delivery of chemotherapeutics agents and, in these studies, we apply this technology for therapeutic development in asthma. In these proof-of-concept experiments, we hypothesized that dexamethasone contained in self-assembling nanoparticles (Dex-NP) and delivered systemically would target the lung and decrease allergic lung inflammation and airways hyper-responsiveness to a greater degree than equivalent doses of dexamethasone (Dex) alone. We found that ovalbumin (Ova)-exposed mice treated with Dex-NP had significantly fewer total cells (2.78±0.44×105 (n = 18) vs. 5.98±1.3×105 (n = 13), P<0.05) and eosinophils (1.09±0.28×105 (n = 18) vs. 2.94±0.6×105 (n = 12), p<0.05) in the lung lavage than Ova-exposed mice alone. Also, lower levels of the inflammatory cytokines IL-4 (3.43±1.2 (n = 11) vs. 8.56±2.1 (n = 8) pg/ml, p<0.05) and MCP-1 (13.1±3.6 (n = 8) vs. 28.8±8.7 (n = 10) pg/ml, p<0.05) were found in lungs of the Dex-NP compared to control, and they were not lower in the Dex alone group. In addition, respiratory system resistance was lower in the Dex-NP compared to the other Ova-exposed groups suggesting a better therapeutic effect on airways hyperresponsiveness. Taken together, these findings from early-stage drug development studies suggest that the encapsulation and protection of anti-inflammatory agents such as corticosteroids in nanoparticle formulations can improve efficacy. Further development of novel drugs in nanoparticles is warranted to explore potential treatments for chronic inflammatory diseases such as asthma. PMID:24204939

N-Arachidonoyl Dopamine Modulates Acute Systemic Inflammation via Nonhematopoietic TRPV1

PubMed Central

Lawton, Samira K.; Xu, Fengyun; Tran, Alphonso; Wong, Erika; Schumacher, Mark; Wilhelmsen, Kevin

2017-01-01

N-Arachidonoyl dopamine (NADA) is an endogenous lipid that potently activates the transient receptor potential vanilloid 1 (TRPV1), which mediates pain and thermosensation. NADA is also an agonist of cannabinoid receptors 1 and 2. We have reported that NADA reduces the activation of cultured human endothelial cells by LPS and TNF-α. Thus far, in vivo studies using NADA have focused on its neurologic and behavioral roles. In this article, we show that NADA potently decreases in vivo systemic inflammatory responses and levels of the coagulation intermediary plasminogen activator inhibitor 1 in three mouse models of inflammation: LPS, bacterial lipopeptide, and polymicrobial intra-abdominal sepsis. We also found that the administration of NADA increases survival in endotoxemic mice. Additionally, NADA reduces blood levels of the neuropeptide calcitonin gene-related peptide but increases the neuropeptide substance P in LPS-treated mice. We demonstrate that the anti-inflammatory effects of NADA are mediated by TRPV1 expressed by nonhematopoietic cells and provide data suggesting that neuronal TRPV1 may mediate NADA’s anti-inflammatory effects. These results indicate that NADA has novel TRPV1-dependent anti-inflammatory properties and suggest that the endovanilloid system might be targeted therapeutically in acute inflammation. PMID:28701511

Bovine milk fat enriched in conjugated linoleic and vaccenic acids attenuates allergic airway disease in mice.

PubMed

Kanwar, R K; Macgibbon, A K; Black, P N; Kanwar, J R; Rowan, A; Vale, M; Krissansen, G W

2008-01-01

It has been argued that a reduction in the Western diet of anti-inflammatory unsaturated lipids, such as n-3 polyunsaturated fatty acids, has contributed to the increase in the frequency and severity of allergic diseases. We investigated whether feeding milk fat enriched in conjugated linoleic acid and vaccenic acids (VAs) ('enriched' milk fat), produced by supplementing the diet of pasture-fed cows with fish and sunflower oil, will prevent development of allergic airway responses. C57BL/6 mice were fed a control diet containing soybean oil and diets supplemented with milk lipids. They were sensitized by intraperitoneal injection of ovalbumin (OVA) on days 14 and 28, and challenged intranasally with OVA on day 42. Bronchoalveolar lavage fluid, lung tissues and serum samples were collected 6 days after the intranasal challenge. Feeding of enriched milk fat led to marked suppression of airway inflammation as evidenced by reductions in eosinophilia and lymphocytosis in the airways, compared with feeding of normal milk fat and control diet. Enriched milk fat significantly reduced circulating allergen-specific IgE and IgG1 levels, together with reductions in bronchoalveolar lavage fluid of IL-5 and CCL11. Treatment significantly inhibited changes in the airway including airway epithelial cell hypertrophy, goblet cell metaplasia and mucus hypersecretion. The two major components of enriched milk fat, cis-9, trans-11 conjugated linoleic acid and VA, inhibited airway inflammation when fed together to mice, whereas alone they were not effective. Milk fat enriched in conjugated linoleic and VAs suppresses inflammation and changes to the airways in an animal model of allergic airway disease.

Surfactant protein D attenuates sub-epithelial fibrosis in allergic airways disease through TGF-β.

PubMed

Ogawa, Hirohisa; Ledford, Julie G; Mukherjee, Sambuddho; Aono, Yoshinori; Nishioka, Yasuhiko; Lee, James J; Izumi, Keisuke; Hollingsworth, John W

2014-11-29

Surfactant protein D (SP-D) can regulate both innate and adaptive immunity. Recently, SP-D has been shown to contribute to the pathogenesis of airway allergic inflammation and bleomycin-induced pulmonary fibrosis. However, in allergic airways disease, the role of SP-D in airway remodeling remains unknown. The objective of this study was to determine the contribution of functional SP-D in regulating sub-epithelial fibrosis in a mouse chronic house dust mite model of allergic airways disease. C57BL/6 wild-type (WT) and SP-D-/- mice (C57BL/6 background) were chronically challenged with house dust mite antigen (Dermatophagoides pteronyssinus, Dp). Studies with SP-D rescue and neutralization of TGF-β were conducted. Lung histopathology and the concentrations of collagen, growth factors, and cytokines present in the airspace and lung tissue were determined. Cultured eosinophils were stimulated by Dp in presence or absence of SP-D. Dp-challenged SP-D-/- mice demonstrate increased sub-epithelial fibrosis, collagen production, eosinophil infiltration, TGF-β1, and IL-13 production, when compared to Dp-challenged WT mice. By immunohistology, we detected an increase in TGF-β1 and IL-13 positive eosinophils in SP-D-/- mice. Purified eosinophils stimulated with Dp produced TGF-β1 and IL-13, which was prevented by co-incubation with SP-D. Additionally, treatment of Dp challenged SP-D-/- mice with exogenous SP-D was able to rescue the phenotypes observed in SP-D-/- mice and neutralization of TGF-β1 reduced sub-epithelial fibrosis in Dp-challenged SP-D-/- mice. These data support a protective role for SP-D in the pathogenesis of sub-epithelial fibrosis in a mouse model of allergic inflammation through regulation of eosinophil-derived TGF-β.

