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Sample records for airway inflammatory responses

  1. Pertussis Toxin Exacerbates and Prolongs Airway Inflammatory Responses during Bordetella pertussis Infection

    PubMed Central

    Connelly, Carey E.; Sun, Yezhou

    2012-01-01

    Throughout infection, pathogenic bacteria induce dramatic changes in host transcriptional repertoires. An understanding of how bacterial factors influence host reprogramming will provide insight into disease pathogenesis. In the human respiratory pathogen Bordetella pertussis, the causative agent of whooping cough, pertussis toxin (PT) is a key virulence factor that promotes colonization, suppresses innate immune responses during early infection, and causes systemic disease symptoms. To determine the full extent of PT-associated gene regulation in the airways through the peak of infection, we measured global transcriptional profiles in the lungs of BALB/c mice infected with wild-type (WT) or PT-deficient (ΔPT) B. pertussis. ΔPT bacteria were inoculated at a dose equivalent to the WT dose and at a high dose (ΔPThigh) to distinguish effects caused by higher bacterial loads achieved in WT infection from effects associated with PT. The results demonstrated that PT was associated with a significant upregulation of immune and inflammatory response genes as well as several other genes implicated in airway pathology. In contrast to the early, transient responses observed for ΔPThigh infection, WT infection induced a prolonged expression of inflammatory genes and increased the extent and duration of lung histopathology. In addition, the administration of purified PT to ΔPThigh-infected mice 1 day after bacterial inoculation exacerbated and prolonged inflammatory responses and airway pathology. These data indicate that PT not only is associated with exacerbated host airway responses during peak B. pertussis infection but also may inhibit host mechanisms of attenuating and resolving inflammation in the airways, suggesting possible links between PT and pertussis disease symptoms. PMID:23027529

  2. A murine model of stress controllability attenuates Th2-dominant airway inflammatory responses

    PubMed Central

    Deshmukh, Aniket; Kim, Byung-Jin; Gonzales, Xavier; Caffrey, James; Vishwanatha, Jamboor; Jones, Harlan P.

    2010-01-01

    Epidemiological and experimental studies suggest a positive correlation between chronic respiratory inflammatory disease and the ability to cope with adverse stress. Interactions between neuroendocrine and immune systems are believed to provide insight toward the biological mechanisms of action. The utility of an experimental murine model was employed to investigate the immunological consequences of stress-controllability and ovalbumin-induced airway inflammation. Pre-conditioned uncontrollable stress exacerbated OVA-induced lung histopathological changes that were typical of Th2-predominant inflammatory response along respiratory tissues. Importantly, mice given the ability to exert control over aversive stress attenuated inflammatory responses and reduced lung pathology. This model represents a means of investigating the neuro-immune axis in defining mechanisms of stress and respiratory disease. PMID:20462642

  3. Absence of inflammatory response from upper airway epithelial cells after X irradiation.

    PubMed

    Reiter, R; Deutschle, T; Wiegel, T; Riechelmann, H; Bartkowiak, D

    2009-03-01

    Radiotherapy of head and neck tumors causes adverse reactions in normal tissue, especially mucositis. The dose- and time-dependent response of upper airway cells to X radiation should be analyzed in terms of the pro-inflammatory potential. Immortalized BEAS-2B lung epithelial cells were treated with 2, 5 and 8 Gy. Out of 1232 genes, those that were transcribed differentially after 2, 6 and 24 h were assigned to biological themes according to the Gene Ontology Consortium. Enrichment of differentially regulated gene clusters was determined with GOTree ( http://bioinfo.vanderbilt.edu/gotm ). Eleven cytokines were measured in culture supernatants. The cell cycle response up to 24 h and induction of apoptosis up to 4 days after exposure were determined by flow cytometry. A significant dose- and time-dependent gene activation was observed for the categories response to DNA damage, oxidative stress, cell cycle arrest and cell death/apoptosis but not for immune/inflammatory response. This correlated with functional G(2) arrest and apoptosis. Pro-inflammatory cytokines accumulated in supernatants of control cells but not of X-irradiated cells. The complex gene expression pattern of X-irradiated airway epithelial cells is accompanied by cell cycle arrest and induction of apoptosis. In vivo, this may impair the epithelial barrier. mRNA and protein expression suggest at most an indirect contribution of epithelial cells to early radiogenic mucositis. PMID:19267554

  4. Inflammatory responses of airway smooth muscle cells and effects of endothelin receptor antagonism.

    PubMed

    Knobloch, Jürgen; Lin, Yingfeng; Konradi, Jürgen; Jungck, David; Behr, Juergen; Strauch, Justus; Stoelben, Erich; Koch, Andrea

    2013-07-01

    Endothelin receptor antagonists (ETRAs), authorized for pulmonary hypertension, have failed to prove their utility in chronic lung diseases with corticosteroid-resistant airway inflammation when applied at late disease stages with emphysema/fibrosis. Earlier administration might prove effective by targeting the interaction between airway inflammation and tissue remodeling. We hypothesized that human airway smooth muscle cells (HASMCs) participate in linking inflammation with remodeling and that associated genes become differentially suppressed by ambrisentan (A-receptor selective ETRA) and bosentan (nonselective/dual ETRA). Inflammatory responses of ex vivo-cultivated HASMCs to TNF-α were investigated by whole-genome microarray analyses. qRT-PCR and ELISA were used to test inflammatory and remodeling genes for sensitivity to bosentan and ambrisentan and to investigate differential sensitivities mechanistically. ETRA and corticosteroid effects were compared in HASMCs from patients with chronic obstructive pulmonary disease. TNF-α induced the expression of 18 cytokines/chemokines and five tissue remodeling genes involved in severe, corticosteroid-insensitive asthma, chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, and/or pulmonary hypertension. Thirteen cytokines/chemokines, MMP13, and WISP1 were suppressed by ETRAs. Eight genes had differential sensitivity to bosentan and ambrisentan depending on the endothelin-B receptor impact on transcriptional regulation and mRNA stabilization. Chemokine (C-C motif) ligands 2 and 5, granulocyte macrophage colony-stimulating factor, and MMP13 had increased sensitivity to bosentan or bosentan/dexamethasone combination versus dexamethasone alone. Suppression of cytokine and remodeling gene expression by ETRAs was confirmed in TNF-α-activated human bronchial epithelial cells. HASMCs and human bronchial epithelial cells participate in the interaction of inflammation and tissue remodeling. This interaction is

  5. Neurturin influences inflammatory responses and airway remodeling in different mouse asthma models.

    PubMed

    Mauffray, Marion; Domingues, Olivia; Hentges, François; Zimmer, Jacques; Hanau, Daniel; Michel, Tatiana

    2015-02-15

    Neurturin (NTN) was previously described for its neuronal activities, but recently, we have shown that this factor is also involved in asthma physiopathology. However, the underlying mechanisms of NTN are unclear. The aim of this study was to investigate NTN involvement in acute bronchial Th2 responses, to analyze its interaction with airway structural cells, and to study its implication in remodeling during acute and chronic bronchial inflammation in C57BL/6 mice. We analyzed the features of allergic airway inflammation in wild-type and NTN(-/-) mice after sensitization with two different allergens, OVA and house dust mite. We showed that NTN(-/-) dendritic cells and T cells had a stronger tendency to activate the Th2 pathway in vitro than similar wild-type cells. Furthermore, NTN(-/-) mice had significantly increased markers of airway remodeling like collagen deposition. NTN(-/-) lung tissues showed higher levels of neutrophils, cytokine-induced neutrophil chemoattractant, matrix metalloproteinase 9, TNF-α, and IL-6. Finally, NTN had the capacity to decrease IL-6 and TNF-α production by immune and epithelial cells, showing a direct anti-inflammatory activity on these cells. Our findings support the hypothesis that NTN could modulate the allergic inflammation in different mouse asthma models. PMID:25595789

  6. KGF alters gene expression in human airway epithelia: potential regulation of the inflammatory response.

    PubMed

    Prince, L S; Karp, P H; Moninger, T O; Welsh, M J

    2001-07-17

    Keratinocyte growth factor (KGF) regulates several functions in adult and developing lung epithelia; it causes proliferation, stimulates secretion of fluid and electrolytes, enhances repair, and may minimize injury. To gain insight into the molecular processes influenced by KGF, we applied KGF to primary cultures of well-differentiated human airway epithelia and used microarray hybridization to assess the abundance of gene transcripts. Of 7,069 genes tested, KGF changed expression levels of 910. Earlier studies showed that KGF causes epithelial proliferation, and as expected, treatment altered expression of numerous genes involved in cell proliferation. We found that KGF stimulated transepithelial Cl(-) transport, but the number of cystic fibrosis (CF) transmembrane conductance regulator (CFTR) transcripts fell. Although transcripts for ClC-1 and ClC-7 Cl(-) channels increased, KGF failed to augment transepithelial Cl(-) transport in CF epithelia, suggesting that KGF-stimulated Cl(-) transport in differentiated airway epithelia depends on the CFTR Cl(-) channel. Interestingly, KGF decreased transcripts for many interferon (IFN)-induced genes. IFN causes trafficking of Stat dimers to the nucleus, where they activate transcription of IFN-induced genes. We found that KGF prevented the IFN-stimulated trafficking of Stat1 from the cytosol to the nucleus, suggesting a molecular mechanism for KGF-mediated suppression of the IFN-signaling pathway. These results suggest that in addition to stimulating proliferation and repair of damaged airway epithelia, KGF stimulates Cl(-) transport and may dampen the response of epithelial cells to inflammatory mediators. PMID:11459923

  7. Comprehensive evaluation of poly(I:C) induced inflammatory response in an airway epithelial model

    PubMed Central

    Lever, Amanda R; Park, Hyoungshin; Mulhern, Thomas J; Jackson, George R; Comolli, James C; Borenstein, Jeffrey T; Hayden, Patrick J; Prantil-Baun, Rachelle

    2015-01-01

    Respiratory viruses invade the upper airway of the lung, triggering a potent immune response that often exacerbates preexisting conditions such as asthma and COPD. Poly(I:C) is a synthetic analog of viral dsRNA that induces the characteristic inflammatory response associated with viral infection, such as loss of epithelial integrity, and increased production of mucus and inflammatory cytokines. Here, we explore the mechanistic responses to poly(I:C) in a well-defined primary normal human bronchial epithelial (NHBE) model that recapitulates in vivo functions and responses. We developed functional and quantifiable methods to evaluate the physiology of our model in both healthy and inflamed states. Through gene and protein expression, we validated the differentiation state and population of essential cell subtypes (i.e., ciliated, goblet, club, and basal cells) as compared to the human lung. Assays for total mucus production, cytokine secretion, and barrier function were used to evaluate in vitro physiology and response to viral insult. Cells were treated apically with poly(I:C) and evaluated 48 h after induction. Results revealed a dose-dependent increase in goblet cell differentiation, as well as, an increase in mucus production relative to controls. There was also a dose-dependent increase in secretion of IL-6, IL-8, TNF-α, and RANTES. Epithelial barrier function, as measured by TEER, was maintained at 1501 ± 355 Ω*cm² postdifferentiation, but dropped significantly when challenged with poly(I:C). This study provides first steps toward a well-characterized model with defined functional methods for understanding dsRNA stimulated inflammatory responses in a physiologically relevant manner. PMID:25847914

  8. Different airway inflammatory responses in asthmatic and healthy humans exposed to diesel.

    PubMed

    Stenfors, N; Nordenhäll, C; Salvi, S S; Mudway, I; Söderberg, M; Blomberg, A; Helleday, R; Levin, J O; Holgate, S T; Kelly, F J; Frew, A J; Sandström, T

    2004-01-01

    Particulate matter (PM) pollution adversely affects the airways, with asthmatic subjects thought to be especially sensitive. The authors hypothesised that exposure to diesel exhaust (DE), a major source of PM, would induce airway neutrophilia in healthy subjects, and that either these responses would be exaggerated in subjects with mild allergic asthma, or DE would exacerbate pre-existent allergic airways. Healthy and mild asthmatic subjects were exposed for 2 h to ambient levels of DE (particles with a 50% cut-off aerodynamic diameter of 10 microm (PM10) 108 microg x m(-3)) and lung function and airway inflammation were assessed. Both groups showed an increase in airway resistance of similar magnitude after DE exposure. Healthy subjects developed airway inflammation 6 h after DE exposure, with airways neutrophilia and lymphocytosis together with an increase in interleukin-8 (IL-8) protein in lavage fluid, increased IL-8 messenger ribonucleic acid expression in the bronchial mucosa and upregulation of the endothelial adhesion molecules. In asthmatic subjects, DE exposure did not induce a neutrophilic response or exacerbate their pre-existing eosinophilic airway inflammation. Epithelial staining for the cytokine IL-10 was increased after DE in the asthmatic group. Differential effects on the airways of healthy subjects and asthmatics of particles with a 50% cut-off aerodynamic diameter of 10 microm at concentrations below current World Health Organisation air quality standards have been observed in this study. Further work is required to elucidate the significance of these differential responses. PMID:14738236

  9. Does Moderate Intensity Exercise Attenuate the Postprandial Lipemic and Airway Inflammatory Response to a High-Fat Meal?

    PubMed Central

    Kurti, Stephanie P.; Rosenkranz, Sara K.; Levitt, Morton; Cull, Brooke J.; Teeman, Colby S.; Emerson, Sam R.; Harms, Craig A.

    2015-01-01

    We investigated whether an acute bout of moderate intensity exercise in the postprandial period attenuates the triglyceride and airway inflammatory response to a high-fat meal (HFM) compared to remaining inactive in the postprandial period. Seventeen (11 M/6 F) physically active (≥150 min/week of moderate-vigorous physical activity (MVPA)) subjects were randomly assigned to an exercise (EX; 60% VO2peak) or sedentary (CON) condition after a HFM (10 kcal/kg, 63% fat). Blood analytes and airway inflammation via exhaled nitric oxide (eNO) were measured at baseline, and 2 and 4 hours after HFM. Airway inflammation was assessed with induced sputum and cell differentials at baseline and 4 hours after HFM. Triglycerides doubled in the postprandial period (~113 ± 18%, P < 0.05), but the increase did not differ between EX and CON. Percentage of neutrophils was increased 4 hours after HFM (~17%), but the increase did not differ between EX and CON. Exhaled nitric oxide changed nonlinearly from baseline to 2 and 4 hours after HFM (P < 0.05,  η2 = 0.36). Our findings suggest that, in active individuals, an acute bout of moderate intensity exercise does not attenuate the triglyceride or airway inflammatory response to a high-fat meal. PMID:26000301

  10. Does moderate intensity exercise attenuate the postprandial lipemic and airway inflammatory response to a high-fat meal?

    PubMed

    Kurti, Stephanie P; Rosenkranz, Sara K; Levitt, Morton; Cull, Brooke J; Teeman, Colby S; Emerson, Sam R; Harms, Craig A

    2015-01-01

    We investigated whether an acute bout of moderate intensity exercise in the postprandial period attenuates the triglyceride and airway inflammatory response to a high-fat meal (HFM) compared to remaining inactive in the postprandial period. Seventeen (11 M/6 F) physically active (≥ 150 min/week of moderate-vigorous physical activity (MVPA)) subjects were randomly assigned to an exercise (EX; 60% VO 2peak) or sedentary (CON) condition after a HFM (10 kcal/kg, 63% fat). Blood analytes and airway inflammation via exhaled nitric oxide (eNO) were measured at baseline, and 2 and 4 hours after HFM. Airway inflammation was assessed with induced sputum and cell differentials at baseline and 4 hours after HFM. Triglycerides doubled in the postprandial period (~113 ± 18%, P < 0.05), but the increase did not differ between EX and CON. Percentage of neutrophils was increased 4 hours after HFM (~17%), but the increase did not differ between EX and CON. Exhaled nitric oxide changed nonlinearly from baseline to 2 and 4 hours after HFM (P < 0.05, η (2) = 0.36). Our findings suggest that, in active individuals, an acute bout of moderate intensity exercise does not attenuate the triglyceride or airway inflammatory response to a high-fat meal. PMID:26000301

  11. MyD88 in lung resident cells governs airway inflammatory and pulmonary function responses to organic dust treatment.

    PubMed

    Poole, Jill A; Wyatt, Todd A; Romberger, Debra J; Staab, Elizabeth; Simet, Samantha; Reynolds, Stephen J; Sisson, Joseph H; Kielian, Tammy

    2015-01-01

    Inhalation of organic dusts within agriculture environments contributes to the development and/or severity of airway diseases, including asthma and chronic bronchitis. MyD88 KO (knockout) mice are nearly completely protected against the inflammatory and bronchoconstriction effects induced by acute organic dust extract (ODE) treatments. However, the contribution of MyD88 in lung epithelial cell responses remains unclear. In the present study, we first addressed whether ODE-induced changes in epithelial cell responses were MyD88-dependent by quantitating ciliary beat frequency and cell migration following wounding by electric cell-substrate impedance sensing. We demonstrate that the normative ciliary beat slowing response to ODE is delayed in MyD88 KO tracheal epithelial cells as compared to wild type (WT) control. Similarly, the normative ODE-induced slowing of cell migration in response to wound repair was aberrant in MyD88 KO cells. Next, we created MyD88 bone marrow chimera mice to investigate the relative contribution of MyD88-dependent signaling in lung resident (predominately epithelial cells) versus hematopoietic cells. Importantly, we demonstrate that ODE-induced airway hyperresponsiveness is MyD88-dependent in lung resident cells, whereas MyD88 action in hematopoietic cells is mainly responsible for ODE-induced TNF-α release. MyD88 signaling in lung resident and hematopoietic cells are necessary for ODE-induced IL-6 and neutrophil chemoattractant (CXCL1 and CXCL2) release and neutrophil influx. Collectively, these findings underscore an important role for MyD88 in lung resident cells for regulating ciliary motility, wound repair and inflammatory responses to ODE, and moreover, show that airway hyperresponsiveness appears uncoupled from airway inflammatory consequences to organic dust challenge in terms of MyD88 involvement. PMID:26376975

  12. A-kinase-anchoring proteins coordinate inflammatory responses to cigarette smoke in airway smooth muscle

    PubMed Central

    Heijink, Irene H.; Holtzer, Laura J.; Skroblin, Philipp; Klussmann, Enno; Halayko, Andrew J.; Timens, Wim; Maarsingh, Harm; Schmidt, Martina

    2015-01-01

    β2-Agonist inhibitors can relieve chronic obstructive pulmonary disease (COPD) symptoms by stimulating cyclic AMP (cAMP) signaling. A-kinase-anchoring proteins (AKAPs) compartmentalize cAMP signaling by establishing protein complexes. We previously reported that the β2-agonist fenoterol, direct activation of protein kinase A (PKA), and exchange factor directly activated by cAMP decrease cigarette smoke extract (CSE)-induced release of neutrophil attractant interleukin-8 (IL-8) from human airway smooth muscle (ASM) cells. In the present study, we tested the role of AKAPs in CSE-induced IL-8 release from ASM cells and assessed the effect of CSE on the expression levels of different AKAPs. We also studied mRNA and protein expression of AKAPs in lung tissue from patients with COPD. Our data show that CSE exposure of ASM cells decreases AKAP5 and AKAP12, both capable of interacting with β2-adrenoceptors. In lung tissue of patients with COPD, mRNA levels of AKAP5 and AKAP12 were decreased compared with lung tissue from controls. Using immunohistochemistry, we detected less AKAP5 protein in ASM of patients with COPD Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage II compared with control subjects. St-Ht31, which disrupts AKAP-PKA interactions, augmented CSE-induced IL-8 release from ASM cells and diminished its suppression by fenoterol, an effect mediated by disturbed ERK signaling. The modulatory role of AKAP-PKA interactions in the anti-inflammatory effects of fenoterol in ASM cells and the decrease in expression of AKAP5 and AKAP12 in response to cigarette smoke and in lungs of patients with COPD suggest that cigarette smoke-induced changes in AKAP5 and AKAP12 in patients with COPD may affect efficacy of pharmacotherapy. PMID:25637608

  13. A-kinase-anchoring proteins coordinate inflammatory responses to cigarette smoke in airway smooth muscle.

    PubMed

    Poppinga, Wilfred J; Heijink, Irene H; Holtzer, Laura J; Skroblin, Philipp; Klussmann, Enno; Halayko, Andrew J; Timens, Wim; Maarsingh, Harm; Schmidt, Martina

    2015-04-15

    β2-Agonist inhibitors can relieve chronic obstructive pulmonary disease (COPD) symptoms by stimulating cyclic AMP (cAMP) signaling. A-kinase-anchoring proteins (AKAPs) compartmentalize cAMP signaling by establishing protein complexes. We previously reported that the β2-agonist fenoterol, direct activation of protein kinase A (PKA), and exchange factor directly activated by cAMP decrease cigarette smoke extract (CSE)-induced release of neutrophil attractant interleukin-8 (IL-8) from human airway smooth muscle (ASM) cells. In the present study, we tested the role of AKAPs in CSE-induced IL-8 release from ASM cells and assessed the effect of CSE on the expression levels of different AKAPs. We also studied mRNA and protein expression of AKAPs in lung tissue from patients with COPD. Our data show that CSE exposure of ASM cells decreases AKAP5 and AKAP12, both capable of interacting with β2-adrenoceptors. In lung tissue of patients with COPD, mRNA levels of AKAP5 and AKAP12 were decreased compared with lung tissue from controls. Using immunohistochemistry, we detected less AKAP5 protein in ASM of patients with COPD Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage II compared with control subjects. St-Ht31, which disrupts AKAP-PKA interactions, augmented CSE-induced IL-8 release from ASM cells and diminished its suppression by fenoterol, an effect mediated by disturbed ERK signaling. The modulatory role of AKAP-PKA interactions in the anti-inflammatory effects of fenoterol in ASM cells and the decrease in expression of AKAP5 and AKAP12 in response to cigarette smoke and in lungs of patients with COPD suggest that cigarette smoke-induced changes in AKAP5 and AKAP12 in patients with COPD may affect efficacy of pharmacotherapy. PMID:25637608

  14. Distending Pressure Did Not Activate Acute Phase or Inflammatory Responses in the Airways and Lungs of Fetal, Preterm Lambs

    PubMed Central

    Petersen, Rebecca Y.; Royse, Emily; Kemp, Matthew W.; Miura, Yuichiro; Noe, Andres; Jobe, Alan H.; Hillman, Noah H.

    2016-01-01

    Background Mechanical ventilation at birth causes airway injury and lung inflammation in preterm sheep. Continuous positive airway pressure (CPAP) is being increasingly used clinically to transition preterm infants at birth. Objective To test if distending pressures will activate acute phase reactants and inflammatory changes in the airways of fetal, preterm lambs. Methods The head and chest of fetal lambs at 128±1 day GA were surgically exteriorized. With placental circulation intact, fetal lambs were then randomized to one of five 15 minute interventions: PEEP of 0, 4, 8, 12, or 16 cmH2O. Recruitment volumes were recorded. Fetal lambs remained on placental support for 30 min after the intervention. The twins of each 0 cmH2O animal served as controls. Fetal lung fluid (FLF), bronchoalveolar lavage fluid (BAL), right mainstem bronchi and peripheral lung tissue were evaluated for inflammation. Results Recruitment volume increased from 0.4±0.04 mL/kg at 4 cmH2O to 2.4±0.3 mL/kg at 16 cmH2O. The lambs were surfactant deficient, and all pressures were below the opening inflection pressure on pressure-volume curve. mRNA expression of early response genes and pro-inflammatory cytokines did not increase in airway tissue or lung tissue at any pressure compared to controls. FLF and BAL also did not have increases in early response proteins. No histologic changes or Egr-1 activation was present at the pressures used. Conclusion Distending pressures as high as 16 cmH2O did not recruit lung volume at birth and did not increase markers of injury in the lung or airways in non-breathing preterm fetal sheep. PMID:27463520

  15. Cultured human airway epithelial cells (calu-3): a model of human respiratory function, structure, and inflammatory responses.

    PubMed

    Zhu, Yan; Chidekel, Aaron; Shaffer, Thomas H

    2010-01-01

    This article reviews the application of the human airway Calu-3 cell line as a respiratory model for studying the effects of gas concentrations, exposure time, biophysical stress, and biological agents on human airway epithelial cells. Calu-3 cells are grown to confluence at an air-liquid interface on permeable supports. To model human respiratory conditions and treatment modalities, monolayers are placed in an environmental chamber, and exposed to specific levels of oxygen or other therapeutic modalities such as positive pressure and medications to assess the effect of interventions on inflammatory mediators, immunologic proteins, and antibacterial outcomes. Monolayer integrity and permeability and cell histology and viability also measure cellular response to therapeutic interventions. Calu-3 cells exposed to graded oxygen concentrations demonstrate cell dysfunction and inflammation in a dose-dependent manner. Modeling positive airway pressure reveals that pressure may exert a greater injurious effect and cytokine response than oxygen. In experiments with pharmacological agents, Lucinactant is protective of Calu-3 cells compared with Beractant and control, and perfluorocarbons also protect against hyperoxia-induced airway epithelial cell injury. The Calu-3 cell preparation is a sensitive and efficient preclinical model to study human respiratory processes and diseases related to oxygen- and ventilator-induced lung injury. PMID:20948883

  16. Role of M2 Muscarinic Receptor in the Airway Response to Methacholine of Mice Selected for Minimal or Maximal Acute Inflammatory Response

    PubMed Central

    Castro, Juciane Maria de Andrade; Resende, Rodrigo R.; Florsheim, Esther; Albuquerque, Layra Lucy; Lino-dos-Santos-Franco, Adriana; Gomes, Eliane; Tavares de Lima, Wothan; de Franco, Marcelo; Ribeiro, Orlando Garcia

    2013-01-01

    Airway smooth muscle constriction induced by cholinergic agonists such as methacholine (MCh), which is typically increased in asthmatic patients, is regulated mainly by muscle muscarinic M3 receptors and negatively by vagal muscarinic M2 receptors. Here we evaluated basal (intrinsic) and allergen-induced (extrinsic) airway responses to MCh. We used two mouse lines selected to respond maximally (AIRmax) or minimally (AIRmin) to innate inflammatory stimuli. We found that in basal condition AIRmin mice responded more vigorously to MCh than AIRmax. Treatment with a specific M2 antagonist increased airway response of AIRmax but not of AIRmin mice. The expression of M2 receptors in the lung was significantly lower in AIRmin compared to AIRmax animals. AIRmax mice developed a more intense allergic inflammation than AIRmin, and both allergic mouse lines increased airway responses to MCh. However, gallamine treatment of allergic groups did not affect the responses to MCh. Our results confirm that low or dysfunctional M2 receptor activity is associated with increased airway responsiveness to MCh and that this trait was inherited during the selective breeding of AIRmin mice and was acquired by AIRmax mice during allergic lung inflammation. PMID:23691511

  17. Ozone-induced lung function decrements do not correlate with early airway inflammatory or antioxidant responses.

    PubMed

    Blomberg, A; Mudway, I S; Nordenhäll, C; Hedenström, H; Kelly, F J; Frew, A J; Holgate, S T; Sandström, T

    1999-06-01

    This study sought to clarify the early events occurring within the airways of healthy human subjects performing moderate intermittent exercise following ozone challenge. Thirteen healthy nonsmoking subjects were exposed in a single blinded, crossover control fashion to 0.2 parts per million (ppm) O3 and filtered air for 2 h, using a standard intermittent exercise and rest protocol. Lung function was assessed pre- and immediately post-exposure. Bronchoscopy was performed with endobronchial mucosal biopsies, bronchial wash (BW) and bronchoalveolar lavage (BAL) 1.5 h after the end of the exposure period. Respiratory tract lining fluid (RTLF) redox status was assessed by measuring a range of antioxidants and oxidative damage markers in BW and BAL fluid samples. There was a significant upregulation after O3 exposure in the expression of vascular endothelial P-selectin (p<0.005) and intercellular adhesion molecule-1 (p<0.005). This was associated with a 2-fold increase in submucosal mast cells (p<0.005) in biopsy samples, without evidence of neutrophilic inflammation, and a decrease in BAL fluid macrophage numbers (1.6-fold, p<0.005), with an activation of the remaining macrophage subset (2.5-fold increase in % human leukocyte antigen (HLA)-DR+ cells, p<0.005). In addition, exposure led to a 4.5-fold and 3.1-fold increase of reduced glutathione (GSH) concentrations, in BW and BAL fluid respectively (p<0.05), with alterations in urate and alpha-tocopherol plasma/RTLF partitioning ratios (p<0.05). Spirometry showed reductions in forced vital capacity (p<0.05) and forced expiratory volume in one second (p<0.01), with evidence of small airway narrowing using forced expiratory flow values (p<0.005). Evidence was found of O3-induced early adhesion molecule upregulation, increased submucosal mast cell numbers and alterations to the respiratory tract lining fluid redox status. No clear relationship was demonstrable between changes in these early markers and the lung function

  18. Haemophilus influenzae increases the susceptibility and inflammatory response of airway epithelial cells to viral infections.

    PubMed

    Gulraiz, Fahad; Bellinghausen, Carla; Bruggeman, Cathrien A; Stassen, Frank R

    2015-03-01

    Nontypeable Haemophilus influenzae (NTHI), a common colonizer of lungs of patients with chronic obstructive pulmonary disease (COPD), can enhance expression of the cellular receptor intercellular adhesion molecule 1 (ICAM-1), which in turn can be used by major group human rhinoviruses (HRVs) for attachment. Here, we evaluated the effect of NTHI-induced up-regulation of ICAM-1 on viral replication and inflammatory responses toward different respiratory viruses. Therefore, human bronchial epithelial cells were pretreated with heat-inactivated NTHI (hi-NTHI) and subsequently infected with either HRV16 (major group), HRV1B (minor group), or respiratory syncytial virus (RSV). Pretreatment with hi-NTHI significantly up-regulated ICAM-1 in BEAS-2B cells and primary bronchial epithelial cells. Concomitantly, release of infectious HRV16 particles was increased in cells pretreated with hi-NTHI. Pretreatment with hi-NTHI also caused a significant increase in HRV16 RNA, whereas replication of HRV1B and RSV were increased to a far lesser extent and only at later time points. Interestingly, release of IL-6 and IL-8 after RSV, but not HRV, infection was synergistically increased in hi-NTHI-pretreated BEAS-2B cells. In summary, exposure to hi-NTHI significantly enhanced sensitivity toward HRV16 but not HRV1B or RSV, probably through ICAM-1 up-regulation. Furthermore, hi-NTHI pretreatment may enhance the inflammatory response to RSV infection, suggesting that preexisting bacterial infections might exaggerate inflammation during secondary viral infection. PMID:25411435

  19. Suppression of ovalbumin-induced airway inflammatory responses in a mouse model of asthma by Mimosa pudica extract.

    PubMed

    Yang, Eun Ju; Lee, Ji-Sook; Yun, Chi-Young; Ryang, Yong Suk; Kim, Jong-Bae; Kim, In Sik

    2011-01-01

    Asthma is an inflammatory airway disease. The pathogenic mechanisms of asthma include the infiltration of leukocytes and release of cytokines. Mimosa pudica (Mp) has been used traditionally for the treatment of insomnia, diarrhea and inflammatory diseases. Although Mp extract has various therapeutic properties, the effect of this extract on asthma has not yet been reported. This study investigated the suppressive effects of Mp extract on asthmatic responses both in vitro and in vivo. Mp extract was acquired from dried and powdered whole plants of M. pudica using 80% ethanol. BALB/c mice were used for the mouse model of asthma induced by ovalbumin. Mp extract significantly inhibited the HMC-1 cell migration induced by stem cell factor and blocked the release of monocyte chemotactic protein-1 (MCP-1) and interleukin-6 (IL-6) in EoL-1 cells. Leukocytosis, eosinophilia and mucus hypersecretion in asthmatic lung were significantly suppressed by Mp extract. The release of ovalbumin-specific IgE in bronchoalveolar lavage fluid and serum was also decreased. Mp extract treatment resulted in no liver cytotoxicity. The Mp extract has inhibitory properties on asthma and may be used as a potent therapeutic agent for allergic lung inflammation. PMID:20623591

  20. Allergen-induced airway responses.

    PubMed

    Gauvreau, Gail M; El-Gammal, Amani I; O'Byrne, Paul M

    2015-09-01

    Environmental allergens are an important cause of asthma and can contribute to loss of asthma control and exacerbations. Allergen inhalation challenge has been a useful clinical model to examine the mechanisms of allergen-induced airway responses and inflammation. Allergen bronchoconstrictor responses are the early response, which reaches a maximum within 30 min and resolves by 1-3 h, and late responses, when bronchoconstriction recurs after 3-4 h and reaches a maximum over 6-12 h. Late responses are followed by an increase in airway hyperresponsiveness. These responses occur when IgE on mast cells is cross-linked by an allergen, causing degranulation and the release of histamine, neutral proteases and chemotactic factors, and the production of newly formed mediators, such as cysteinyl leukotrienes and prostaglandin D2. Allergen-induced airway inflammation consists of an increase in airway eosinophils, basophils and, less consistently, neutrophils. These responses are mediated by the trafficking and activation of myeloid dendritic cells into the airways, probably as a result of the release of epithelial cell-derived thymic stromal lymphopoietin, and the release of pro-inflammatory cytokines from type 2 helper T-cells. Allergen inhalation challenge has also been a widely used model to study potential new therapies for asthma and has an excellent negative predictive value for this purpose. PMID:26206871

  1. Lower airway colonization and inflammatory response in COPD: a focus on Haemophilus influenzae

    PubMed Central

    Finney, Lydia J; Ritchie, Andrew; Pollard, Elizabeth; Johnston, Sebastian L; Mallia, Patrick

    2014-01-01

    Bacterial infection of the lower respiratory tract in chronic obstructive pulmonary disease (COPD) patients is common both in stable patients and during acute exacerbations. The most frequent bacteria detected in COPD patients is Haemophilus influenzae, and it appears this organism is uniquely adapted to exploit immune deficiencies associated with COPD and to establish persistent infection in the lower respiratory tract. The presence of bacteria in the lower respiratory tract in stable COPD is termed colonization; however, there is increasing evidence that this is not an innocuous phenomenon but is associated with airway inflammation, increased symptoms, and increased risk for exacerbations. In this review, we discuss host immunity that offers protection against H. influenzae and how disturbance of these mechanisms, combined with pathogen mechanisms of immune evasion, promote persistence of H. influenzae in the lower airways in COPD. In addition, we examine the role of H. influenzae in COPD exacerbations, as well as interactions between H. influenzae and respiratory virus infections, and review the role of treatments and their effect on COPD outcomes. This review focuses predominantly on data derived from human studies but will refer to animal studies where they contribute to understanding the disease in humans. PMID:25342897

  2. Dendritic cells induce Th2-mediated airway inflammatory responses to house dust mite via DNA-dependent protein kinase

    PubMed Central

    Mishra, Amarjit; Brown, Alexandra L.; Yao, Xianglan; Yang, Shutong; Park, Sung-Jun; Liu, Chengyu; Dagur, Pradeep K.; McCoy, J. Philip; Keeran, Karen J.; Nugent, Gayle Z.; Jeffries, Kenneth R.; Qu, Xuan; Yu, Zu-Xi; Levine, Stewart J.; Chung, Jay H.