Breastfeeding, Childhood Asthma, and Allergic Disease.

PubMed

Oddy, Wendy H

2017-01-01

The worldwide prevalence of childhood asthma has been increasing considerably, and the protection afforded by breastfeeding in its development has been the subject of controversy for more than 80 years. Previous systematic reviews have generally found a protective effect of breastfeeding on allergic outcomes, although many studies have methodological limitations. Although breastfeeding is protective against lower respiratory tract infection during infancy, such protection has not been demonstrated for asthma in all studies. Breastfeeding has health benefits for the mother and child. Exclusive breastfeeding for the first 6 months of an infant's life, with continued breastfeeding for up to 2 years or longer, is recognized as the "gold" standard for infant feeding because human milk is uniquely suited to the human infant, and its nutritional content and bioactivity promote a healthy development. There is increasing concern that the practice of delaying complementary foods until 6 months may exacerbate the risk of allergic disease. Breast milk contains immunological components that protect against infections and allergic disease in infancy. The composition of human breast milk is complex, containing factors that interact with the infant immune system and intestinal milieu including allergens, cytokines, immunoglobulins, polyunsaturated fatty acids, and chemokines. Transforming growth factor β is a cytokine in human milk involved in maintaining intestinal homeostasis, inflammation regulation, and oral tolerance development. Modern day society, with increased standards of hygiene, has changed the gut flora of Western infants, potentially impacting the risk of developing immune-mediated diseases including allergic disease and asthma. Microbial diversity is intrinsic to healthy immune maturation and function. Compared to breastfed infants, formula-fed infants had lower bacterial diversity and an altered intestinal microbiota in the first few weeks of life associated with

Targeting Mast Cells and Basophils with Anti-FcεRIα Fab-Conjugated Celastrol-Loaded Micelles Suppresses Allergic Inflammation.

PubMed

Peng, Xia; Wang, Juan; Li, Xianyang; Lin, Lihui; Xie, Guogang; Cui, Zelin; Li, Jia; Wang, Yuping; Li, Li

2015-12-01

Mast cells and basophils are effector cells in the pathophysiology of allergic diseases. Targeted elimination of these cells may be a promising strategy for the treatment of allergic disorders. Our present study aims at targeted delivery of anti-FcεRIα Fab-conjugated celastrol-loaded micelles toward FcεRIα receptors expressed on mast cells and basophils to have enhanced anti-allergic effect. To achieve this aim, we prepared celastrol-loaded (PEO-block-PPO-block-PEO, Pluronic) polymeric nanomicelles using thin-film hydration method. The anti-FcεRIα Fab Fragment was then conjugated to carboxyl groups on drug-loaded micelles via EDC amidation reaction. The anti-FcεRIα Fab-conjugated celastrol-loaded micelles revealed uniform particle size (93.43 ± 12.93 nm) with high loading percentage (21.2 ± 1.5% w/w). The image of micelles showed oval and rod like. The anti-FcεRIα Fab-conjugated micelles demonstrated enhanced cellular uptake and cytotoxity toward target KU812 cells than non-conjugated micelles in vitro. Furthermore, diffusion of the drug into the cells allowed an efficient induction of cell apoptosis. In mouse model of allergic asthma, treatment with anti-FcεRIα Fab-conjugated micelles increased lung accumulation of micelles, and significantly reduced OVA-sIgE, histamine and Th2 cytokines (IL-4, IL-5, TNF-α) levels, eosinophils infiltration and mucus production. In addition, in mouse model of passive cutaneous anaphylaxis, anti-FcεRIα Fab-conjugated celastrol-loaded micelles treatment significantly decreased extravasated evan's in the ear. These results indicate that anti-FcεRIα Fab-conjugated celastrol-loaded micelles can target and selectively kill mast cells and basophils which express FcεRIα, and may be efficient reagents for the treatment of allergic disorders and mast cell related diseases.

Neutrophil-derived JAML Inhibits Repair of Intestinal Epithelial Injury During Acute Inflammation

PubMed Central

Weber, Dominique A.; Sumagin, Ronen; McCall, Ingrid C.; Leoni, Giovanna; Neumann, Philipp A.; Andargachew, Rakieb; Brazil, Jennifer C.; Medina-Contreras, Oscar; Denning, Timothy L.; Nusrat, Asma; Parkos, Charles A.

2014-01-01

Neutrophil transepithelial migration (TEM) during acute inflammation is associated with mucosal injury. Using models of acute mucosal injury in-vitro and in-vivo, we describe a new mechanism by which neutrophils infiltrating the intestinal mucosa disrupt epithelial homeostasis. We report that junctional adhesion molecule-like protein (JAML) is cleaved from neutrophil surface by zinc-metalloproteases during TEM. Neutrophil-derived soluble JAML bound to the epithelial tight junction protein coxsackie-adenovirus receptor (CAR) resulting in compromised barrier and inhibition of wound repair, through decreased epithelial proliferation. The deleterious effects of JAML on barrier and wound repair were reversed with an anti-JAML mAb that inhibits JAML-CAR binding. Thus, JAML released from transmigrating neutrophils across inflamed epithelia can promote recruitment of leukocytes and aid in clearance of invading microorganisms. However, sustained release of JAML under pathologic conditions associated with persistence of large numbers of infiltrated neutrophil would compromise intestinal barrier and inhibit mucosal healing. Targeting JAML-CAR interactions may thus improve mucosal healing responses under conditions of dysregulated neutrophil recruitment. PMID:24621992

STRETCHING IMPACTS INFLAMMATION RESOLUTION IN CONNECTIVE TISSUE

PubMed Central

Berrueta, Lisbeth; Muskaj, Igla; Olenich, Sara; Butler, Taylor; Badger, Gary J.; Colas, Romain A.; Spite, Matthew; Serhan, Charles N.; Langevin, Helene M.