    2015-01-01

    DNA-dependent protein kinase (DNA-PK) mediates double stranded DNA break repair, V(D)J recombination, and immunoglobulin class switch recombination, as well as innate immune and pro-inflammatory responses. However, there is limited information regarding the role of DNA-PK in adaptive immunity mediated by dendritic cells (DCs), which are the primary antigen-presenting cells in allergic asthma. Here we show that house dust mite induces DNA-PK phosphorylation, which is a marker of DNA-PK activation, in DCs via the generation of intracellular reactive oxygen species. We also demonstrate that pharmacological inhibition of DNA-PK, as well as the specific deletion of DNA-PK in DCs, attenuates the induction of allergic sensitization and Th2 immunity via a mechanism that involves the impaired presentation of mite antigens. Furthermore, pharmacological inhibition of DNA-PK following antigen priming similarly reduces the manifestations of mite-induced airway disease. Collectively, these findings suggest that DNA-PK may be a potential target for treatment of allergic asthma. PMID:25692509

  3. Mainstream cigarette smoke exposure attenuates airway immune inflammatory responses to surrogate and common environmental allergens in mice, despite evidence of increased systemic sensitization.

    PubMed

    Robbins, Clinton S; Pouladi, Mahmoud A; Fattouh, Ramzi; Dawe, David E; Vujicic, Neda; Richards, Carl D; Jordana, Manel; Inman, Mark D; Stampfli, Martin R

    2005-09-01

    The purpose of this study was to investigate the impact of mainstream cigarette smoke exposure (MTS) on allergic sensitization and the development of allergic inflammatory processes. Using two different experimental murine models of allergic airways inflammation, we present evidence that MTS increased cytokine production by splenocytes in response to OVA and ragweed challenge. Paradoxically, MTS exposure resulted in an overall attenuation of the immune inflammatory response, including a dramatic reduction in the number of eosinophils and activated (CD69+) and Th2-associated (T1ST2+) CD4 T lymphocytes in the lung. Although MTS did not impact circulating levels of OVA-specific IgE and IgG1, we observed a striking reduction in OVA-specific IgG2a production and significantly diminished airway hyperresponsiveness. MTS, therefore, plays a disparate role in the development of allergic responses, inducing a heightened state of allergen-specific sensitization, but dampening local immune inflammatory processes in the lung. PMID:16116169

  4. Effects of air pollution-related heavy metals on the viability and inflammatory responses of human airway epithelial cells.

    PubMed

    Honda, Akiko; Tsuji, Kenshi; Matsuda, Yugo; Hayashi, Tomohiro; Fukushima, Wataru; Sawahara, Takahiro; Kudo, Hitomi; Murayama, Rumiko; Takano, Hirohisa

    2015-01-01

    Various metals produced from human activity are ubiquitously detected in ambient air. The metals may lead to induction and/or exacerbation of respiratory diseases, but the significant metals and factors contributing to such diseases have not been identified. To compare the effects of each metal and different oxidation states of metals on human airway, we examined the viability and production of interleukin (IL)-6 and IL-8 using BEAS-2B cell line, derived from human airway epithelial cells. Airway epithelial cells were exposed to Mn(2+), V(4+), V(5+), Cr(3+), Cr(6+), Zn(2+), Ni(2+), and Pb(2+) at a concentration of 0.5, 5, 50, or 500 μmol/L for 24 hours. Mn and V decreased the cell viability in a concentration-dependent manner, and V(5+) tended to have a greater effect than V(4+). The Cr decreased the cell viability, and (Cr(+6)) at concentrations of 50 and 500 μmol/L was more toxic than (Cr(+3)). Zn at a concentration of 500 μmol/L greatly decreased the cell viability, whereas Ni at the same concentration increased it. Pb produced fewer changes. Mn and Ni at a concentration of 500 μmol/L induced the significant production of IL-6 and IL-8. However, most of the metals including (V(+4), V(+5)), (Cr(+3), Cr(+6)), Zn, and Pb inhibited the production of both IL-6 and IL-8. The present results indicate that various heavy metals have different effects on toxicity and the proinflammatory responses of airway epithelial cells, and those influences also depend on the oxidation states of the metals. PMID:25808165

  5. Airway purinergic responses in healthy, atopic nonasthmatic, and atopic asthmatic subjects exposed to ozone**

    EPA Science Inventory

    Context: Ozone exposure triggers airway inflammatory responses that maybe influenced bybiologically active purine metabolites. Objective:To examinethe relationships between airway purine metabolites and established inflammatory markers of ozone exposure, and to determine if thes...

  6. Macrophage adaptation in airway inflammatory resolution.

    PubMed

    Kaur, Manminder; Bell, Thomas; Salek-Ardakani, Samira; Hussell, Tracy

    2015-09-01

    Bacterial and viral infections (exacerbations) are particularly problematic in those with underlying respiratory disease, including post-viral infection, asthma, chronic obstructive pulmonary disease and pulmonary fibrosis. Patients experiencing exacerbations tend to be at the more severe end of the disease spectrum and are often difficult to treat. Most of the unmet medical need remains in this patient group. Airway macrophages are one of the first cell populations to encounter airborne pathogens and, in health, exist in a state of reduced responsiveness due to interactions with the respiratory epithelium and specific factors found in the airway lumen. Granulocyte-macrophage colony-stimulating factor, interleukin-10, transforming growth factor-β, surfactant proteins and signalling via the CD200 receptor, for example, all raise the threshold above which airway macrophages can be activated. We highlight that following severe respiratory inflammation, the airspace microenvironment does not automatically re-set to baseline and may leave airway macrophages more restrained than they were at the outset. This excessive restraint is mediated in part by the clearance of apoptotic cells and components of extracellular matrix. This implies that one strategy to combat respiratory exacerbations would be to retune airway macrophage responsiveness to allow earlier bacterial recognition. PMID:26324813

  7. Nonmicrobial-mediated inflammatory airway diseases--an update.

    PubMed

    Ramesh Babu, Polani B; Krishnamoorthy, P

    2014-03-01

    In lungs, airways are in constant contact with air, microbes, allergens, and environmental pollutants. The airway epithelium represents the first line of lung defense through different mechanisms, which facilitate clearance of inhaled pathogens and environmental particles while minimizing an inflammatory response. The innate immune system facilitates immediate recognition of both foreign pathogens and tissue damage through toll-like receptor, which acts as a gateway for all intracellular events leading to inflammation. In the absence of microbial stimulus, the immune system is capable of detecting a wide range of insults against the host. This review focuses on various molecular mechanisms involved in pathophysiology of airway inflammation mediated by environmental factors, cellular stress, and pharmacological and clinical agents. PMID:24293217

  8. Antileukotrienes in upper airway inflammatory diseases.

    PubMed

    Cingi, Cemal; Muluk, Nuray Bayar; Ipci, Kagan; Şahin, Ethem

    2015-11-01

    Leukotrienes (LTs) are a family of inflammatory mediators including LTA4, LTB4, LTC4, LTD4, and LTE4. By competitive binding to the cysteinyl LT1 (CysLT1) receptor, LT receptor antagonist drugs, such as montelukast, zafirlukast, and pranlukast, block the effects of CysLTs, improving the symptoms of some chronic respiratory diseases, particularly bronchial asthma and allergic rhinitis. We reviewed the efficacy of antileukotrienes in upper airway inflammatory diseases. An update on the use of antileukotrienes in upper airway diseases in children and adults is presented with a detailed literature survey. Data on LTs, antileukotrienes, and antileukotrienes in chronic rhinosinusitis and nasal polyps, asthma, and allergic rhinitis are presented. Antileukotriene drugs are classified into two groups: CysLT receptor antagonists (zafirlukast, pranlukast, and montelukast) and LT synthesis inhibitors (5-lipoxygenase inhibitors such as zileuton, ZD2138, Bay X 1005, and MK-0591). CysLTs have important proinflammatory and profibrotic effects that contribute to the extensive hyperplastic rhinosinusitis and nasal polyposis (NP) that characterise these disorders. Patients who receive zafirlukast or zileuton tend to show objective improvements in, or at least stabilisation of, NP. Montelukast treatment may lead to clinical subjective improvement in NP. Montelukast treatment after sinus surgery can lead to a significant reduction in eosinophilic cationic protein levels in serum, with a beneficial effect on nasal and pulmonary symptoms and less impact in NP. Combined inhaled corticosteroids and long-acting β-agonists treatments are most effective for preventing exacerbations among paediatric asthma patients. Treatments with medium- or high-dose inhaled corticosteroids, combined inhaled corticosteroids and LT receptor antagonists, and low-dose inhaled corticosteroids have been reported to be equally effective. Antileukotrienes have also been reported to be effective for allergic

  9. Take the Wnt out of the inflammatory sails: modulatory effects of Wnt in airway diseases.

    PubMed

    Reuter, Sebastian; Beckert, Hendrik; Taube, Christian

    2016-02-01

    Bronchial asthma and chronic obstructive pulmonary disease (COPD) are chronic diseases that are associated with inflammation and structural changes in the airways and lungs. Recent findings have implicated Wnt pathways in critically regulating inflammatory responses, especially in asthma. Furthermore, canonical and noncanonical Wnt pathways are involved in structural changes such as airway remodeling, goblet cell metaplasia, and airway smooth muscle (ASM) proliferation. In COPD, Wnt pathways are not only associated with structural changes in the airways but also involved in the development of emphysema. The present review summarizes the role and function of the canonical and noncanonical Wnt pathway with regard to airway inflammation and structural changes in asthma and COPD. Further identification of the role and function of different Wnt molecules and pathways could help to develop novel therapeutic options for these diseases. PMID:26595171

  10. Cox4i2, Ifit2, and Prdm11 Mutant Mice: Effective Selection of Genes Predisposing to an Altered Airway Inflammatory Response from a Large Compendium of Mutant Mouse Lines

    PubMed Central

    Bönisch, Clemens; Côme, Christophe; Kolster-Fog, Cathrine; Jensen, Klaus T.; Lund, Anders H.; Lee, Icksoo; Grossman, Lawrence I.; Sinkler, Christopher; Hüttemann, Maik; Bohn, Erwin; Fuchs, Helmut; Ollert, Markus; Gailus-Durner, Valérie; Hrabĕ de Angelis, Martin; Beckers, Johannes

    2015-01-01

    We established a selection strategy to identify new models for an altered airway inflammatory response from a large compendium of mutant mouse lines that were systemically phenotyped in the German Mouse Clinic (GMC). As selection criteria we included published gene functional data, as well as immunological and transcriptome data from GMC phenotyping screens under standard conditions. Applying these criteria we identified a few from several hundred mutant mouse lines and further characterized the Cox4i2tm1Hutt, Ifit2tm1.1Ebsb, and Prdm11tm1.1ahl lines following ovalbumin (OVA) sensitization and repeated OVA airway challenge. Challenged Prdm11tm1.1ahl mice exhibited changes in B cell counts, CD4+ T cell counts, and in the number of neutrophils in bronchoalveolar lavages, whereas challenged Ifit2tm1.1Ebsb mice displayed alterations in plasma IgE, IgG1, IgG3, and IgM levels compared to the challenged wild type littermates. In contrast, challenged Cox4i2tm1Hutt mutant mice did not show alterations in the humoral or cellular immune response compared to challenged wild type mice. Transcriptome analyses from lungs of the challenged mutant mouse lines showed extensive changes in gene expression in Prdm11tm1.1ahl mice. Functional annotations of regulated genes of all three mutant mouse lines were primarily related to inflammation and airway smooth muscle (ASM) remodeling. We were thus able to define an effective selection strategy to identify new candidate genes for the predisposition to an altered airway inflammatory response under OVA challenge conditions. Similar selection strategies may be used for the analysis of additional genotype – envirotype interactions for other diseases. PMID:26263558

  11. Comparison of three inhaled non-steroidal anti-inflammatory drugs on the airway response to sodium metabisulphite and adenosine 5'-monophosphate challenge in asthma.

    PubMed Central

    Wang, M.; Wisniewski, A.; Pavord, I.; Knox, A.; Tattersfield, A.

    1996-01-01

    BACKGROUND: Non-steroidal anti-inflammatory drugs (NSAIDs) are used to assess the role of prostaglandins in asthma but their effects on bronchoconstrictor challenges have been inconsistent. The effects of three nebulised nonsteroidal anti-inflammatory drugs on the airway response to inhaled sodium metabisulphite (MBS) and adenosine 5'-monophosphate (AMP) were compared in the same asthmatic subjects to see whether contractile prostaglandins were involved in MBS or AMP induced bronchoconstriction. A possible protective effect of the osmolarity or pH of the inhaled solutions was also assessed. METHODS: Two double blind placebo controlled studies were carried out. In study 1, 15 non-aspirin sensitive patients with mild asthma attended on four occasions and inhaled 5 ml of lysine aspirin (L-aspirin) 900 mg, indomethacin 50 mg, sodium salicylate 800 mg, or saline 20 minutes before an inhaled MBS challenge. On four further occasions 14 of the patients inhaled the same solutions followed by an inhaled AMP challenge. In study 2, 10 of the patients attended on four additional occasions and inhaled 5 ml of 0.9%, 3%, 10%, or 9.5% saline with indomethacin 50 mg 20 minutes before an inhaled MBS challenge. RESULTS: In study 1 inhaled lysine aspirin had a similar effect on MBS and AMP induced bronchoconstriction, increasing the provocative dose causing a 20% fall in FEV1 (PD20) by 1.29 (95% CI 0.54 to 2.03) and 1.23 (95% CI 0.53 to 1.93) doubling doses, respectively. Indomethacin increased the MBS PD20 and AMP PD20 by 0.64 (95% CI -0.1 to 1.38) and 0.99 (95% CI 0.29 to 1.69) doubling doses, respectively. Sodium salicylate had no significant effect on either challenge. The two solutions causing most inhibition were the most acidic and the most alkaline. In study 2 inhaled 9.5% saline with indomethacin (osmolarity 3005 mOsm/kg) increased the MBS PD20 by 1.1 doubling doses (95% CI 0.2 to 2.0) compared with only 0.09 (95% CI -0.83 to 1.0) and 0.04 (95% CI -0.88 to 0.95) doubling doses

  12. Porous antioxidant polymer microparticles as therapeutic systems for the airway inflammatory diseases.

    PubMed

    Jeong, Dahee; Kang, Changsun; Jung, Eunkyeong; Yoo, Donghyuck; Wu, Dongmei; Lee, Dongwon

    2016-07-10

    Inhaling steroidal anti-inflammatory drugs is the most common treatment for airway inflammatory diseases such as asthma. However, frequent steroid administration causes adverse side effects. Therefore, the successful clinical translation of numerous steroidal drugs greatly needs pulmonary drug delivery systems which are formulated from biocompatible and non-immunogenic polymers. We have recently developed a new family of biodegradable polymer, vanillyl alcohol-containing copolyoxalate (PVAX) which is able to scavenge hydrogen peroxide and exert potent antioxidant and anti-inflammatory activity. In this work, we report the therapeutic potential of porous PVAX microparticles which encapsulate dexamethasone (DEX) as a therapeutic system for airway inflammatory diseases. PVAX microparticles themselves reduced oxidative stress and suppressed the expression of pro-inflammatory tumor necrosis factor-alpha and inducible nitric oxide synthase in the lung of ovalbumin-challenged asthmatic mice. However, DEX-loaded porous PVAX microparticles showed significantly enhanced therapeutic effects than PVAX microparticles, suggesting the synergistic effects of PVAX with DEX. In addition, PVAX microparticles showed no inflammatory responses to lung tissues. Given their excellent biocompatibility and intrinsic antioxidant and anti-inflammatory activity, PVAX microparticles hold tremendous potential as therapeutic systems for the treatment of airway inflammatory diseases such as asthma. PMID:27151077