2016-01-01

Acute inflammation is accompanied from its outset by the release of specialized pro-resolving mediators (SPMs), including resolvins, that orchestrate the resolution of local inflammation. We showed earlier that, in rats with subcutaneous inflammation of the back induced by carrageenan, stretching for 10 minutes twice daily reduced inflammation and improved pain, two weeks after carrageenan injection. In this study, we hypothesized that stretching of connective tissue activates local pro-resolving mechanisms within the tissue in the acute phase of inflammation. In rats injected with carrageenan and randomized to stretch vs. no stretch for 48 hours, stretching reduced inflammatory lesion thickness and neutrophil count, and increased resolvin (RvD1) concentrations within lesions. Furthermore, subcutaneous resolvin injection mimicked the effect of stretching. In ex vivo experiments, stretching of connective tissue reduced the migration of neutrophils and increased tissue RvD1 concentration. These results demonstrate a direct mechanical impact of stretching on inflammation-regulation mechanisms within connective tissue. PMID:26588184

Discovery of a potent nanoparticle P-selectin antagonist with anti-inflammatory effects in allergic airway disease

PubMed Central

John, Alison E.; Lukacs, Nicholas W.; Berlin, Aaron A.; Palecanda, Aiyappa; Bargatze, Robert F.; Stoolman, Lloyd M.; Nagy, Jon O.

2010-01-01

The severity of allergic asthma is dependent, in part, on the intensity of peribronchial inflammation. P-selectin is known to play a role in the development of allergen-induced peribronchial inflammation and airway hyperreactivity. Selective inhibitors of P-selectin-mediated leukocyte endothelial-cell interactions may therefore attenuate the inflammatory processes associated with allergic airway disease. Novel P-selectin inhibitors were created using a polyvalent polymer nanoparticle capable of displaying multiple synthetic, low molecular weight ligands. By assembling a particle that presents an array of groups, which as monomers interact with only low affinity, we created a construct that binds extremely efficiently to P-selectin. The ligands acted as mimetics of the key binding elements responsible for the high-avidity adhesion of P-selectin to the physiologic ligand, PSGL-1. The inhibitors were initially evaluated using an in vitro shear assay system in which interactions between circulating cells and P-selectin-coated capillary tubes were measured. The nanoparticles were shown to preferentially bind to selectins expressed on activated endothelial cells. We subsequently demonstrated that nanoparticles displaying P-selectin blocking arrays were functionally active in vivo, significantly reducing allergen-induced airway hyperreactivity and peribronchial eosinophilic inflammation in a murine model of asthma. PMID:14563683

Where Does Inflammation Fit?

PubMed

Biasucci, Luigi M; La Rosa, Giulio; Pedicino, Daniela; D'Aiello, Alessia; Galli, Mattia; Liuzzo, Giovanna

2017-09-01

This review focuses on the complex relationship between inflammation and the onset of acute coronary syndrome and heart failure. In the last few years, two important lines of research brought new and essential information to light in the pathogenesis of acute coronary syndrome: a) the understanding of the immune mediate mechanisms of inflammation in Ischemic Heart Disease (IHD) and b) evidence that the inflammatory mechanisms associated with atherosclerosis and its complications can be modulated by anti-inflammatory molecules. A large amount of data also suggests that inflammation is a major component in the development and exacerbation of heart failure (HF), in a symbiotic relationship. In particular, recent evidence underlies peculiar aspects of the phenomenon: oxidative stress and autophagy; DAMPS and TLR-4 signaling activation; different macrophages lineage and the contribution of NLRP-3 inflammasome; adaptive immune system. A possible explanation that could unify the pathogenic mechanism of these different conditions is the rising evidence that increased bowel permeability may allow translation of gut microbioma product into the circulation. These findings clearly establish the role of inflammation as the great trigger for two of the major cardiovascular causes of death and morbidity. Further studies are needed, to better clarify the issue and to define more targeted approaches to reduce pathological inflammation while preserving the physiological one.

Calycophyllum spruceanum BENTH ameliorates acute inflammation in mice.

PubMed

da Silva, Ana Paula Azevedo Barros; Amorim, Renata Morais Ferreira; de Freitas Lopes, Roberta; Mota, Mário Rogério Lima; da Silva, Felipe Moura Araújo; Koolen, Hector Henrique Ferreira; Lima, Emerson Silva; Assreuy, Ana Maria S; da Cunha, Renildo Moura

2018-06-12

Calycophyllum spruceanum (Benth.) Hook. F. ex K. Schum. is widely distributed in the Amazonian region of Brazil, where it is popularly known as "mulateiro", "pau-mulato", "pau-mulato-de-várzea", "escorrega-macaco" or "pau-marfim". Preparations of C. spruceanum barks are used in the form of tea, poultice or skin patches to treat stomach diseases, skin inflammation and uterus tumors. To investigate in vivo the antinociceptive and anti-inflammatory activities of the hydroalcoholic extract of Calycophyllum spruceanum barks (HECSb) in order to validate its popular usage in inflammatory conditions. Chemical analysis of HECSb was performed using the UHPLC-MS system. Mice were treated per oral with HECSb (5-5000 mg/kg) and evaluated for acute toxicity (during 15 days); motor activity (Rota rod test); body weight (up to 72 h); antinociceptive activity: writhes induced by 0.8% acetic acid; paw licking induced by 2.5% formalin; paw withdrawal (von Frey test) induced by carrageenan (300 μg) or PGE2 (100 ng); anti-inflammatory (paw edema model). For histopathological analysis subplantar tissue fragments were collected 1 h after paw edema induction. HECSb chemical analysis revealed the presence of caffeoylquinic derivatives, small organic acids, and phenolic compounds. HECSb showed antinociceptive effect, reducing the number of acetic acid-induced writhes by 72% at 120 mg/kg, paw licking (phase 2- Formalin test) by 33% at 60 mg/kg and 49% at 120 mg/kg; and paw withdrawal elicited by carrageenan (53% at 120 mg/kg) and PGE2 (120 mg/kg) at 0.5 h (48%) and 1 h (45%). HECSb (120 mg/kg) also inhibited the paw edema elicited both by carrageenan (48%) and PGE2 (92%). Histopathological analysis (leukocyte infiltration, edema, focal areas of hemorrhage, vascular congestion) of HECSb treatment at 120 mg/kg demonstrated normal morphology [median 0 (0,1)] compared to PGE2, showing severe alterations [median 3 (2,3); p = 0,0035]. HECSb did not induce acute

Does Regional Lung Strain Correlate With Regional Inflammation in Acute Respiratory Distress Syndrome During Nonprotective Ventilation? An Experimental Porcine Study.

PubMed

Retamal, Jaime; Hurtado, Daniel; Villarroel, Nicolás; Bruhn, Alejandro; Bugedo, Guillermo; Amato, Marcelo Britto Passos; Costa, Eduardo Leite Vieira; Hedenstierna, Göran; Larsson, Anders; Borges, João Batista

2018-06-01

It is known that ventilator-induced lung injury causes increased pulmonary inflammation. It has been suggested that one of the underlying mechanisms may be strain. The aim of this study was to investigate whether lung regional strain correlates with regional inflammation in a porcine model of acute respiratory distress syndrome. Retrospective analysis of CT images and positron emission tomography images using [F]fluoro-2-deoxy-D-glucose. University animal research laboratory. Seven piglets subjected to experimental acute respiratory distress syndrome and five ventilated controls. Acute respiratory distress syndrome was induced by repeated lung lavages, followed by 210 minutes of injurious mechanical ventilation using low positive end-expiratory pressures (mean, 4 cm H2O) and high inspiratory pressures (mean plateau pressure, 45 cm H2O). All animals were subsequently studied with CT scans acquired at end-expiration and end-inspiration, to obtain maps of volumetric strain (inspiratory volume - expiratory volume)/expiratory volume, and dynamic positron emission tomography imaging. Strain maps and positron emission tomography images were divided into 10 isogravitational horizontal regions-of-interest, from which spatial correlation was calculated for each animal. The acute respiratory distress syndrome model resulted in a decrease in respiratory system compliance (20.3 ± 3.4 to 14.0 ± 4.9 mL/cm H2O; p < 0.05) and oxygenation (PaO2/FIO2, 489 ± 80 to 92 ± 59; p < 0.05), whereas the control animals did not exhibit changes. In the acute respiratory distress syndrome group, strain maps showed a heterogeneous distribution with a greater concentration in the intermediate gravitational regions, which was similar to the distribution of [F]fluoro-2-deoxy-D-glucose uptake observed in the positron emission tomography images, resulting in a positive spatial correlation between both variables (median R = 0.71 [0.02-0.84]; p < 0.05 in five of seven animals

Long term evaluation of mesenchymal stem cell therapy in a feline model of chronic allergic asthma

PubMed Central

Trzil, Julie E; Masseau, Isabelle; Webb, Tracy L; Chang, Chee-hoon; Dodam, John R; Cohn, Leah A; Liu, Hong; Quimby, Jessica M; Dow, Steven W; Reinero, Carol R

2014-01-01

Background Mesenchymal stem cells (MSCs) decrease airway eosinophilia, airway hyperresponsiveness (AHR), and remodeling in murine models of acutely induced asthma. We hypothesized that MSCs would diminish these hallmark features in a chronic feline asthma model. Objective To document effects of allogeneic, adipose-derived MSCs on airway inflammation, airway hyperresponsiveness (AHR), and remodeling over time and investigate mechanisms by which MSCs alter local and systemic immunologic responses in chronic experimental feline allergic asthma. Methods Cats with chronic, experimentally-induced asthma received six intravenous infusions of MSCs (0.36–2.5X10E7 MSCs/infusion) or placebo bimonthly at the time of study enrollment. Cats were evaluated at baseline and longitudinally for one year. Outcome measures included: bronchoalveolar lavage fluid cytology to assess airway eosinophilia; pulmonary mechanics and clinical scoring to assess AHR; and thoracic computed tomographic (CT) scans to assess structural changes (airway remodeling). CT scans were evaluated using a scoring system for lung attenuation (LA) and bronchial wall thickening (BWT). To assess mechanisms of MSC action, immunologic assays including allergen-specific IgE, cellular IL-10 production, and allergen-specific lymphocyte proliferation were performed. Results There were no differences between treatment groups or over time with respect to airway eosinophilia or AHR. However, significantly lower LA and BWT scores were noted in CT images of MSC-treated animals compared to placebo-treated cats at month 8 of the study (LA p=0.0311; BWT p=0.0489). No differences were noted between groups in the immunologic assays. Conclusions and Clinical Relevance When administered after development of chronic allergic feline asthma, MSCs failed to reduce airway inflammation and AHR. However, repeated administration of MSCs at the start of study did reduce computed tomographic measures of airway remodeling by month 8, though

Allergic Reactions

MedlinePlus

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Acinetobacter baumannii Infection Inhibits Airway Eosinophilia and Lung Pathology in a Mouse Model of Allergic Asthma

PubMed Central

Qiu, Hongyu; KuoLee, Rhonda; Harris, Greg; Zhou, Hongyan; Miller, Harvey; Patel, Girishchandra B.; Chen, Wangxue

2011-01-01

Allergic asthma is a dysregulation of the immune system which leads to the development of Th2 responses to innocuous antigens (allergens). Some infections and microbial components can re-direct the immune response toward the Th1 response, or induce regulatory T cells to suppress the Th2 response, thereby inhibiting the development of allergic asthma. Since Acinetobacter baumannii infection can modulate lung cellular and cytokine responses, we studied the effect of A. baumannii in modulating airway eosinophilia in a mouse model of allergic asthma. Ovalbumin (OVA)-sensitized mice were treated with live A. baumannii or phosphate buffered saline (PBS), then intranasally challenged with OVA. Compared to PBS, A. baumannii treatment significantly reduced pulmonary Th2 cytokine and chemokine responses to OVA challenge. More importantly, the airway inflammation in A. baumannii-treated mice was strongly suppressed, as seen by the significant reduction of the proportion and the total number of eosinophils in the bronchoalveolar lavage fluid. In addition, A. baumannii-treated mice diminished lung mucus overproduction and pathology. However, A. baumannii treatment did not significantly alter systemic immune responses to OVA. Serum OVA-specific IgE, IgG1 and IgG2a levels were comparable between A. baumannii- and PBS-treated mice, and tracheobronchial lymph node cells from both treatment groups produced similar levels of Th1 and Th2 cytokines in response to in vitro OVA stimulation. Moreover, it appears that TLR-4 and IFN-γ were not directly involved in the A. baumannii-induced suppression of airway eosinophilia. Our results suggest that A. baumannii inhibits allergic airway inflammation by direct suppression of local pulmonary Th2 cytokine responses to the allergen. PMID:21789200

The hallucinogenic diterpene salvinorin A inhibits leukotriene synthesis in experimental models of inflammation.