  13. Chronic inflammatory airway diseases: the central role of the epithelium revisited.

    PubMed

    Gohy, S T; Hupin, C; Pilette, C; Ladjemi, M Z

    2016-04-01

    The respiratory epithelium plays a critical role for the maintenance of airway integrity and defense against inhaled particles. Physical barrier provided by apical junctions and mucociliary clearance clears inhaled pathogens, allergens or toxics, to prevent continuous stimulation of adaptive immune responses. The "chemical barrier", consisting of several anti-microbial factors such as lysozyme and lactoferrin, constitutes another protective mechanism of the mucosae against external aggressions before adaptive immune response starts. The reconstruction of damaged respiratory epithelium is crucial to restore this barrier. This review examines the role of the airway epithelium through recent advances in health and chronic inflammatory diseases in the lower conducting airways (in asthma and chronic obstructive pulmonary disease). Better understanding of normal and altered epithelial functions continuously provides new insights into the physiopathology of chronic airway diseases and should help to identify new epithelial-targeted therapies. PMID:27021118

  14. Effect of inflammatory mediators on airway nerves and muscle

    SciTech Connect

    Daniel, E.E.; O'Byrne, P. )

    1991-03-01

    The neuromuscular mechanisms underlying airway hyperresponsiveness have been reviewed on the basis of studies of the changes induced by ozone inhalation in dogs. In vivo, there is increased, nonspecific airway hyperresponsiveness based on studies of the response to inhaled acetylcholine or histamine. The underlying inflammatory mechanism involves release of LTB4 and/or other chemotactic agents from epithelial or lumenal cells, ingress of macrophages, neutrophils, and platelets from the blood vessels between the muscle and epithelium, and migration of mast cells into the epithelium. The hyperresponsiveness seems to depend upon the influx of neutrophils and actions of thromboxane A2 released from the neutrophils. In vitro, there is increased responsiveness to field stimulation of cholinergic nerves and to acetylcholine (not to KCI) in tracheal strips. These effects can be mimicked by a thromboxane A2 analog (U44619). In the sucrose gap, the TxA2 analog does not affect the excitatory junction potential, but in low concentration it increases and prolongs a series of fading membrane oscillations closely related to the contractions. We consider these oscillations to reflect ongoing release and/or action of acetylcholine. In high concentrations the analog causes a small depolarization and a tonic contraction, but it does not enhance the sensitivity to acetylcholine. TxA2 may be acting either presynaptically or postsynaptically or both to produce these effects; however, changes in release of an epithelial-derived relaxing factor do not seem to be involved. We conclude that TxA2 actions probably underlie hyperresponsiveness developed in vivo and in vitro after ozone inhalation.

  15. Airway responsiveness to psychological processes in asthma and health

    PubMed Central

    Ritz, Thomas

    2012-01-01

    Psychosocial factors have been found to impact airway pathophysiology in respiratory disease with considerable consistency. Influences on airway mechanics have been studied particularly well. The goal of this article is to review the literature on airway responses to psychological stimulation, discuss potential pathways of influence, and present a well-established emotion-induction paradigm to study airway obstruction elicited by unpleasant stimuli. Observational studies have found systematic associations between lung function and daily mood changes. The laboratory-based paradigm of bronchoconstrictive suggestion has been used successfully to elicit airway obstruction in a substantial proportion of asthmatic individuals. Other studies have demonstrated modulation of airway responses to standard airway challenges with exercise, allergens, or pharmacological agents by psychological factors. Standardized emotion-induction techniques have consistently shown airway constriction during unpleasant stimulation, with surgery, blood, and injury stimuli being particularly powerful. Findings with various forms of stress induction have been more mixed. A number of methodological factors may account for variability across studies, such as choice of measurement technique, temporal association between stimulation and measurement, and the specific quality and intensity of the stimulus material, in particular the extent of implied action-orientation. Research has also begun to elucidate physiological processes associated with psychologically induced airway responses, with vagal excitation and ventilatory influences being the most likely candidate pathways, whereas the role of specific central nervous system pathways and inflammatory processes has been less studied. The technique of emotion-induction using films has the potential to become a standardized challenge paradigm for the further exploration of airway hyperresponsiveness mediated by central nervous system processes. PMID

  16. The Role of CLCA Proteins in Inflammatory Airway Disease

    PubMed Central

    Patel, Anand C.; Brett, Tom J.; Holtzman, Michael J.

    2014-01-01

    Inflammatory airway diseases such as asthma and chronic obstructive pulmonary disease (COPD) exhibit stereotyped traits that are variably expressed in each person. In experimental mouse models of chronic lung disease, these individual disease traits can be genetically segregated and thereby linked to distinct determinants. Functional genomic analysis indicates that at least one of these traits, mucous cell metaplasia, depends on members of the calcium-activated chloride channel (CLCA) gene family. Here we review advances in the biochemistry of the CLCA family and the evidence of a role for CLCA family members in the development of mucous cell metaplasia and possibly airway hyperreactivity in experimental models and in humans. Based on this information, we develop the model that CLCA proteins are not integral membrane proteins with ion channel function, but instead are secreted signaling molecules that specifically regulate airway target cells in healthy and disease conditions. PMID:18954282

  17. The microbiome in chronic inflammatory airway disease: A threatened species.

    PubMed

    Green, Robin John; Van Niekerk, Andre; Jeevarathnum, Ashley C; Feldman, Charles; Richards On Behalf Of The South African Allergic Rhinitis Working Group, Guy A

    2016-08-01

    The human body is exposed to a multitude of microbes and infectious organisms throughout life. Many of these organisms colonise the skin, gastrointestinal tract (GIT) and airway. We now recognise that this colonisation includes the lower airway, previously thought to be sterile. These colonising organisms play an important role in disease prevention, including an array of chronic inflammatory conditions that are unrelated to infectious diseases. However, new evidence of immune dysregulation suggests that early colonisation, especially of the GITand airway, by pathogenic micro-organisms, has deleterious effects that may contribute to the potential to induce chronic inflammation in young children, which may only express itself in adult life. PMID:27499401

  18. Antioxidant and anti-inflammatory effects of resveratrol in airway disease.

    PubMed

    Wood, Lisa G; Wark, Peter A B; Garg, Manohar L

    2010-11-15

    Respiratory diseases, such as asthma and chronic obstructive pulmonary disease (COPD), are a significant and increasing global health problem. These diseases are characterized by airway inflammation, which develops in response to various stimuli. In asthma, inflammation is driven by exposure to a variety of triggers, including allergens and viruses, which activate components of both the innate and acquired immune responses. In COPD, exposure to cigarette smoke is the primary stimulus of airway inflammation. Activation of airway inflammatory cells leads to the release of excessive quantities of reactive oxygen species (ROS), resulting in oxidative stress. Antioxidants provide protection against the damaging effects of oxidative stress and thus may be useful in the management of inflammatory airways disease. Resveratrol, a polyphenol that demonstrates both antioxidative and anti-inflammatory functions, has been shown to improve outcomes in a variety of diseases, in particular, in cancer. We review the evidence for a protective role of resveratrol in respiratory disease. Mechanisms of resveratrol action that may be relevant to respiratory disease are described. We conclude that resveratrol has potential as a therapeutic agent in respiratory disease, which should be further investigated. PMID:20214495

  19. Inflammatory Mediator Profiling of n-butanol Exposed Upper Airways in Individuals with Multiple Chemical Sensitivity

    PubMed Central

    Dantoft, Thomas Meinertz; Skovbjerg, Sine; Andersson, Linus; Claeson, Anna-Sara; Lind, Nina; Nordin, Steven; Brix, Susanne

    2015-01-01

    Background Multiple Chemical Sensitivity (MCS) is a chronic condition characterized by reports of recurrent symptoms in response to low level exposure to various chemical substances. Recent findings suggests that dysregulation of the immune system may play a role in MCS pathophysiology. Objectives The aim of this study was to examine baseline and low dose n-butanol-induced upper airway inflammatory response profiles in MCS subjects versus healthy controls. Method Eighteen participants with MCS and 18 age- and sex-matched healthy controls were enrolled in the study. Epithelial lining fluid was collected from the nasal cavity at three time points: baseline, within 15 minutes after being exposed to 3.7 ppm n-butanol in an exposure chamber and four hours after exposure termination. A total of 19 cytokines and chemokines were quantified. Furthermore, at baseline and during the exposure session, participants rated the perceived intensity, valence and levels of symptoms and autonomic recordings were obtained. Results The physiological and psychophysical measurements during the n-butanol exposure session verified a specific response in MCS individuals only. However, MCS subjects and healthy controls displayed similar upper airway inflammatory mediator profiles (P>0.05) at baseline. Likewise, direct comparison of mediator levels in the MCS group and controls after n-butanol exposure revealed no significant group differences. Conclusion We demonstrate no abnormal upper airway inflammatory mediator levels in MCS subjects before or after a symptom-eliciting exposure to low dose n-butanol, implying that upper airways of MCS subjects are functionally intact at the level of cytokine and chemokine production and secretory capacity. This suggests that previous findings of increased cytokine plasma levels in MCS are unlikely to be caused by systemic priming via excessive upper airway inflammatory processes. PMID:26599866

  20. Anti-inflammatory drug (BW755C) inhibits airway hyperresponsiveness induced by ozone in dogs

    SciTech Connect

    Fabbri, L.M.; Aizawa, H.; O'Byrne, P.M.; Bethel, R.A.; Walters, E.H.; Holtzman, M.J.; Nadel, J.A.

    1985-08-01

    To follow up a previous observation that airway hyperresponsiveness induced by ozone is linked to airway inflammation, the authors investigated the effect of BW755C, an anti-inflammatory drug, on ozone-induced hyperresponsiveness in dogs. Airway responsiveness was assessed with dose-response curves of acetylcholine aerosol versus pulmonary resistance in two sets of experiments. In one set (placebo treatment), five dogs were given only saline solution treatment and were studied before treatment or ozone exposure and then after treatment both before and after ozone (3.0 ppm, 2 hours); in another set (BW755C treatment), the same dogs were studied before BW755C treatment or ozone and then after treatment (10 mg/kg intravenously) both before and after ozone. When the dogs were given no BW755C treatment, ozone induced a marked increase in airway responsiveness to acetylcholine. When the dogs were given BW755C, responsiveness was no different during treatment than before treatment but, more importantly, responsiveness did not increase significantly after ozone. The authors conclude that BW755C markedly inhibits ozone-induced airway hyperresponsiveness in dogs, probably by inhibiting the formation of oxygenation products of arachidonic acid.

  1. The innate immune function of airway epithelial cells in inflammatory lung disease.

    PubMed

    Hiemstra, Pieter S; McCray, Paul B; Bals, Robert

    2015-04-01

    The airway epithelium is now considered to be central to the orchestration of pulmonary inflammatory and immune responses, and is also key to tissue remodelling. It acts as the first barrier in the defence against a wide range of inhaled challenges, and is critically involved in the regulation of both innate and adaptive immune responses to these challenges. Recent progress in our understanding of the developmental regulation of this tissue, the differentiation pathways, recognition of pathogens and antimicrobial responses is now exploited to help understand how epithelial cell function and dysfunction contributes to the pathogenesis of a variety of inflammatory lung diseases. Herein, advances in our knowledge of the biology of airway epithelium, as well as its role and (dys)function in asthma, chronic obstructive pulmonary fibrosis and cystic fibrosis will be discussed. PMID:25700381

  2. The innate immune function of airway epithelial cells in inflammatory lung disease

    PubMed Central

    Hiemstra, Pieter S.; McCray, Paul B.; Bals, Robert

    2016-01-01

    The airway epithelium is now considered central to the orchestration of pulmonary inflammatory and immune responses, and is also key to tissue remodelling. It acts as a first barrier in the defence against a wide range of inhaled challenges, and is critically involved in the regulation of both innate and adaptive immune responses to these challenges. Recent progress in our understanding of the developmental regulation of this tissue, the differentiation pathways, recognition of pathogens and antimicrobial responses is now exploited to help understand how epithelial cell function and dysfunction contributes to the pathogenesis of a variety of inflammatory lung diseases. In the review, advances in our knowledge of the biology of airway epithelium, as well as its role and (dys)function in asthma, COPD and cystic fibrosis, are discussed. PMID:25700381

  3. The Role of the Extracellular Matrix Protein Mindin in Airway Response to Environmental Airways Injury

    PubMed Central

    Frush, Sarah; Li, Zhuowei; Potts, Erin N.; Du, Wanglei; Eu, Jerry P.; Garantziotis, Stavros; He, You-Wen; Foster, W. Michael

    2011-01-01

    Background: Our previous work demonstrated that the extracellular matrix protein mindin contributes to allergic airways disease. However, the role of mindin in nonallergic airways disease has not previously been explored. Objectives: We hypothesized that mindin would contribute to airways disease after inhalation of either lipopolysaccharide (LPS) or ozone. Methods: We exposed C57BL/6J and mindin-deficient (–/–) mice to aerosolized LPS (0.9 μg/m3 for 2.5 hr), saline, ozone (1 ppm for 3 hr), or filtered air (FA). All mice were evaluated 4 hr after LPS/saline 
exposure or 24 hr after ozone/FA exposure. We characterized the physiological and biological responses by analysis of airway hyperresponsiveness (AHR) with a computer-controlled small-animal ventilator (FlexiVent), inflammatory cellular recruitment, total protein in bronchoalveolar lavage fluid (BALF), proinflammatory cytokine profiling, and ex vivo bronchial ring studies. Results: After inhalation of LPS, mindin–/– mice demonstrated significantly reduced total cell and neutrophil recruitment into the airspace compared with their wild-type counterparts. Mindin–/– mice also exhibited reduced proinflammatory cytokine production and lower AHR to methacholine challenge by FlexiVent. After inhalation of ozone, mice had no detectible differences in cellular inflammation or total BALF protein dependent on mindin. However, mindin–/– mice were protected from increased proinflammatory cytokine production and AHR compared with their C57BL/6J counterparts. After ozone exposure, bronchial rings derived from mindin–/– mice demonstrated reduced constriction in response to carbachol. Conclusions: These data demonstrate that the extracellular matrix protein mindin modifies the airway response to both LPS and ozone. Our data support a conserved role of mindin in production of proinflammatory cytokines and the development of AHR in two divergent models of reactive airways disease, as well as a role of

  4. The effect of ozone on inflammatory cell infiltration and airway hyperresponsiveness in the guinea pig lung

    SciTech Connect

    Schultheis, A.J.H.

    1993-01-01

    Inflammatory cells may contribute to the development of exaggerated bronchoconstrictor responses since a persistent link has been noted between pulmonary inflammation and airway hyperresponsiveness. In these studies guinea pigs were exposed to 2.0 ppm ozone for 4 hours, then immediately sacrificed or allowed to breathe filtered air for up to 14 days. Following ozone exposure there was an immediate massive neutrophil infiltration into the lung. Neutrophils in lung digest dropped to control values within 3-12 hours post-ozone but remained elevated in BAL fluid for 3 days. There was probable eosinophil degranulation within the first 24 hours post-ozone. Guinea pigs were hyperresponsive to vigal stimulation through 3 days post-ozone. Although they were also hyperresponsive to ACh, responses to MCh were unchanged. Neuronal M[sub 2] receptors were dysfunctional through 3 days post-ozone. There was resolution of inflammation, airway responsiveness, and neuronal M[sub 2] receptor function by 14 days post-exposure. This investigation has (1) confirmed an immediate lung inflammation following acute ozone exposure; (2) established that cells in BAL give a distorted reflection of inflammatory events in lung digest; (3) demonstrated that ozone-induced hyperresponsiveness is at least partially due to efferent cholinergic mechanisms without functional changes of muscarinic receptors on airway smooth muscle; (4) shown that ACh may not be an appropriate agent to test ozone-induced airway hyperresponsiveness; and (5) demonstrated that inhibitory neuronal M[sub 2] receptors are dysfunctional following ozone exposure. There was close linkage between these events, suggesting that they may be causally related. This investigation proposes a specific mechanism, dysfunction of neuronal M[sub 2] receptors, by which inflammatory cells could cause airway hyperresponsiveness following acute ozone exposure.