PubMed

Rossi, Antonietta; Pace, Simona; Tedesco, Federica; Pagano, Ester; Guerra, Germano; Troisi, Fabiana; Werner, Markus; Roviezzo, Fiorentina; Zjawiony, Jordan K; Werz, Oliver; Izzo, Angelo A; Capasso, Raffaele

2016-04-01

Leukotrienes (LTs) are lipid mediators derived from arachidonic acid (AA) involved in a number of autoimmune/inflammatory disorders including asthma, allergic rhinitis and cardiovascular diseases. Salvinorin A (SA), a diterpene isolated from the hallucinogenic plant Salvia divinorum, is a well-established analgesic compound, but its anti-inflammatory properties are under-researched and its effects on LT production is unknown to date. Here, we studied the possible effect of SA on LT production and verified its actions on experimental models of inflammation in which LTs play a prominent role. Peritoneal macrophages (PM) stimulated by calcium ionophore A23187 were chosen as in vitro system to evaluate the effect of SA on LT production. Zymosan-induced peritonitis in mice and carrageenan-induced pleurisy in rats were selected as LT-related models to evaluate the effect of SA on inflammation as well as on LT biosynthesis. SA inhibited, in a concentration-dependent manner, A23187-induced LTB4 biosynthesis in isolated PM. In zymosan-induced peritonitis, SA inhibited cell infiltration, myeloperoxidase activity, vascular permeability and LTC4 production in the peritoneal cavity without decreasing the production of prostaglandin E2. In carrageenan-induced pleurisy in rats, a more sophisticated model of acute inflammation related to LTs, SA significantly inhibited LTB4 production in the inflammatory exudates, along with reducing the phlogistic process in the lung. In conclusion, SA inhibited LT production and it was effective in experimental models of inflammation in which LTs play a pivotal role. SA might be considered as a lead compound for the development of drugs useful in LTs-related diseases. Copyright © 2016 Elsevier Ltd. All rights reserved.

Inhibiting glycogen synthase kinase-3 reduces endotoxaemic acute renal failure by down-regulating inflammation and renal cell apoptosis

PubMed Central

Wang, Y; Huang, WC; Wang, CY; Tsai, CC; Chen, CL; Chang, YT; Kai, JI; Lin, CF

2009-01-01

Background and purpose: Excessive inflammation and apoptosis are pathological features of endotoxaemic acute renal failure. Activation of glycogen synthase kinase-3 (GSK-3) is involved in inflammation and apoptosis. We investigated the effects of inhibiting GSK-3 on lipopolysaccharide (LPS)-induced acute renal failure, nuclear factor-κB (NF-κB), inflammation and apoptosis. Experimental approach: The effects of inhibiting GSK-3 with inhibitors, including lithium chloride (LiCl) and 6-bromo-indirubin-3′-oxime (BIO), on LPS-treated (15 mg·kg−1) C3H/HeN mice (LiCl, 40 mg·kg−1 and BIO, 2 mg·kg−1) and LPS-treated (1 µg·mL−1) renal epithelial cells (LiCl, 20 mM and BIO, 5 µM) were studied. Mouse survival was monitored and renal function was analysed by histological and serological examination. Cytokine and chemokine production, and cell apoptosis were measured by enzyme-linked immunosorbent assay and terminal deoxynucleotidyl transferase-mediated dUTP–biotin nick-end labelling staining, respectively. Activation of NF-κB and GSK-3 was determined by immunostaining and Western blotting, respectively. Key results: Mice treated with GSK-3 inhibitors showed decreased mortality, renal tubular dilatation, vacuolization and sloughing, blood urea nitrogen, creatinine and renal cell apoptosis in response to endotoxaemia. Inhibiting GSK-3 reduced LPS-induced tumour necrosis factor-α (TNF-α) and CCL5/RANTES (released upon activation of normal T-cells) in vivo in mice and in vitro in murine kidney cortical collecting duct epithelial M1 cells. Inhibiting GSK-3 did not block TNF-α-induced cytotoxicity in rat kidney proximal tubular epithelial NRK52E or in M1 cells. Conclusions and implications: These results suggest that GSK-3 inhibition protects against endotoxaemic acute renal failure mainly by down-regulating pro-inflammatory TNF-α and RANTES. PMID:19508392

Allergy and allergic mediators in tears.

PubMed

Leonardi, Andrea

2013-12-01

The identification of inflammatory mediators in the tear fluid have been extensively used in ocular allergy to find either a 'disease marker', to better understand the immune mechanisms involved in the ocular surface inflammation, or to identify potential targets for therapeutic interventions. While the clinical characteristics allow a relatively convincing diagnosis of ocular allergic diseases, in the initial, non active phases, or in the chronic stages, the diagnosis may not be clear. Although not highly specific, total tear IgE can be measured with local tests by inserting a paper strip in the lower meniscus. The measurement of tear specific inflammatory markers, such as histamine, tryptase, ECP, IL-4, IL-5 and eotaxin, may be useful for the diagnosis or monitoring ocular allergy. New technologies such as multiplex bead assays, membrane-bound antibody array and proteomic techniques can characterize the distribution of a wide range of bioactive trace proteins in tears. Dozens of mediators, cytokines, chemokines, growth factors, angiogenic modulators, enzymes and inhibitors were thus identified in small tear samples using these techniques, providing the possible identification of specific biomarker for either specific disease or disease activity. However, to date, there is no a single specific laboratory test suitable for the diagnosis and monitoring of allergic conjunctivitis. Copyright © 2013 Elsevier Ltd. All rights reserved.

Effect of oral tolerance in a mouse model of allergic rhinitis.

PubMed

Shin, Ji-Hyeon; Kang, Jun Myung; Kim, Sung Won; Cho, Jin-Hee; Park, Yong Jin; Kim, Soo Whan

2010-03-01

Induction of oral tolerance (OT) is known to prevent allergic inflammation in models of asthma. This study investigated the preventive effect of OT and airway remodeling in a mouse model of allergic rhinitis (AR). An in vivo study using an animal model. Catholic Research Institutes of Medical Science. Forty six-week-old, female BALB/c mice were divided into four groups: control, AR, low-dose OT, and high-dose OT. To induce OT, mice were fed ovalbumin (OVA) before sensitization with OVA/aluminum hydroxide, 1 mg for six days in the low-dose OT group and a 25 mg single dose in the high-dose OT group. Mice in the AR group were fed phosphate-buffered saline. After sensitization followed by challenges with OVA during six weeks, nasal behaviors, interleukin (IL)-13 and interferon gamma (IFN-gamma) levels in nasal lavage (NAL) fluids, as well as OVA-specific IgE levels in serum, were measured. The degree of goblet cell hyperplasia and thickness of lamina propria were observed in nasal tissues by periodic acid-Schiff and Masson's trichrome stain. A P value < 0.05 was accepted as statistically significant. Both OT groups showed a significant decrease in inflammatory cells, IL-13 and IFN-gamma in NAL fluids, as well as OVA-specific IgE levels in serum compared with the AR group. In addition, the degree of goblet cell hyperplasia and thickness of lamina propria were attenuated in both OT groups compared with the AR group. Further, these alterations did not differ significantly between the two OT groups. These results suggest that OT may effectively reduce allergic inflammation as well as airway remodeling in a mouse model of AR. Copyright 2010 American Academy of Otolaryngology-Head and Neck Surgery Foundation. Published by Mosby, Inc. All rights reserved.

Pesticides are Associated with Allergic and Non-Allergic Wheeze among Male Farmers

PubMed Central

Hoppin, Jane A.; Umbach, David M.; Long, Stuart; London, Stephanie J.; Henneberger, Paul K.; Blair, Aaron; Alavanja, Michael; Freeman, Laura E. Beane; Sandler, Dale P.

2016-01-01

Background: Growing evidence suggests that pesticide use may contribute to respiratory symptoms. Objective: We evaluated the association of currently used pesticides with allergic and non-allergic wheeze among male farmers. Methods: Using the 2005–2010 interview data of the Agricultural Health Study, a prospective study of farmers in North Carolina and Iowa, we evaluated the association between allergic and non-allergic wheeze and self-reported use of 78 specific pesticides, reported by ≥ 1% of the 22,134 men interviewed. We used polytomous regression models adjusted for age, BMI, state, smoking, and current asthma, as well as for days applying pesticides and days driving diesel tractors. We defined allergic wheeze as reporting both wheeze and doctor-diagnosed hay fever (n = 1,310, 6%) and non-allergic wheeze as reporting wheeze but not hay fever (n = 3,939, 18%); men without wheeze were the referent. Results: In models evaluating current use of specific pesticides, 19 pesticides were significantly associated (p < 0.05) with allergic wheeze (18 positive, 1 negative) and 21 pesticides with non-allergic wheeze (19 positive, 2 negative); 11 pesticides were associated with both. Seven pesticides (herbicides: 2,4-D and simazine; insecticides: carbaryl, dimethoate, disulfoton, and zeta-cypermethrin; and fungicide pyraclostrobin) had significantly different associations for allergic and non-allergic wheeze. In exposure–response models with up to five exposure categories, we saw evidence of an exposure–response relationship for several pesticides including the commonly used herbicides 2,4-D and glyphosate, the insecticides permethrin and carbaryl, and the rodenticide warfarin. Conclusions: These results for farmers implicate several pesticides that are commonly used in agricultural and residential settings with adverse respiratory effects. Citation: Hoppin JA, Umbach DM, Long S, London SJ, Henneberger PK, Blair A, Alavanja M, Beane Freeman LE, Sandler DP. 2017

Females have stronger neurogenic response than males after non-specific nasal challenge in patients with seasonal allergic rhinitis.

PubMed

Tomljenovic, Dejan; Baudoin, Tomislav; Megla, Zeljka Bukovec; Geber, Goran; Scadding, Glenis; Kalogjera, Livije

2018-07-01

Epidemiological studies show female predominance in the prevalence of non- allergic rhinitis (NAR) and local allergic rhinitis (LAR). Experimental studies show female patients with allergic rhinitis (AR) demonstrate higher levels of sensitivity to irritants and airway hyperresponsiveness than males. Bronchial asthma shows female predominance in post-puberty patients, and gender interaction with severe asthma endotypes. Fibromyalgia, chronic fatigue syndrome, migraine and chronic cough, syndromes, which are commonly related to neurokinin substance P (SP) in the literature, also show strong female predominance. Studies have demonstrated that sex hormones, primarily oestrogens, affect mast cell activation. Mast cell proteases can amplify neurogenic inflammatory responses including the release of SP. Based on human epidemiological data and animal experimental data we hypothesized that female patients have different interaction between mast cell activation and neurogenic inflammation, i.e. substance P release, resulting in a different nasal symptom profile. To test the hypothesis we performed allergen and non-specific nasal challenges in patients with seasonal allergic rhinitis (SAR) out of season and looked for gender differences in subjective and objective responses. The interaction between subjective and objective reactivity was evaluated through the comparison of subjective symptom scores, concentrations of neurokinin substance P (SP) and cellular markers in nasal lavages after low doses of nasal allergen challenges. Female allergic subjects tended to have higher substance P (SP) concentrations both before and after non-specific challenges. The difference between post-allergen and post - hypertonic saline (HTS) challenge was highly significant in female patients (p = 0.001), while insignificant in male subjects (p = 0.14). Female patients had significantly stronger burning sensation after HTS challenge than male. These data indicate difference in the

Effects of Liver × receptor agonist treatment on signal transduction pathways in acute lung inflammation

PubMed Central

2010-01-01

Background Liver × receptor α (LXRα) and β (LXRβ) are members of the nuclear receptor super family of ligand-activated transcription factors, a super family which includes the perhaps better known glucocorticoid receptor, estrogen receptor, thyroid receptor, and peroxisome proliferator-activated receptors. There is limited evidence that LXL activation may reduces acute lung inflammation. The aim of this study was to investigate the effects of T0901317, a potent LXR receptor ligand, in a mouse model of carrageenan-induced pleurisy. Methods Injection of carrageenan into the pleural cavity of mice elicited an acute inflammatory response characterized by: accumulation of fluid containing a large number of neutrophils (PMNs) in the pleural cavity, infiltration of PMNs in lung tissues and subsequent lipid peroxidation, and increased production of nitrite/nitrate (NOx), tumor necrosis factor-α, (TNF-α) and interleukin-1β (IL-1β). Furthermore, carrageenan induced the expression of iNOS, nitrotyrosine and PARP, as well as induced apoptosis (TUNEL staining and Bax and Bcl-2 expression) in the lung tissues. Results Administration of T0901317, 30 min after the challenge with carrageenan, caused a significant reduction in a dose dependent manner of all the parameters of inflammation measured. Conclusions Thus, based on these findings we propose that LXR ligand such as T0901317, may be useful in the treatment of various inflammatory diseases. PMID:20175894

In utero and postnatal exposure to a phytoestrogen-enriched diet increases parameters of acute inflammation in a rat model of TNBS-induced colitis.