  5. Regulation of CYP1A1 and Inflammatory Cytokine by NCOA7 Isoform 4 in Response to Dioxin Induced Airway Inflammation

    PubMed Central

    Cho, Sung-Hwan; Park, Shin Young; Lee, Eun Jeong; Cho, Yo Han; Park, Hyun Sun; Hong, Seok-Ho

    2015-01-01

    Background Aryl hydrocarbon receptor (AhR), a ligand-dependent transcription factor, binds to a wide variety of synthetic and naturally occurring compounds. AhR is involved in the regulation of inflammatory response during acute and chronic respiratory diseases. We investigated whether nuclear receptor coactivator 7 (NCOA7) could regulate transcriptional levels of AhR target genes and inflammatory cytokines in 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-treated human bronchial epithelial cells. This study was based on our previous study that NCOA7 was differentially expressed between normal and chronic obstructive pulmonary disease lung tissues. Methods BEAS-2B and A549 cells grown under serum-free conditions were treated with or without TCDD (0.15 nM and 6.5 nM) for 24 hours after transfection of pCMV-NCOA7 isoform 4. Expression levels of cytochrome P4501A1 (CYP1A1), IL-6, and IL-8 were measured by quantitative real-time polymerase chain reaction. Results The transcriptional activities of CYP1A1 and inflammatory cytokines were strongly induced by TCDD treatment in both BEAS-2B and A549 cell lines. The NCOA7 isoform 4 oppositely regulated the transcriptional activities of CYP1A1 and inflammatory cytokines between BEAS-2B and A549 cell lines. Conclusion Our results suggest that NCOA7 could act as a regulator in the TCDD-AhR signaling pathway with dual roles in normal and abnormal physiological conditions. PMID:25861343

  6. Patterns of airway involvement in inflammatory bowel diseases

    PubMed Central

    Papanikolaou, Ilias; Kagouridis, Konstantinos; Papiris, Spyros A

    2014-01-01

    Extraintestinal manifestations occur commonly in inflammatory bowel diseases (IBD). Pulmonary manifestations (PM) of IBD may be divided in airway disorders, interstitial lung disorders, serositis, pulmonary vasculitis, necrobiotic nodules, drug-induced lung disease, thromboembolic lung disease and enteropulmonary fistulas. Pulmonary involvement may often be asymptomatic and detected solely on the basis of abnormal screening tests. The common embryonic origin of the intestine and the lungs from the primitive foregut, the co-existence of mucosa associated lymphoid tissue in both organs, autoimmunity, smoking and bacterial translocation from the colon to the lungs may all be involved in the pathogenesis of PM in IBD. PM are mainly detected by pulmonary function tests and high-resolution computed tomography. This review will focus on the involvement of the airways in the context of IBD, especially stenoses of the large airways, tracheobronchitis, bronchiectasis, bronchitis, mucoid impaction, bronchial granulomas, bronchiolitis, bronchiolitis obliterans syndrome and the co-existence of IBD with asthma, chronic obstructive pulmonary disease, sarcoidosis and a1-antitrypsin deficiency. PMID:25400999

  7. Anti-inflammatory effects of methoxyphenolic compounds on human airway cells

    PubMed Central

    2012-01-01

    Background The respiratory epithelium plays a central role in the inflammatory response in asthma and other diseases. Methoxyphenolic compounds are purported to be effective anti-inflammatory agents, but their effects on the airway epithelium have not been well characterized. Methods Human airway cells were stimulated with TNF-α in the presence or absence of 4-substituted methoxyphenols and resveratrol. The expression of various cytokines was measured by qPCR, ELISAs, and protein arrays. Reactive oxygen species (ROS) production was measured with a reactive fluorescent probe (3',6'-diacetate-2',7'-dichlorofluorescein). Activation of NF-κB was measured by nuclear translocation and phosphorylation. Ribonuclear protein association with mRNA was assessed with a biotin-RNA affinity isolation assay. Results Multiple inflammatory mediators were inhibited by methoxyphenols, including: CCL2, CCL5, IL-6, IL-8, ICAM-1, MIF, CXCL1, CXCL10, and Serpin E1. IC50 values were obtained for each compound that showed significant anti-inflammatory activity: diapocynin (20.3 μM), resveratrol (42.7 μM), 2-methoxyhydroquinone (64.3 μM), apocynin (146.6 μM), and 4-amino-2-methoxyphenol (410 μM). The anti-inflammatory activity did not correlate with inhibition of reactive oxygen species production or NF-κB activation. However, methoxyphenols inhibited binding of the RNA-binding protein HuR to mRNA, indicating that they may act post-transcriptionally. Conclusions Methoxyphenols demonstrate anti-inflammatory activity in human airway cells. More potent compounds that act via similar mechanisms may have therapeutic potential as novel anti-inflammatory agents. PMID:22414048

  8. A new compound, 1H,8H-pyrano[3,4-c]pyran-1,8-dione, suppresses airway epithelial cell inflammatory responses in a murine model of asthma.

    PubMed

    Lee, H; Han, A R; Kim, Y; Choi, S H; Ko, E; Lee, N Y; Jeong, J H; Kim, S H; Bae, H

    2009-01-01

    Clinical and experimental studies have established eosinophilia as a sign of allergic disorders. Activation of eosinophils in the airways is believed to cause epithelial tissue injury, contraction of airway smooth muscle and increased bronchial responsiveness. As part of the search for new antiasthmatic agents produced by medicinal plants, the effects of 270 standardized medicinal plant extracts on cytokine-activated A549 human lung epithelial cells were evaluated. After several rounds of activity-guided screening, the new natural compound, 1H,8H-Pyrano[3,4-c]pyran-1,8-dione (PPY), was isolated from Vitex rotundifolia L. To elucidate the mechanism by which the anti-asthmatic responses of PPY occurred in vitro, lung epithelial cells (A549 cell) were stimulated with TNF-alpha, IL-4 and IL-1beta to induce the expression of chemokines and adhesion molecules involved in eosinophil chemotaxis. PPY treatments reduced the expression of eotaxin, IL-8, IL-16 and VCAM-1 mRNA significantly. Additionally, PPY reduced eotaxin secretion in a dose-dependent manner and significantly inhibited eosinophil migration toward A549 medium. In addition, PPY treatment suppressed the phosphorylation of p65 and ERK1/2, suggesting that it can inhibit the MAPK/NF-KB pathway. To clarify the anti-inflammatory and antiasthmatic effects of PPY in vivo, we examined the influence of PPY on the development of pulmonary eosinophilic inflammation in a murine model of asthma. To accomplish this, mice were sensitized and challenged with ovalbumin (OVA) and then examined for the following typical asthmatic reactions: an increase in the number of eosinophils in BALF; the presence of Th2 cytokines such as IL-4 and IL-5 in the BALF; the presence of allergen-specific IgE in the serum; and a marked influx of inflammatory cells into the lung. Taken together, our results revealed that PPY exerts profound inhibitory effects on the accumulation of eosinophils into the airways while reducing the levels of IL-4, IL-5

  9. Airway epithelial cell responses to ozone injury

    SciTech Connect

    Leikauf, G.D.; Simpson, L.G.; Zhao, Qiyu

    1995-03-01

    The airway epithelial cell is an important target in ozone injury. Once activated, the airway epithelium responds in three phases. The initial, or immediate phase, involves activation of constitutive cells, often through direct covalent interactions including the formation of secondary ozonolysis products-hydroxyhydroperoxides, aldehydes, and hydrogen peroxide. Recently, we found hydroxyhydroperoxides to be potent agonists; of bioactive eicosanoid formation by human airway epithelial cells in culture. Other probable immediate events include activation and inactivation of enzymes present on the epithelial surface (e.g., neutral endopeptidase). During the next 2 to 24 hr, or early phase, epithelial cells respond by synthesis and release of chemotactic factors, including chemokines-macrophage inflammatory protein-2, RANTES, and interleukin-8. Infiltrating leukocytes during this period also release elastase, an important agonist of epithelial cell mucus secretion and additional chemokine formation. The third (late) phase of ozone injury is characterized by eosinophil or monocyte infiltration. Cytokine expression leads to alteration of structural protein synthesis, with increases in fibronectin evident by in situ hybridization. Synthesis of epithelial antiproteases, e.g., secretary leukocyte protease inhibitor, may also increase locally 24 to 48 hr after elastase concentrations become excessive. Thus, the epithelium is not merely a passive barrier to ozone injury but has a dynamic role in directing the migration, activating, and then counteracting inflammatory cells. Through these complex interactions, epithelial cells can be viewed as the initiators (alpha) and the receptors (omega) of ozone-induced airway disease. 51 refs., 2 figs., 3 tabs.

  10. Adjuvant and anti-inflammatory properties of cigarette smoke in murine allergic airway inflammation.

    PubMed

    Trimble, Nancy J; Botelho, Fernando M; Bauer, Carla M T; Fattouh, Ramzi; Stämpfli, Martin R

    2009-01-01

    The impact of cigarette smoke on allergic asthma remains controversial both clinically and experimentally. The objective of this study was to investigate, in a murine model, how cigarette smoke affects immune inflammatory processes elicited by a surrogate allergen. In our experimental design, mice were concurrently exposed to cigarette smoke and ovalbumin (OVA), an innocuous antigen that, unless introduced in the context of an adjuvant, induces inhalation tolerance. We show that cigarette smoke exposure has adjuvant properties, allowing for allergic mucosal sensitization to OVA. Specifically, concurrent exposure to cigarette smoke and OVA for 2 weeks led to airway eosinophilia and goblet cell hyperplasia. In vivo OVA recall challenge 1 month after the last smoke exposure showed that concurrent exposure to OVA and cigarette smoke induced antigen-specific memory. Robust eosinophilia and OVA-specific IgG1 and IgE characterized the ensuing inflammatory response. Mechanistically, allergic sensitization was, in part, granulocyte macrophage colony-stimulating factor (GM-CSF) dependent, as a significant reduction in BAL eosinophilia was observed in mice treated with an anti-GM-CSF antibody. Of note, continuous smoke exposure attenuated the OVA recall response; decreased airway eosinophilia was observed in mice continuously exposed to cigarette smoke compared with mice that ceased the smoke exposure protocol. In conclusion, we demonstrate experimentally that while cigarette smoke acts as an adjuvant allowing for allergic sensitization, it also attenuates the ensuing eosinophilic inflammatory response. PMID:18635815

  11. Repeated allergen exposure reduce early phase airway response and leukotriene release despite upregulation of 5-lipoxygenase pathways

    PubMed Central

    2012-01-01

    Background Allergen induced early phase airway response and airway plasma exudation are predominantly mediated by inflammatory mast cell mediators including histamine, cysteinyl leukotrienes (cysLTs) and thromboxane A2 (TXA2). The aim of the present study was to evaluate whether repeated allergen exposure affects early phase airway response to allergen challenge. Methods A trimellitic anhydride (TMA) sensitized guinea pig model was used to investigate the effects of low dose repeated allergen exposure on cholinergic airway responsiveness, early phase airway response and plasma exudation, as well as local airway production of mast cell derived cysteinyl leukotrienes and thromboxane B2 (TXB2) after allergen challenge. Results Repeated low dose allergen exposure increased cholinergic airway responsiveness. In contrast, early phase airway response and plasma exudation in response to a high-dose allergen challenge were strongly attenuated after repeated low dose allergen exposure. Inhibition of the airway response was unspecific to exposed allergen and independent of histamine receptor blocking. Furthermore, a significant reduction of cysteinyl leukotrienes and TXB2 was found in the airways of animals repeatedly exposed to a low dose allergen. However, in vitro stimulation of airway tissue from animals repeatedly exposed to a low dose allergen with arachidonic acid and calcium ionophore (A23187) induced production of cysteinyl leukotrienes and TXB2, suggesting enhanced activity of 5-lipoxygenase and cyclooxygenase pathways. Conclusions The inhibition of the early phase airway response, cysteinyl leukotriene and TXB2 production after repeated allergen exposure may result from unresponsive effector cells. PMID:22439792

  12. The effect of phytocannabinoids on airway hyper-responsiveness, airway inflammation, and cough.

    PubMed

    Makwana, Raj; Venkatasamy, Radhakrishnan; Spina, Domenico; Page, Clive

    2015-04-01

    Cannabis has been demonstrated to have bronchodilator, anti-inflammatory, and antitussive activity in the airways, but information on the active cannabinoids, their receptors, and the mechanisms for these effects is limited. We compared the effects of Δ(9)-tetrahydrocannabinol, cannabidiol, cannabigerol, cannabichromene, cannabidiolic acid, and tetrahydrocannabivarin on contractions of the guinea pig-isolated trachea and bronchoconstriction induced by nerve stimulation or methacholine in anesthetized guinea pigs following exposure to saline or the proinflammatory cytokine, tumor necrosis factor α (TNF-α). CP55940 (2-[(1R,2R,5R)-5-hydroxy-2-(3-hydroxypropyl) cyclohexyl]-5-(2-methyloctan-2-yl)phenol), a synthetic cannabinoid agonist, was also investigated in vitro. The cannabinoids were also evaluated on TNF-α- and lipopolysaccharide-induced leukocyte infiltration into the lungs and citric acid-induced cough responses in guinea pigs. TNF-α, but not saline, augmented tracheal contractility and bronchoconstriction induced by nerve stimulation, but not methacholine. Δ(9)-Tetrahydrocannabinol and CP55940 reduced TNF-α-enhanced nerve-evoked contractions in vitro to the magnitude of saline-incubated trachea. This effect was antagonized by the cannabinoid 1 (CB(1)) and CB(2) receptor antagonists AM251 [N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-caroxamide] and JTE907 [N-(1,3-benzodioxol-5-ylmethyl)-1,2-dihydro-7-methoxy-2-oxo-8-(pentyloxy)-3-quinolinecarboxamide], respectively. Tetrahydrocannabivarin partially inhibited the TNF-α-enhanced nerve-evoked contractions, whereas the other cannabinoids were without effect. The effect of cannabidiol and Δ(9)-tetrahydrocannabinol together did not differ from that of the latter alone. Only Δ(9)-tetrahydrocannabinol inhibited TNF-α-enhanced vagal-induced bronchoconstriction, neutrophil recruitment to the airways, and citric acid-induced cough responses. TNF-α potentiated contractions

  13. Chemokines and their receptors in the allergic airway inflammatory process.

    PubMed

    Velazquez, Juan Raymundo; Teran, Luis Manuel

    2011-08-01

    The development of the allergic airway disease conveys several cell types, such as T-cells, eosinophils, mast cells, and dendritic cells, which act in a special and temporal synchronization. Cellular mobilization and its complex interactions are coordinated by a broad range of bioactive mediators known as chemokines. These molecules are an increasing family of small proteins with common structural motifs and play an important role in the recruitment and cell activation of both leukocytes and resident cells at the allergic inflammatory site via their receptors. Trafficking and recruitment of cell populations with specific chemokines receptors assure the presence of reactive allergen-specific T-cells in the lung, and therefore the establishment of an allergic inflammatory process. Different approaches directed against chemokines receptors have been developed during the last decades with promising therapeutic results in the treatment of asthma. In this review we explore the role of the chemokines and chemokine receptors in allergy and asthma and discuss their potential as targets for therapy. PMID:20352527

  14. Clinical application of expectorant therapy in chronic inflammatory airway diseases (Review)

    PubMed Central

    ZHANG, TING; ZHOU, XIANGDONG

    2014-01-01

    Airway mucus hypersecretion is a significant clinical and pathological feature of chronic inflammatory airway diseases. Its clinical presentations include recurrent coughing and phlegm. Airway mucus is closely associated with the occurrence, development and prognosis of chronic inflammatory airway diseases and critically affects the lung function, quality of life, hospitalization rate and mortality of patients with chronic inflammatory airway diseases. Therefore, expectorant therapies targeting the potential mechanisms of mucus hypersecretion have been the focus of numerous studies. Conventional expectorants are mainly mucoactive medicines, including nausea-stimulating expectorants, mucolytics, mucokinetics, and proteases and nucleases. In addition, certain traditional Chinese herbal medicines and non-mucoactive agents, including muscarinic acetylcholine receptor antagonists, corticosteroids, leukotriene receptor antagonists and macrolide antibiotics, have also shown expectorant effects. Several novel medicines for expectorant therapy have emerged, including cholesterol-lowering statins, epidermal growth factor receptor tyrosine kinase inhibitors, phosphodiesterase-4 inhibitors, stanozolol, surfactants, flavonoids, tachykinin receptor antagonists, protease inhibitors, cytokine antagonists and purinergic agonists. With the increasing number of multidisciplinary studies, the effectiveness of expectorant therapy for the treatment of chronic inflammatory airway diseases has been confirmed. Therefore, the development of novel expectorants and the standardization of expectorant therapy are the direction and focus of future studies, thus benefiting patients who have a chronic inflammatory airway disease. PMID:24660026

  15. THE EFFECTS OF COMBINATORIAL EXPOSURE OF PRO-INFLAMMATORY AND ANTI-INFLAMMATORY CYTOKINES ON AIRWAY EPITHELIAL CELL RELEASE OF CHEMOTACTIC MEDIATORS

    EPA Science Inventory

    Asthma is a chronic inflammatory disorder of the airways affecting nearly 15 million individuals nationally. Within the inflamed asthmatic airway there exist complex interactions between many cells and the cytokines they release, in particular mast cells, eosinophils, T-lymphocy...

  16. Plasticity of Airway Epithelial Cell Transcriptome in Response to Flagellin

    PubMed Central

    Clark, Joan G.; Kim, Kyoung-Hee; Basom, Ryan S.; Gharib, Sina A.

    2015-01-01

    Airway epithelial cells (AEC) are critical components of the inflammatory and immune response during exposure to pathogens. AECs in monolayer culture and differentiated epithelial cells in air-liquid interface (ALI) represent two distinct and commonly used in vitro models, yet differences in their response to pathogens have not been investigated. In this study, we compared the transcriptional effects of flagellin on AECs in monolayer culture versus ALI culture using whole-genome microarrays and RNA sequencing. We exposed monolayer and ALI AEC cultures to flagellin in vitro and analyzed the transcriptional response by microarray and RNA-sequencing. ELISA and RT-PCR were used to validate changes in select candidates. We found that AECs cultured in monolayer and ALI have strikingly different transcriptional states at baseline. When challenged with flagellin, monolayer AEC cultures greatly increased transcription of numerous genes mapping to wounding response, immunity and inflammatory response. In contrast, AECs in ALI culture had an unexpectedly muted response to flagellin, both in number of genes expressed and relative enrichment of inflammatory and immune pathways. We conclude that in vitro culturing methods have a dramatic effect on the transcriptional profile of AECs at baseline and after stimulation with flagellin. These differences suggest that epithelial responses to pathogen challenges are distinctly different in culture models of intact and injured epithelium. PMID:25668187

  17. Plasticity of airway epithelial cell transcriptome in response to flagellin.

    PubMed

    Clark, Joan G; Kim, Kyoung-Hee; Basom, Ryan S; Gharib, Sina A

    2015-01-01

    Airway epithelial cells (AEC) are critical components of the inflammatory and immune response during exposure to pathogens. AECs in monolayer culture and differentiated epithelial cells in air-liquid interface (ALI) represent two distinct and commonly used in vitro models, yet differences in their response to pathogens have not been investigated. In this study, we compared the transcriptional effects of flagellin on AECs in monolayer culture versus ALI culture using whole-genome microarrays and RNA sequencing. We exposed monolayer and ALI AEC cultures to flagellin in vitro and analyzed the transcriptional response by microarray and RNA-sequencing. ELISA and RT-PCR were used to validate changes in select candidates. We found that AECs cultured in monolayer and ALI have strikingly different transcriptional states at baseline. When challenged with flagellin, monolayer AEC cultures greatly increased transcription of numerous genes mapping to wounding response, immunity and inflammatory response. In contrast, AECs in ALI culture had an unexpectedly muted response to flagellin, both in number of genes expressed and relative enrichment of inflammatory and immune pathways. We conclude that in vitro culturing methods have a dramatic effect on the transcriptional profile of AECs at baseline and after stimulation with flagellin. These differences suggest that epithelial responses to pathogen challenges are distinctly different in culture models of intact and injured epithelium. PMID:25668187

  18. Novel Roles for Chloride Channels, Exchangers, and Regulators in Chronic Inflammatory Airway Diseases

    PubMed Central

    Sala-Rabanal, Monica; Yurtsever, Zeynep; Berry, Kayla N.; Brett, Tom J.

    2015-01-01

    Chloride transport proteins play critical roles in inflammatory airway diseases, contributing to the detrimental aspects of mucus overproduction, mucus secretion, and airway constriction. However, they also play crucial roles in contributing to the innate immune properties of mucus and mucociliary clearance. In this review, we focus on the emerging novel roles for a chloride channel regulator (CLCA1), a calcium-activated chloride channel (TMEM16A), and two chloride exchangers (SLC26A4/pendrin and SLC26A9) in chronic inflammatory airway diseases. PMID:26612971

  19. Difficult Airway Response Team: A Novel Quality Improvement Program for Managing Hospital-Wide Airway Emergencies

    PubMed Central

    Mark, Lynette J.; Herzer, Kurt R.; Cover, Renee; Pandian, Vinciya; Bhatti, Nasir I.; Berkow, Lauren C.; Haut, Elliott R.; Hillel, Alexander T.; Miller, Christina R.; Feller-Kopman, David J.; Schiavi, Adam J.; Xie, Yanjun J.; Lim, Christine; Holzmueller, Christine; Ahmad, Mueen; Thomas, Pradeep; Flint, Paul W.; Mirski, Marek A.

    2015-01-01

    Background Difficult airway cases can quickly become emergencies, increasing the risk of life-threatening complications or death. Emergency airway management outside the operating room is particularly challenging. Methods We developed a quality improvement program—the Difficult Airway Response Team (DART)—to improve emergency airway management outside the operating room. DART was implemented by a team of anesthesiologists, otolaryngologists, trauma surgeons, emergency medicine physicians, and risk managers in 2005 at The Johns Hopkins Hospital in Baltimore, Maryland. The DART program had three core components: operations, safety, and education. The operations component focused on developing a multidisciplinary difficult airway response team, standardizing the emergency response process, and deploying difficult airway equipment carts throughout the hospital. The safety component focused on real-time monitoring of DART activations and learning from past DART events to continuously improve system-level performance. This objective entailed monitoring the paging system, reporting difficult airway events and DART activations to a web-based registry, and using in situ simulations to identify and mitigate defects in the emergency airway management process. The educational component included development of a multispecialty difficult airway curriculum encompassing case-based lectures, simulation, and team building/communication to ensure consistency of care. Educational materials were also developed for non-DART staff and patients to inform them about the needs of patients with difficult airways and ensure continuity of care with other providers after discharge. Results Between July 2008 and June 2013, DART managed 360 adult difficult airway events comprising 8% of all code activations. Predisposing patient factors included body mass index > 40, history of head and neck tumor, prior difficult intubation, cervical spine injury, airway edema, airway bleeding, and previous

  20. How the airway smooth muscle in cystic fibrosis reacts in proinflammatory conditions: implications for airway hyper-responsiveness and asthma in cystic fibrosis.

    PubMed

    McCuaig, Sarah; Martin, James G

    2013-04-01

    Among patients with cystic fibrosis there is a high prevalence (40-70%) of asthma signs and symptoms such as cough and wheezing and airway hyper-responsiveness to inhaled histamine or methacholine. Whether these abnormal airway responses are due to a primary deficiency in the cystic fibrosis transmembrane conductance regulator (CFTR) or are secondary to the inflammatory environment in the cystic fibrosis lungs is not clear. A role for the CFTR in smooth muscle function is emerging, and alterations in contractile signalling have been reported in CFTR-deficient airway smooth muscle. Persistent bacterial infection, especially with Pseudomonas aeruginosa, stimulates interleukin-8 release from the airway epithelium, resulting in neutrophilic inflammation. Increased neutrophilia and skewing of CFTR-deficient T-helper cells to type 2 helper T cells creates an inflammatory environment characterised by high concentrations of tumour necrosis factor α, interleukin-8, and interleukin-13, which might all contribute to increased contractility of airway smooth muscle in cystic fibrosis. An emerging role of interleukin-17, which is raised in patients with cystic fibrosis, in airway smooth muscle proliferation and hyper-responsiveness is apparent. Increased understanding of the molecular mechanisms responsible for the altered smooth muscle physiology in patients with cystic fibrosis might provide insight into airway dysfunction in this disease. PMID:24429094

  1. Prolonged increased responsiveness of canine peripheral airways after exposure to O/sub 3/

    SciTech Connect

    Beckett, W.S.; Freed, A.N.; Turner, C.; Menkes, H.A.

    1988-02-01

    Because it is relatively insoluble, the oxidant gas O3 may penetrate to small peripheral airways when it is inhaled. Increased responsiveness in large airways after O3 breathing has been associated with the presence of inflammatory cells. To determine whether O3 produces prolonged hyperresponsiveness of small airways associated with the presence of inflammatory cells, we exposed the peripheral lungs of anesthetized dogs to 1.0 ppm O3 for 2 h using a wedged bronchoscope technique. A contralateral sublobar segment was simultaneously exposed to air as a control. In the O3-exposed segments, collateral resistance (Rcs) was increased within 15 min and remained elevated approximately 150% throughout the 2-h exposure period. Fifteen hours later, the base-line Rcs of the O3-exposed sublobar segments was significantly elevated, and these segments demonstrated increased responsiveness to aerosolized acetylcholine (100 and 500 micrograms/ml). There were no differences in neutrophils, mononuclear cells, or mast cells (numbers or degree of mast cell degranulation) between O3 and air-exposed airways at 15 h. The small airways of the lung periphery thus are capable of remaining hyperresponsive hours after cessation of localized exposure to O3, but this does not appear to be dependent on the presence of inflammatory cells in the small airway wall.

  2. Individuals with increased inflammatory response to ozone demonstrate muted signaling of immune cell trafficking pathways

    EPA Science Inventory

    Background Exposure to ozone activates innate immune function and causes neutrophilic (PMN) airway inflammation that in some individuals is robustly elevated. The interplay between immunoinflammatory function and genomic signaling in those with heightened inflammatory responsive...

  3. A fungal protease allergen provokes airway hyper-responsiveness in asthma.

    PubMed

    Balenga, Nariman A; Klichinsky, Michael; Xie, Zhihui; Chan, Eunice C; Zhao, Ming; Jude, Joseph; Laviolette, Michel; Panettieri, Reynold A; Druey, Kirk M

    2015-01-01

    Asthma, a common disorder that affects >250 million people worldwide, is defined by exaggerated bronchoconstriction to inflammatory mediators including acetylcholine (ACh), bradykinin and histamine-also termed airway hyper-responsiveness. Nearly 10% of people with asthma have severe, treatment-resistant disease, which is frequently associated with immunoglobulin-E sensitization to ubiquitous fungi, typically Aspergillus fumigatus (Af). Here we show that a major Af allergen, Asp f13, which is a serine protease, alkaline protease 1 (Alp 1), promotes airway hyper-responsiveness by infiltrating the bronchial submucosa and disrupting airway smooth muscle (ASM) cell-extracellular matrix (ECM) interactions. Alp 1-mediated ECM degradation evokes pathophysiological RhoA-dependent Ca(2+) sensitivity and bronchoconstriction. These findings support a pathogenic mechanism in asthma and other lung diseases associated with epithelial barrier impairment, whereby ASM cells respond directly to inhaled environmental allergens to generate airway hyper-responsiveness. PMID:25865874

  4. Hormonal control of inflammatory responses

    PubMed Central

    Farsky, Sandra P.

    1993-01-01

    Almost any stage of inflammatory and immunological responses is affected by hormone actions. This provides the basis for the suggestion that hormones act as modulators of the host reaction against trauma and infection. Specific hormone receptors are detected in the reactive structures in inflamed areas and binding of hormone molecules to such receptors results in the generation of signals that influence cell functions relevant for the development of inflammatory responses. Diversity of hormonal functions accounts for recognized pro- and anti-inflammatory effects exerted by these substances. Most hormone systems are capable of influencing inflammatory events. Insulin and glucocorticoids, however, exert direct regulatory effects at concentrations usually found in plasma. Insulin is endowed with facilitatory actions on vascular reactivity to inflammatory mediators and inflammatory cell functions. Increased concentrations of circulating glucocorticoids at the early stages of inflammation results in downregulation of inflammatory responses. Oestrogens markedly reduce the response to injury in a variety of experimental models. Glucagon and thyroid hormones exert indirect anti-inflammatory effects mediated by the activity of the adrenal cortex. Accordingly, inflammation is not only merely a local response, but a hormone-controlled process. PMID:18475521

  5. Cigarette smoke inhalation and the acute airway response.

    PubMed Central

    Higenbottam, T; Feyeraband, C; Clark, T J

    1980-01-01

    The acute airway response to smoking varying numbers (one to four) of identical cigarettes in rapid succession and smoking single cigarettes of differing tar/nicotine yields was assessed repeatedly in 13 healthy smokers. The airway response was variable, indicating airway narrowing consistently in only three subjects. There appeared no difference between forced spirometry and measurement of airway resistance in detecting the airway response. No relationship was observed between the airway response and amount of smoke inhaled into the lungs as measured either by changes in venous blood nicotine or percentage carboxyhaemoglobin. When five smokers inhaled smoke directly from a cigarette acute airway narrowing was consistently observed. A normal smoking pattern consisting of an initial drag of smoke into the mouth, followed after a pause by inhalation of smoke diluted with air, did not consistently cause airway narrowing although similar amounts of smoke as the direct drag were inhaled as assessed by changes in venous blood nicotine. The manner of smoke inhalation affects the relative concentrations of the different constituents of smoke reaching the lungs and also appears to be the main determinant of the acute airway response to smoking, which was unrelated to the number of cigarettes smoked or the tar content of the smoke. This suggests that patterns of smoke inhalation may influence the pathogenesis of bronchial disease associated with smoking. PMID:7434266

  6. Janus Kinase-3 Dependent Inflammatory Responses in Allergic Asthma

    PubMed Central

    Malaviya, Rama; Laskin, Debra L.; Malaviya, Ravi

    2010-01-01

    Summary Allergic asthma is a chronic inflammatory condition of the lung characterized by reversible airway obstruction, high serum immunoglobulin (Ig) E levels, and chronic airway inflammation. A number of cells including mast cells, T-cells, macrophages and dendritic cells play a role in the pathogenesis of the disease. Janus Kinase (JAK) −3, a nonreceptor protein tyrosine kinase, traditionally known to mediate cytokine signaling, also regulates functional responses of these cells. In this review the role of JAK-3 in regulating various pathogenic processes in allergic asthma is discussed. We propose that targeting JAK-3 is a rationale approach to control the inflammatory responses of multiple cell types responsible for the pathogenesis of allergic asthma. PMID:20430118

  7. Innate Immune Responses to Engineered Nanomaterials During Allergic Airway Inflammation

    NASA Astrophysics Data System (ADS)

    Shipkowski, Kelly Anne

    disease would modulate the innate immune response to MWCNTs. We hypothesized that Th2 cytokines and the allergic asthmatic microenvironment would alter MWCNT-induced inflammasome activation and IL- 1beta secretion both in vitro and in vivo. In vitro, THP-1 cells, a human monocytic cell line, were differentiated into macrophages and exposed to MWCNTs and or recombinant Th2 cytokines, specifically IL-4 and/or IL-13. Exposure of THP-1 cells to MWCNTs alone caused dose-dependent secretion of IL-1beta, while co-exposure to IL-4 and/or IL-13 suppressed MWCNT-induced IL-1beta. Further analysis determined that IL-4 and IL-13 were phosphorylating the protein signal transducer and activator of transcription 6 (STAT6) and subsequently inhibiting inflammasome activation and function through suppression of caspase-1, a cysteine protease responsible for cleavage of pro-IL-1beta into an active, secretable form. In vivo, wild-type C57BL6 mice were sensitized intranasally with HDM allergen and exposed to MWCNTs via oropharyngeal aspiration. Treatment with MWCNTs alone induced secretion of IL-1beta in the bronchoalveolar lavage fluid (BALF) one day post-exposure, while sensitization with HDM prior to MWCNT exposure suppressed MWCNT-induced IL-1beta. Immunohistochemical (IHC) analysis of lung sections from exposed animals showed that HDM sensitization inhibited MWCNT-induced pro-casapse-1 protein expression, responsible for inflammasome activation, in the airway epithelium and macrophages. MWCNT exposure combined with HDM sensitization increased inflammatory cell infiltration and subsequent acute lung inflammation and chronic fibrosis. Analysis of the systemic effects of MWCNT exposure during allergic airway sensitization showed that MWCNTs and/or HDM allergen upregulated STAT3 mRNA expression in the lungs, liver, and spleen of exposed animals, and at the same induced mixed T helper (Th) responses in the different tissues. Collectively, these data suggest that the allergic microenvironment

  8. Airway epithelial cell response to human metapneumovirus infection

    SciTech Connect

    Bao, X.; Liu, T.; Spetch, L.; Kolli, D.; Garofalo, R.P.; Casola, A.

    2007-11-10

    Human metapneumovirus (hMPV) is a major cause of lower respiratory tract infections (LRTIs) in infants, elderly and immunocompromised patients. In this study, we show that hMPV can infect in a similar manner epithelial cells representative of different tracts of the airways. hMPV-induced expression of chemokines IL-8 and RANTES in primary small alveolar epithelial cells (SAE) and in a human alveolar type II-like epithelial cell line (A549) was similar, suggesting that A549 cells can be used as a model to study lower airway epithelial cell responses to hMPV infection. A549 secreted a variety of CXC and CC chemokines, cytokines and type I interferons, following hMPV infection. hMPV was also a strong inducer of transcription factors belonging to nuclear factor (NF)-{kappa}B, interferon regulatory factors (IRFs) and signal transducers and activators of transcription (STATs) families, which are known to orchestrate the expression of inflammatory and immunomodulatory mediators.