PubMed

Seibel, Jan; Molzberger, Almut F; Hertrampf, Torsten; Laudenbach-Leschowski, Ute; Degen, Gisela H; Diel, Patrick

2008-12-01

Inflammatory bowel disease (IBD) is very common in Europe and USA. Its incidence in East Asia has been traditionally low, albeit the risk of IBD increases in Asian immigrants adopting western lifestyles, suggesting a strong role of environmental/dietary factors in IBD. A lifelong exposure to phytoestrogen-rich diets has been associated with a decreased risk of developing breast cancer and might also be protective against IBD. We studied the influence of in utero and postnatal exposure to a phytoestrogen (PE)-rich diet on acute inflammation in an animal model of TNBS-induced colitis. Wistar rats were exposed in utero and postnatally to high (genistein: 240 microg/g feed; daidzein: 232 microg/g feed) or very low levels (genistein and daidzein <10 microg/g feed) of phytoestrogen isoflavones fed to pregnant dams with the diet and throughout nursing. After weaning, the offspring had free access to these diets. At the age of 11 weeks, colitis was induced with an enema of TNBS. After 3 days, animals were sacrificed and tissues were collected for histological evaluation and analysis of molecular markers of inflammation. Animals kept on a PE-rich diet (PRD) had higher colon weights than animals on low PE-levels (PDD), suggesting enhanced acute inflammation by phytoestrogens. This result was supported by histological findings and by analysis of myeloperoxidase activity. Interestingly, relative mRNA and protein expression of cyclooxygenase-2 (COX-2) were modulated in rats on PRD, providing evidence that COX-2, the inducible isoform of the enzyme, is involved in the management of colonic inflammation. Our results suggest that early-in-life exposure to PE might not protect against the development of IBD but enhances the extent of acute inflammation.

The role of pseudoephedrine on daytime somnolence in patients suffering from perennial allergic rhinitis (PAR).

PubMed

Sherkat, Amir A; Sardana, Niti; Safaee, Sahar; Lehman, Erik B; Craig, Timothy J

2011-02-01

Allergic rhinitis is one of several inflammatory diseases affecting the nasal mucosa. Cellular inflammation of nasal mucosa is a hallmark of this disease and is characterized by the accumulation of eosinophils and the release of various chemical messengers such as chemokines, cytokines, and histamine. This inflammation of the nose leads to nasal congestion and a reduction in sleep quality, resulting in daytime somnolence. Drugs that significantly reduce the symptoms of nasal congestion also may help in alleviating sleep-related symptoms of allergic rhinitis. Pseudoephedrine is a sympathomimetic amine that is indicated for treatment of nasal congestion associated with allergic rhinitis. Despite relieving nasal congestion, we speculated that, because of pseudoephedrine's well-known stimulant profile, sleep would not be improved. Fourteen subjects who met the inclusion criteria were enrolled into a double-blind, placebo-controlled, randomized study to either pseudoephedrine or placebo once per day in the morning, using the traditional crossover design. Skin testing test was performed to ensure a positive response to a relevant perennial allergen and a negative response to a seasonal allergen. Several questionnaires were used to evaluate the patients' sleep-related symptoms, allergic rhinitis symptoms, and quality of life. Our results showed that pseudoephedrine did not have a positive or negative effect on quality of sleep, daytime sleepiness, or daytime fatigue as compared with placebo. Pseudoephedrine did show a statistical significance in improving stuffy nose (P = .0172). With respect to quality of life, pseudoephedrine led to a statistically significant decrease in intimate relationships and sexual activity as compared with the placebo group (P = .0310). Our research suggests that sleep quality is not significantly affected by pseudoephedrine. As expected, congestion is reduced, but side effects such as a decline of intimate relationships and sexual activity may

Occupational allergic diseases in kitchen and health care workers: an underestimated health issue.

PubMed

Bilge, Ugur; Unluoglu, Ilhami; Son, Nazan; Keskin, Ahmet; Korkut, Yasemin; Unalacak, Murat

2013-01-01

This study evaluated the frequencies of allergic symptoms and rate of upper respiratory infections during the past year in the general population, kitchen workers (KW) and health care workers (HCW). The European Community Respiratory Health Survey (ECRHS) was used to inquire retrospectively about asthma and asthma-like symptoms and the number of treatments required for previous upper respiratory tract infections (URTI: acute pharyngitis, acute sinusitis, etc.) during the past year for health care workers, kitchen workers, and members of the general population. Adjusted odds ratios by gender, age, and smoking status were calculated. 579 subjects (186 from the general population, 205 KW, and 188 HCW; 263 females, 316 males) participated in the study. Noninfectious (allergic) rhinitis was significantly higher in the HCW and KW groups than in the general population (P < 0.001). Cumulative asthma was significantly higher only in the HCW group (P < 0.05). In addition, the HCW and KW groups had significantly higher risks of ≥2/year URTI (OR: 1.59, 95% CI: 1.07-2.38 versus OR: 1.57, 95% CI: 1.05-2.38) than the general population. Occupational allergic respiratory diseases are an important and growing health issue. Health care providers should become familiar with workplace environments and environmental causes of occupational rhinitis and asthma.

Pesticides are Associated with Allergic and Non-Allergic Wheeze among Male Farmers.