  9. AIRWAY EPITHELIAL CELL RESPONSE TO HUMAN METAPNEUMOVIRUS INFECTION

    PubMed Central

    X, Bao; T, Liu; L, Spetch; D, Kolli; R.P, Garofalo; A, Casola

    2007-01-01

    Human metapneumovirus (hMPV) is a major cause of lower respiratory tract infections (LRTIs) in infants, elderly and immunocompromised patients. In this study, we show that hMPV can infect in a similar manner epithelial cells representative of different tracts of the airways. hMPV-induced expression of chemokines IL-8 and RANTES in primary small alveolar epithelial cells (SAE) and in a human alveolar type II-like epithelial cell line (A549) was similar, suggesting that A549 cells can be used as a model to study lower airway epithelial cell responses to hMPV infection. A549 secreted a variety of CXC and CC chemokines, cytokines and type I interferons, following hMPV infection. hMPV was also a strong inducer of transcription factors belonging to nuclear factor (NF)-κB, interferon regulatory factors (IRFs) and signal transducers and activators of transcription (STATs) families, which are known to orchestrate the expression of inflammatory and immuno-modulatory mediators. PMID:17655903

  10. Antioxidant airway responses following experimental exposure to wood smoke in man

    PubMed Central

    2010-01-01

    Background Biomass combustion contributes to the production of ambient particulate matter (PM) in rural environments as well as urban settings, but relatively little is known about the health effects of these emissions. The aim of this study was therefore to characterize airway responses in humans exposed to wood smoke PM under controlled conditions. Nineteen healthy volunteers were exposed to both wood smoke, at a particulate matter (PM2.5) concentration of 224 ± 22 μg/m3, and filtered air for three hours with intermittent exercise. The wood smoke was generated employing an experimental set-up with an adjustable wood pellet boiler system under incomplete combustion. Symptoms, lung function, and exhaled NO were measured over exposures, with bronchoscopy performed 24 h post-exposure for characterisation of airway inflammatory and antioxidant responses in airway lavages. Results Glutathione (GSH) concentrations were enhanced in bronchoalveolar lavage (BAL) after wood smoke exposure vs. air (p = 0.025), together with an increase in upper airway symptoms. Neither lung function, exhaled NO nor systemic nor airway inflammatory parameters in BAL and bronchial mucosal biopsies were significantly affected. Conclusions Exposure of healthy subjects to wood smoke, derived from an experimental wood pellet boiler operating under incomplete combustion conditions with PM emissions dominated by organic matter, caused an increase in mucosal symptoms and GSH in the alveolar respiratory tract lining fluids but no acute airway inflammatory responses. We contend that this response reflects a mobilisation of GSH to the air-lung interface, consistent with a protective adaptation to the investigated wood smoke exposure. PMID:20727160

  11. Differential Roles of Hydrogen Peroxide in Adaptive and Inflammatory Gene Expression Induced by Exposure of Human Airway Epithelial Cells to Zn2+

    EPA Science Inventory

    Oxidant stress is believed to play an important role in particulate matter (PM)–mediated toxicity in the respiratory tract. Zinc (Zn2+) is a ubiquitous component of PM that has been shown to induce adverse responses such as inflammatory and adaptive gene expression in airway epit...

  12. Nitrogen Dioxide Exposure and Airway Responsiveness in Individuals with Asthma

    EPA Science Inventory

    Controlled human exposure studies evaluating the effect of inhaled NO2 on the inherent responsiveness of the airways to challenge by bronchoconstricting agents have had mixed results. In general, existing meta-analyses show statistically significant effects of NO2 on the airway r...

  13. Airway smooth muscle responsiveness from dogs with airway hyperresponsiveness after O/sub 3/ inhalation

    SciTech Connect

    Jones, G.L.; O'Byrne, P.M.; Pashley, M.; Serio, R.; Jury, J.; Lane, C.G.; Daniel, E.E.

    1988-07-01

    Airway hyperresponsiveness occurs after inhalation of O3 in dogs. The purpose of this study was to examine the responsiveness of trachealis smooth muscle in vitro to electrical field stimulation, exogenous acetylcholine, and potassium chloride from dogs with airway hyperresponsiveness after inhaled O3 in vivo and to compare this with the responsiveness of trachealis muscle from control dogs. In addition, excitatory junction potentials were measured with the use of single and double sucrose gap techniques in both groups of dogs to determine whether inhaled O3 affects the release of acetylcholine from parasympathetic nerves in trachealis muscle. Airway hyperresponsiveness developed in all dogs after inhaled O3 (3 ppm for 30 min). The acetylcholine provocative concentration decreased from 4.11 mg/ml before O3 inhalation to 0.66 mg/ml after O3 (P less than 0.0001). The acetylcholine provocative concentration increased slightly after control inhalation of dry room air. Airway smooth muscle showed increased responses to both electrical field stimulation and exogenous acetylcholine but not to potassium chloride in preparations from dogs with airway hyperresponsiveness in vivo. The increased response to electrical field stimulation was not associated with a change in excitatory junctional potentials. These results suggest that a postjunctional alteration in trachealis muscle function occurs after inhaled O3 in dogs, which may account for airway hyperresponsiveness after O3 in vivo.

  14. Molecular cues guiding inflammatory responses.

    PubMed

    Barreiro, Olga; Martín, Pilar; González-Amaro, Roberto; Sánchez-Madrid, Francisco

    2010-05-01

    Alarm signals generated at inflammatory foci reach the vascular lumen to attract immune cells towards the affected tissue. Different leucocyte subsets decipher and integrate these complex signals in order to make adequate decisions for their migration towards the inflamed tissue. Soluble cues (cytokines and chemokines) and membrane receptors in both endothelium and leucocytes orchestrate the coordinated recruitment of specific inflammatory cell subsets. All these molecules are spatio-temporally organized in specialized structures at the luminal side of endothelium and the leucocyte membrane or are generated as chemical gradients in the damaged tissue. Thus, the repertoire of chemokines and their receptors as well as adhesion molecules expressed by each leucocyte subset determine their recruitment for participation in specific inflammatory pathologies. Whenever inflammatory signals are altered or misprocessed, inflammation can become chronic, causing extensive tissue damage. To combat chronic inflammation and autoimmune diseases, novel therapeutic strategies attempt to silence the predominant signals in each inflammatory scenario. In this review, we provide a general overview of all these aspects related to the molecular regulation of leucocyte guidance in inflammatory responses. PMID:20053659

  15. Inflammatory response and extracorporeal circulation.

    PubMed

    Kraft, Florian; Schmidt, Christoph; Van Aken, Hugo; Zarbock, Alexander

    2015-06-01

    Patients undergoing cardiac surgery with extracorporeal circulation (EC) frequently develop a systemic inflammatory response syndrome. Surgical trauma, ischaemia-reperfusion injury, endotoxaemia and blood contact to nonendothelial circuit compounds promote the activation of coagulation pathways, complement factors and a cellular immune response. This review discusses the multiple pathways leading to endothelial cell activation, neutrophil recruitment and production of reactive oxygen species and nitric oxide. All these factors may induce cellular damage and subsequent organ injury. Multiple organ dysfunction after cardiac surgery with EC is associated with an increased morbidity and mortality. In addition to the pathogenesis of organ dysfunction after EC, this review deals with different therapeutic interventions aiming to alleviate the inflammatory response and consequently multiple organ dysfunction after cardiac surgery. PMID:26060024

  16. Small Airway Dysfunction and Abnormal Exercise Responses

    PubMed Central

    Petsonk, Edward L.; Stansbury, Robert C.; Beeckman-Wagner, Lu-Ann; Long, Joshua L.; Wang, Mei Lin

    2016-01-01

    Rationale Coal mine dust exposure can cause symptoms and loss of lung function from multiple mechanisms, but the roles of each disease process are not fully understood. Objectives We investigated the implications of small airway dysfunction for exercise physiology among a group of workers exposed to coal mine dust. Methods Twenty coal miners performed spirometry, first breathing air and then helium-oxygen, single-breath diffusing capacity, and computerized chest tomography, and then completed cardiopulmonary exercise testing. Measurements and Main Results Six participants meeting criteria for small airway dysfunction were compared with 14 coal miners who did not. At submaximal workload, miners with small airway dysfunction used a higher proportion of their maximum voluntary ventilation and had higher ventilatory equivalents for both O2 and CO2. Regression modeling indicated that inefficient ventilation was significantly related to small airway dysfunction but not to FEV1 or diffusing capacity. At the end of exercise, miners with small airway dysfunction had 27% lower O2 consumption. Conclusions Small airway abnormalities may be associated with important inefficiency of exercise ventilation. In dust-exposed individuals with only mild abnormalities on resting lung function tests or chest radiographs, cardiopulmonary exercise testing may be important in defining causes of exercise intolerance. PMID:27073987

  17. Vitamin D Treatment Modulates Organic Dust-Induced Cellular and Airway Inflammatory Consequences

    PubMed Central

    Golden, Gregory A.; Wyatt, Todd A.; Romberger, Debra J.; Reiff, Daniel; McCaskill, Michael; Bauer, Christopher; Gleason, Angela M.; Poole, Jill A.

    2014-01-01

    Exposure to organic dusts elicits airway inflammatory diseases. Vitamin D recently has been associated with various airway inflammatory diseases, but its role in agricultural organic dust exposures is unknown. This study investigated whether vitamin D reduces organic dust-induced inflammatory outcomes in cell culture and animal models. Organic dust extracts obtained from swine confinement facilities induced neutrophil chemokine production (human IL-8, murine CXCL1/CXCL2). Neutrophil chemokine induction was reduced in human blood monocytes, human bronchial epithelial cells and murine lung slices pretreated with 1,25-(OH)2D3. Intranasal inhalation of organic dust extract induced neutrophil influx and CXCL1/CXCL2 release also was decreased in mice fed a relatively high vitamin D diet as compared to mice fed a low vitamin D diet. These findings were associated with reduced tracheal epithelial cell PKCα and PKCε activity and whole lung TLR2 and TLR4 gene expression. Collectively, vitamin D plays a role in modulating organic dust-induced airway inflammatory outcomes. PMID:23281135

  18. NEUROTROPHIN MEDIATION OF ALLERGIC AIRWAYS RESPONSES TO INHALED DIESEL PARTICLES IN MICE

    EPA Science Inventory

    Neurotrophins, including nerve growth factor (NGF) partially mediate many features of allergic airways disease including airway hyper-responsiveness. Diesel exhaust particulates (DEP) associated with the combustion of diesel fuel exacerbate many of these allergic airways respons...

  19. What's in a name? Inflammatory airway disease in racehorses in training.

    PubMed

    Cardwell, J M; Christley, R M; Gerber, V; Malikides, N; Wood, J L N; Newton, J R; Hodgson, J L

    2011-11-01

    The term 'inflammatory airway disease' (IAD) is often used to describe the syndrome of lower airway inflammation that frequently affects young racehorses in training around the world. In practice, this inflammation is generally diagnosed using a combination of endoscopic tracheal examination, including grading of amounts of mucus present and tracheal wash sampling. However, a recent consensus statement from the American College of Veterinary Internal Medicine concluded that bronchoalveolar lavage (BAL) sampling, rather than tracheal wash (TW) sampling, is required for cytological diagnosis of IAD and that tracheal mucus is not an essential criterion. However, as BAL is a relatively invasive procedure that is not commonly used on racing yards, this definition can only be applied routinely to a biased referral population. In contrast, many practitioners continue to diagnose IAD using endoscopic tracheal examination and sampling. We argue that, rather than restricting the use of the term IAD to phenotypes diagnosed by BAL, it is important to distinguish in the literature between airway inflammation diagnosed by BAL and that identified in the field using TW sampling. We suggest the use of the term brIAD for the former and trIAD for the latter. It is essential that we continue to endeavour to improve our understanding of the aetiology, pathogenesis and clinical relevance of airway inflammation identified in racehorses in training using tracheal examination and sampling. Future studies should focus on investigations of the component signs of airway inflammation. PMID:21668488

  20. Changes in airway permeability and responsiveness after exposure to ozone. [Sheep

    SciTech Connect

    Abraham, W.M.; Delehunt, J.C.; Yerger, L.; Marchette, B.; Oliver, W. Jr.

    1984-06-01

    The relationship between airway responsiveness and the permeability of histamine through the airways in conscious sheep after exposure to ozone (O/sub 3/ was examined). Airway responsiveness was assessed by measuring the change from baseline in mean pulmonary flow resistance following a controlled 2-min inhalation challenge with 1% histamine, containing 200 ..mu..Ci/ml of (/sup 3/H)histamine. The rate of appearance of the (/sup 3/H)histamine in the plasma during inhalation challenge was used to estimate airway permeability. To perturb the airways, conscious sheep were exposed to either 0.5 or 1.0 ppm O/sub 3/ for 2 hr via an endotracheal tube. Airway responsiveness and airway permeability were measured prior to and 1 day after exposure. In six sheep exposed to 0.5 ppm O/sub 3/, increased airway responsiveness and airway permeability were obseved 1 day after exposure. Four of seven sheep exposed to 1.0 ppm O/sub 3/ had enhanced airway responsiveness and airway permeability, while the remaining three sheep showed corresponding decreases in airway responsiveness and airway permeability. Since the O/sub 3/-induced directional changes in airway responsiveness paralleled the directional changes in airway permeability in both the positive and negative directions, it was concluded that changes in airway responsiveness to inhaled histamine following exposure to O/sub 3/ may be related to concomitant changes in airway permeability to this agent.

  1. Treatment with Pyranopyran-1, 8-Dione Attenuates Airway Responses in Cockroach Allergen Sensitized Asthma in Mice

    PubMed Central

    Jung, Kyung-Hwa; Song, Joohyun; Kim, You Ah; Cho, Hi Jae; Min, Byung-Il; Bae, Hyunsu

    2014-01-01

    Chronic allergic asthma is characterized by Th2-typed inflammation, and contributes to airway remodeling and the deterioration of lung function. Viticis Fructus (VF) has long been used in China and Korea as a traditional herbal remedy for treating various inflammatory diseases. Previously, we have isolated a novel phytochemical, pyranopyran-1, 8-dione (PPY), from VF. This study was conducted to evaluate the ability of PPY to prevent airway inflammation and to attenuate airway responses in a cockroach allergen-induced asthma model in mice. The mice sensitized to and challenged with cockroach allergen were treated with oral administration of PPY. The infiltration of total cells, eosinophils and lymphocytes into the BAL fluid was significantly inhibited in cockroach allergen-induced asthma mice treated with PPY (1, 2, or 10 mg/kg). Th2 cytokines and chemokine, such as IL-4, IL-5, IL-13 and eotaxin in BAL fluid were also reduced to normal levels following treatment with PPY. In addition, the levels of IgE were also markedly suppressed after PPY treatment. Histopathological examination demonstrated that PPY substantially inhibited eosinophil infiltration into the airway, goblet cell hyperplasia and smooth muscle hypertrophy. Taken together, these results demonstrate that PPY possesses a potent efficacy on controlling allergic asthma response such as airway inflammation and remodeling. PMID:24489937

  2. Treatment with pyranopyran-1, 8-dione attenuates airway responses in cockroach allergen sensitized asthma in mice.

    PubMed

    Park, Soojin; Park, Min-Sun; Jung, Kyung-Hwa; Song, Joohyun; Kim, You Ah; Cho, Hi Jae; Min, Byung-Il; Bae, Hyunsu

    2014-01-01

    Chronic allergic asthma is characterized by Th2-typed inflammation, and contributes to airway remodeling and the deterioration of lung function. Viticis Fructus (VF) has long been used in China and Korea as a traditional herbal remedy for treating various inflammatory diseases. Previously, we have isolated a novel phytochemical, pyranopyran-1, 8-dione (PPY), from VF. This study was conducted to evaluate the ability of PPY to prevent airway inflammation and to attenuate airway responses in a cockroach allergen-induced asthma model in mice. The mice sensitized to and challenged with cockroach allergen were treated with oral administration of PPY. The infiltration of total cells, eosinophils and lymphocytes into the BAL fluid was significantly inhibited in cockroach allergen-induced asthma mice treated with PPY (1, 2, or 10 mg/kg). Th2 cytokines and chemokine, such as IL-4, IL-5, IL-13 and eotaxin in BAL fluid were also reduced to normal levels following treatment with PPY. In addition, the levels of IgE were also markedly suppressed after PPY treatment. Histopathological examination demonstrated that PPY substantially inhibited eosinophil infiltration into the airway, goblet cell hyperplasia and smooth muscle hypertrophy. Taken together, these results demonstrate that PPY possesses a potent efficacy on controlling allergic asthma response such as airway inflammation and remodeling. PMID:24489937

  3. Lipopolysaccharide exposure makes allergic airway inflammation and hyper-responsiveness less responsive to dexamethasone and inhibition of iNOS.