PubMed

Hoppin, Jane A; Umbach, David M; Long, Stuart; London, Stephanie J; Henneberger, Paul K; Blair, Aaron; Alavanja, Michael; Freeman, Laura E Beane; Sandler, Dale P

2017-04-01

Growing evidence suggests that pesticide use may contribute to respiratory symptoms. We evaluated the association of currently used pesticides with allergic and non-allergic wheeze among male farmers. Using the 2005-2010 interview data of the Agricultural Health Study, a prospective study of farmers in North Carolina and Iowa, we evaluated the association between allergic and non-allergic wheeze and self-reported use of 78 specific pesticides, reported by ≥ 1% of the 22,134 men interviewed. We used polytomous regression models adjusted for age, BMI, state, smoking, and current asthma, as well as for days applying pesticides and days driving diesel tractors. We defined allergic wheeze as reporting both wheeze and doctor-diagnosed hay fever ( n = 1,310, 6%) and non-allergic wheeze as reporting wheeze but not hay fever ( n = 3,939, 18%); men without wheeze were the referent. In models evaluating current use of specific pesticides, 19 pesticides were significantly associated ( p < 0.05) with allergic wheeze (18 positive, 1 negative) and 21 pesticides with non-allergic wheeze (19 positive, 2 negative); 11 pesticides were associated with both. Seven pesticides (herbicides: 2,4-D and simazine; insecticides: carbaryl, dimethoate, disulfoton, and zeta-cypermethrin; and fungicide pyraclostrobin) had significantly different associations for allergic and non-allergic wheeze. In exposure-response models with up to five exposure categories, we saw evidence of an exposure-response relationship for several pesticides including the commonly used herbicides 2,4-D and glyphosate, the insecticides permethrin and carbaryl, and the rodenticide warfarin. These results for farmers implicate several pesticides that are commonly used in agricultural and residential settings with adverse respiratory effects.

HDL cholesterol transport during inflammation.

PubMed

van der Westhuyzen, Deneys R; de Beer, Frederick C; Webb, Nancy R

2007-04-01

The aim of this article is to review recent advances made towards understanding how inflammation and acute phase proteins, particularly serum amyloid A and group IIa secretory phospholipase A2, may alter reverse cholesterol transport by HDL during inflammation and the acute phase response. Findings suggest that the decreased apoA-I content and markedly increased serum amyloid A content in HDL during the acute phase response result from reciprocal and coordinate transcriptional regulation of these proteins as well as HDL remodeling by group IIa secretory phospholipase A2. Serum amyloid A functions efficiently in a lipid-free or lipid-poor form to promote cholesterol efflux by ATP binding cassette protein ABCA1, evidently by functioning directly as an acceptor for cholesterol efflux as well as by increasing the availability of cellular free cholesterol. Serum amyloid A increases the ability of acute phase HDL to serve as an acceptor for SR-BI-dependent cellular cholesterol efflux. Altered remodeling of HDL by group IIa secretory phospholipase A2 in concert with cholesterol ester transfer protein may contribute to the generation of lipid-poor apoA-I and serum amyloid A acceptors for cholesterol efflux. Current data support a model for the acute phase response in which serum amyloid A and sPLA2-IIa, present at sites of inflammation and tissue damage, play a protective role by enhancing cellular cholesterol efflux, thereby promoting the removal of excess cholesterol from macrophages.

Autophagy and kidney inflammation.

PubMed

Kimura, Tomonori; Isaka, Yoshitaka; Yoshimori, Tamotsu

2017-06-03

Inflammation plays a pivotal role in pathophysiological processes of kidney diseases. Macroautophagy/autophagy plays multiple roles in inflammatory responses, and the regulation of inflammation by autophagy has great potential as a treatment for damaged kidneys. A growing body of evidence suggests autophagy protects kidney from versatile kidney inflammatory insults, including those that are acute, chronic, metabolic, and aging-related. It is noteworthy that, in kidney, mitophagy is active, and damaged lysosomes are removed by autophagy. In this mode, autophagy suppresses inflammation to protect the kidney. Systemic inflammation also affects the kidney via pro-inflammatory cytokines and infiltration of inflammatory cells, and autophagy also has a regulatory role in systemic inflammation. This review focuses on the roles of autophagy in kidney diseases and aging through inflammation, and discusses the potential usage of autophagy as an inflammatory modulator for the treatment of kidney diseases.

Characterization of inflammatory cell infiltration in feline allergic skin disease.

PubMed

Taglinger, K; Day, M J; Foster, A P

2007-11-01

Sixteen cats with allergic dermatitis and six control cats with no skin disease were examined. Lymphoid and histiocytic cells in skin sections were examined immunohistochemically and mast cells were identified by toluidine blue staining. The 16 allergic cats showed one or more of several features (alopecia, eosinophilic plaques or granulomas, papulocrusting lesions), and histopathological findings were diverse. In control cats there were no cells that expressed IgM or MAC387, a few that were immunolabelled for IgG, IgA or CD3, and moderate numbers of mast cells. In allergic cats, positively labelled inflammatory cells were generally more numerous in lesional than in non-lesional skin sections, and were particularly associated with the superficial dermis and perifollicular areas. There were low numbers of plasma cells expressing cytoplasmic immunoglobulin; moderate numbers of MHC II-, MAC387- and CD3-positive cells; and moderate to numerous mast cells. MHC class II expression was associated with inflammatory cells morphologically consistent with dermal dendritic cells and macrophages, and epidermal Langerhans cells. Dendritic cells expressing MHC class II were usually associated with an infiltrate of CD3 lymphocytes, suggesting that these cells participate in maintenance of the local immune response by presenting antigen to T lymphocytes. These findings confirm that feline allergic skin disease is characterized by infiltration of activated antigen-presenting cells and T lymphocytes in addition to increased numbers of dermal mast cells. This pattern mimics the dermal inflammation that occurs in the chronic phase of both canine and human atopic dermatitis.

Allergic contact dermatitis from color film developers: clinical and histologic features.

PubMed

Brancaccio, R R; Cockerell, C J; Belsito, D; Ostreicher, R

1993-05-01

We evaluated two patients with allergic contact dermatitis that resulted from exposure to color film developers. A lichenoid eruption developed in one patient, whereas an eruption more characteristic of an acute spongiotic dermatitis developed in the second patient. Histologic findings in the first case were those of a "lichenoid dermatitis" but with features distinct from classic lichen planus. The biopsy specimens from the second patient showed a subacute spongiotic process with a bandlike infiltrate suggestive of an evolving lichenoid process. Contact allergy to color developers may result in eruptions similar to lichen planus. This process appears to evolve from an acute spongiotic dermatitis in its early phase to a lichenoid dermatitis in fully developed and more chronic forms. Although the histologic features are those of a "lichenoid" dermatitis, some features, such as the presence of spongiosis, eosinophils, and a less intense inflammatory infiltrate, may enable distinction between lichenoid allergic contact dermatitis and true lichen planus. In addition, clinicopathologic correlation with patch test results should permit accurate diagnosis in most cases.

Underlying chronic inflammation alters the profile and mechanisms of acute neutrophil recruitment.

PubMed

Ma, Bin; Whiteford, James R; Nourshargh, Sussan; Woodfin, Abigail

2016-11-01