    PubMed

    Komlósi, Z I; Pozsonyi, E; Tábi, T; Szöko, E; Nagy, A; Bartos, B; Kozma, G T; Tamási, L; Orosz, M; Magyar, P; Losonczy, G

    2006-07-01

    Allergic airway disease can be refractory to anti-inflammatory treatment, whose cause is unclarified. Therefore, in the present experiment, we have tested the hypothesis that co-exposure to lipopolysacharide (Lps) and allergen results in glucocorticoid-resistant eosinophil airway inflammation and hyper-responsiveness (AHR). Ovalbumin (Ova)-sensitized BALB/c mice were primed with 10 microg intranasal Lps 24 h before the start of Ova challenges (20 min on 3 consecutive days). Dexamethasone (5 mg/kg/day) was given on the last 2 days of Ova challenges. AHR, cellular build-up, cytokine and nitrite concentrations of bronchoalveolar lavage fluid (BALF) and lung histology were examined. To assess the role of iNOS-derived NO in airway responsiveness, mice were treated with a selective inhibitor of this enzyme (1400W) 2 h before AHR measurements. More severe eosinophil inflammation and higher nitrite formation were found in Lps-primed than in non-primed allergized mice. After Lps priming, AHR and concentrations of T-helper type 2 cytokines in BALF were decreased, but still remained significantly higher than in controls. Eosinophil inflammation was partially, while nitrite production and AHR were observed to be largely dexamethasone resistant in Lps-primed allergized animals. 1400W effectively and rapidly diminished the AHR in Ova-sensitized and challenged mice, but failed to affect it after Lps priming plus allergization. In conclusion, Lps inhalation may exaggerate eosinophil inflammation and reduce responsiveness to anti-inflammatory treatment in allergic airway disease. PMID:16839411

  4. Postnatal exposure history and airways: oxidant stress responses in airway explants.

    PubMed

    Murphy, Shannon R; Schelegle, Edward S; Edwards, Patricia C; Miller, Lisa A; Hyde, Dallas M; Van Winkle, Laura S

    2012-12-01

    Postnatally, the lung continues to grow and differentiate while interacting with the environment. Exposure to ozone (O(3)) and allergens during postnatal lung development alters structural elements of conducting airways, including innervation and neurokinin abundance. These changes have been linked with development of asthma in a rhesus monkey model. We hypothesized that O(3) exposure resets the ability of the airways to respond to oxidant stress and that this is mediated by changes in the neurokinin-1 receptor (NK-1R). Infant rhesus monkeys received episodic exposure to O(3) biweekly with or without house dust mite antigen (HDMA) from 6 to 12 months of age. Age-matched monkeys were exposed to filtered air (FA). Microdissected airway explants from midlevel airways (intrapulmonary generations 5-8) for four to six animals in each of four groups (FA, O(3), HDMA, and HDMA+O(3)) were tested for NK-1R gene responses to acute oxidant stress using exposure to hydrogen peroxide (1.2 mM), a lipid ozonide (10 μM), or sham treatment for 4 hours in vitro. Airway responses were measured using real-time quantitative RT-PCR of NK-1R and IL-8 gene expression. Basal NK-1R gene expression levels were not different between the exposure groups. Treatment with ozonide or hydrogen peroxide did not change NK-1R gene expression in animals exposed to FA, HDMA, or HDMA+O(3). However, treatment in vitro with lipid ozonide significantly increased NK-1R gene expression in explants from O(3)-exposed animals. We conclude that a history of prior O(3) exposure resets the steady state of the airways to increase the NK-1R response to subsequent acute oxidant stresses. PMID:22962062

  5. BLUNTING AIRWAYS EOSINOPHILIC INFLAMMATION RESULTS IN A DECREASED AIRWAY NEUTROPHIL RESPONSE TO INHALED LPS IN ATOPIC ASTHMATICS A ROLE FOR CD-14

    EPA Science Inventory

    Recent data demonstrate that atopic inflammation might enhance airway responses to inhaled LPS in individuals with atopic asthma by increasing CD14 expression on airway macrophages. We sought to determine whether blunting airway eosinophilic inflammation decreases CD14 expressio...

  6. Innate Immune Responses to Engineered Nanomaterials During Allergic Airway Inflammation

    NASA Astrophysics Data System (ADS)

    Shipkowski, Kelly Anne

    disease would modulate the innate immune response to MWCNTs. We hypothesized that Th2 cytokines and the allergic asthmatic microenvironment would alter MWCNT-induced inflammasome activation and IL- 1beta secretion both in vitro and in vivo. In vitro, THP-1 cells, a human monocytic cell line, were differentiated into macrophages and exposed to MWCNTs and or recombinant Th2 cytokines, specifically IL-4 and/or IL-13. Exposure of THP-1 cells to MWCNTs alone caused dose-dependent secretion of IL-1beta, while co-exposure to IL-4 and/or IL-13 suppressed MWCNT-induced IL-1beta. Further analysis determined that IL-4 and IL-13 were phosphorylating the protein signal transducer and activator of transcription 6 (STAT6) and subsequently inhibiting inflammasome activation and function through suppression of caspase-1, a cysteine protease responsible for cleavage of pro-IL-1beta into an active, secretable form. In vivo, wild-type C57BL6 mice were sensitized intranasally with HDM allergen and exposed to MWCNTs via oropharyngeal aspiration. Treatment with MWCNTs alone induced secretion of IL-1beta in the bronchoalveolar lavage fluid (BALF) one day post-exposure, while sensitization with HDM prior to MWCNT exposure suppressed MWCNT-induced IL-1beta. Immunohistochemical (IHC) analysis of lung sections from exposed animals showed that HDM sensitization inhibited MWCNT-induced pro-casapse-1 protein expression, responsible for inflammasome activation, in the airway epithelium and macrophages. MWCNT exposure combined with HDM sensitization increased inflammatory cell infiltration and subsequent acute lung inflammation and chronic fibrosis. Analysis of the systemic effects of MWCNT exposure during allergic airway sensitization showed that MWCNTs and/or HDM allergen upregulated STAT3 mRNA expression in the lungs, liver, and spleen of exposed animals, and at the same induced mixed T helper (Th) responses in the different tissues. Collectively, these data suggest that the allergic microenvironment

  7. Role of Rho kinase isoforms in murine allergic airway responses.

    PubMed

    Zhu, M; Liu, P-Y; Kasahara, D I; Williams, A S; Verbout, N G; Halayko, A J; Fedulov, A; Shoji, T; Williams, E S; Noma, K; Shore, S A; Liao, J K

    2011-10-01

    Inhibition of Rho-associated coiled-coil forming kinases (ROCKs) reduces allergic airway responses in mice. The purpose of this study was to determine the roles of the two ROCK isoforms, ROCK1 and ROCK2, in these responses. Wildtype (WT) mice and heterozygous ROCK1 and ROCK2 knockout mice (ROCK1(+/-) and ROCK2(+/-), respectively) were sensitised and challenged with ovalbumin. ROCK expression and activation were assessed by western blotting. Airway responsiveness was measured by forced oscillation. Bronchoalveolar lavage was performed and the lungs were fixed for histological assessment. Compared with WT mice, ROCK1 and ROCK2 expression were 50% lower in lungs of ROCK1(+/-) and ROCK2(+/-) mice, respectively, without changes in the other isoform. In WT lungs, ROCK activation increased after ovalbumin challenge and was sustained for several hours. This activation was reduced in ROCK1(+/-) and ROCK2(+/-) lungs. Airway responsiveness was comparable in WT, ROCK1(+/-), and ROCK2(+/-) mice challenged with PBS. Ovalbumin challenge caused airway hyperresponsiveness in WT, but not ROCK1(+/-) or ROCK2(+/-) mice. Lavage eosinophils and goblet cell hyperplasia were significantly reduced in ovalbumin-challenged ROCK1(+/-) and ROCK2(+/-) versus WT mice. Ovalbumin-induced changes in lavage interleukin-13, interleukin-5 and lymphocytes were also reduced in ROCK1(+/-) mice. In conclusion, both ROCK1 and ROCK2 are important in regulating allergic airway responses. PMID:21565918

  8. Ozone exposure increases eosinophilic airway response induced by previous allergen challenge.

    PubMed

    Vagaggini, Barbara; Taccola, Mauro; Cianchetti, Silvana; Carnevali, Stefano; Bartoli, Maria Laura; Bacci, Elena; Dente, Federico L; Di Franco, Antonella; Giannini, Daniele; Paggiaro, Pier Luigi

    2002-10-15

    We investigated whether exposure to ozone (O(3)) 24 hours after an allergen challenge test would increase airway eosinophilia induced by allergen in subjects with mild asthma with late airway response. Twelve subjects with mild atopic asthma participated in a randomized, single-blind study. Subjects underwent allergen challenge 24 hours before a 2 hour exposure to O(3) (0.27 ppm) or filtered air. Pulmonary function was monitored during the allergen challenge and after the exposure to O(3) or air. Six hours later, induced sputum was collected. After 4 weeks, the experiment was repeated with the same subjects. Allergen induced a comparable late airway response in both challenges. O(3) exposure induced a significant decrease in FVC, FEV(1), and vital capacity, and was associated with a significant increase in total symptom score compared with air exposure. The percentage of eosinophils, but not the percentage of neutrophils, in induced sputum was significantly higher after exposure to O(3) than after exposure to air (p = 0.04). These results indicate that O(3) exposure after a late airway response elicited by allergen challenge can potentiate the eosinophilic inflammatory response induced by the allergen challenge itself in subjects with mild atopic asthma. This observation may help explain the synergistic effect of air pollution and allergen exposure in the exacerbation of asthma. PMID:12379550

  9. Virus-induced airway hyperresponsiveness in the guinea-pig: possible involvement of histamine and inflammatory cells.

    PubMed Central

    Folkerts, G.; De Clerck, F.; Reijnart, I.; Span, P.; Nijkamp, F. P.

    1993-01-01

    histamine, twice a day (30 min) during 4 successive days, do not demonstrate an increased airway responsiveness, but instead show tachyphylaxis in response to histamine in vitro. In addition, no influx of inflammatory cells is found in these animals. 8. These results suggest that histamine does not directly increase the responsiveness of the guinea-pig trachea; however, histamine may be involved in a cascade of events leading to airway hyperresponsiveness after a viral infection, a process that could be related to an influx and/or an activation of broncho-alveolar cells after PI-3 virus stimulation. PMID:8097951

  10. FIBERTOM Nd:YAG laser in treatment of post-inflammatory structures of lower airways

    NASA Astrophysics Data System (ADS)

    Pirozynski, Michal; Polubiec-Kownacka, Malgorzata; Strojecki, Krzysztof; Blachnio, Antoni; Pawlak, Wieslaw; Krusiewicz, Jan

    1996-03-01

    Introduction of the first laser by Maiman in 1960 led to a rapid increase in the biological application of this device. The first application of laser energy in the treatment of airway pathology was by Strong et al. In 1981 Toty et al described the first use of a neodymium:yttrium-aluminum garnet (Nd:YAG) laser for resection of a bronchial tumor. Subglottic and tracheal stenosis have been treated endoscopically for many years with electrocautery, cryosurgery, by mechanical dilatation, and more recently since the mid 1970s with the carbon-dioxide laser. Early series demonstrated a moderate success rate in about 60% of the cases. Recently a new modification of the Nd:YAG laser was made available by Dornier (formerly MBB - Germany). The FIBERTOMTM is a unique method of controlling the temperature at the tip of the light guide allowing precise, direct contact cutting. Eleven patients (age 35.1 plus or minus 20.7 years) with post inflammatory airway stenoses were treated. Thirty-six procedures were carried out. An immediate dilatation of the narrowed airway was produced in 86%. Endoscopic control carried out 52 weeks after the initial procedure confirmed restoration of the airway lumen in 82%. Clinical improvement was seen in all.

  11. Pattern Recognition Scavenger Receptor A/CD204 Regulates Airway Inflammatory Homeostasis Following Organic Dust Extract Exposures

    PubMed Central

    Poole, Jill A.; Anderson, Leigh; Gleason, Angela M.; West, William W.; Romberger, Debra J.; Wyatt, Todd A.

    2014-01-01

    Exposure to agriculture organic dusts, comprised of a diversity of pathogen-associated molecular patterns, results in chronic airway diseases. The multi-functional class A macrophage scavenger receptor (SRA)/CD204 has emerged as an important class of pattern recognition receptors with broad ligand binding ability. Our objective was to determine the role of SRA in mediating repetitive and post-inflammatory organic dust extract (ODE)-induced airway inflammation. Wild-type (WT) and SRA knockout (KO) mice were intra-nasally treated with ODE or saline daily for 3 wk and immediately euthanized or allowed to recover for 1 wk. Results show that lung histopathologic changes were increased in SRA KO mice as compared to WT following repetitive ODE exposures marked predominately by increased size and distribution of lymphoid aggregates. After a 1-wk recovery from daily ODE treatments, there was significant resolution of lung injury in WT mice, but not SRA KO animals. The increased lung histopathology induced by ODE treatment was associated with decreased accumulation of neutrophils, but greater accumulation of CD4+ T-cells. The lung cytokine milieu induced by ODE was consistent with a TH1/TH17 polarization in both WT and SRA KO mice. Overall, our data demonstrate that SRA/CD204 plays an important role in the normative inflammatory lung response to ODE as evidenced by the enhanced dust-mediated injury viewed in the absence of this receptor. PMID:24491035

  12. Dynamics of airway response in lung microsections: a tool for studying airway-extra cellular matrix interactions.

    PubMed

    Khan, Mohammad Afzal

    2016-01-01

    The biological configuration of extracellular matrix (ECM) plays a key role in how mechanical interactions of the airway with its parenchymal attachments affect the dynamics of airway responses in different pulmonary disorders including asthma, emphysema and chronic bronchitis. It is now recognized that mechanical interactions between airway tissue and ECM play a key regulatory role on airway physiology and kinetics that can lead to the reorganization and remodeling of airway connective tissue. A connective tissue is composed of airway smooth muscle cells (ASM) and the ECM, which includes variety of glycoproteins and therefore the extent of interactions between ECM and ASM affects airway dynamics during exacerbations of major pulmonary disorders. Measurement of the velocity and magnitude of airway closure or opening provide important insights into the functions of the airway contractile apparatus and the interactions with its surrounding connective tissues. This review highlights suitability of lung microsection technique in studying measurements of airway dynamics (narrowing/opening) and associated structural distortions in airway compartments. PMID:27176036

  13. Mechanisms of airway responses to esophageal acidification in cats.

    PubMed

    Lang, Ivan M; Haworth, Steven T; Medda, Bidyut K; Forster, Hubert; Shaker, Reza

    2016-04-01

    Acid in the esophagus causes airway constriction, tracheobronchial mucous secretion, and a decrease in tracheal mucociliary transport rate. This study was designed to investigate the neuropharmacological mechanisms controlling these responses. In chloralose-anesthetized cats (n = 72), we investigated the effects of vagotomy or atropine (100 μg·kg(-1)·30 min(-1) iv) on airway responses to esophageal infusion of 0.1 M PBS or 0.1 N HCl at 1 ml/min. We quantified 1) diameter of the bronchi, 2) tracheobronchial mucociliary transport rate, 3) tracheobronchial mucous secretion, and 4) mucous content of the tracheal epithelium and submucosa. We found that vagotomy or atropine blocked the airway constriction response but only atropine blocked the increase in mucous output and decrease in mucociliary transport rate caused by esophageal acidification. The mucous cells of the mucosa produced more Alcian blue- than periodic acid-Schiff (PAS)-stained mucosubstances, and the mucous cells of the submucosa produced more PAS- than Alcian blue-stained mucosubstances. Selective perfusion of the different segments of esophagus with HCl or PBS resulted in significantly greater production of PAS-stained mucus in the submucosa of the trachea adjacent to the HCl-perfused esophagus than in that adjacent to the PBS-perfused esophagus. In conclusion, airway constriction caused by esophageal acidification is mediated by a vagal cholinergic pathway, and the tracheobronchial transport response is mediated by cholinergic receptors. Acid perfusion of the esophagus selectively increases production of neutral mucosubstances of the apocrine glands by a local mechanism. We hypothesize that the airway responses to esophageal acid exposure are part of the innate, rather than acute emergency, airway defense system. PMID:26846551

  14. Differential cellular responses in healthy mice and in mice with established airway inflammation when exposed to hematite nanoparticles.

    PubMed

    Gustafsson, Åsa; Bergström, Ulrika; Ågren, Lina; Österlund, Lars; Sandström, Thomas; Bucht, Anders

    2015-10-01

    The aim of this study was to investigate the inflammatory and immunological responses in airways and lung-draining lymph nodes (LDLNs), following lung exposure to iron oxide (hematite) nanoparticles (NPs). The responses to the hematite NPs were evaluated in both healthy non-sensitized mice, and in sensitized mice with an established allergic airway disease. The mice were exposed intratracheally to either hematite NPs or to vehicle (PBS) and the cellular responses were evaluated on days 1, 2, and 7, post-exposure. Exposure to hematite NPs increased the numbers of neutrophils, eosinophils, and lymphocytes in the airways of non-sensitized mice on days 1 and 2 post-exposure; at these time points the number of lymphocytes was also elevated in the LDLNs. In contrast, exposing sensitized mice to hematite NPs induced a rapid and unspecific cellular reduction in the alveolar space on day 1 post-exposure; a similar decrease of lymphocytes was also observed in the LDLN. The results indicate that cells in the airways and in the LDLN of individuals with established airway inflammation undergo cell death when exposed to hematite NPs. A possible explanation for this toxic response is the extensive generation of reactive oxygen species (ROS) in the pro-oxidative environment of inflamed airways. This study demonstrates how sensitized and non-sensitized mice respond differently to hematite NP exposure, and it highlights the importance of including individuals with respiratory disorders when evaluating health effects of inhaled nanomaterials. PMID:26163175

  15. Interaction with Epithelial Cells Modifies Airway Macrophage Response to Ozone

    EPA Science Inventory

    The initial innate immune response to ozone (03) in the lung is orchestrated by structural cells, such as epithelial cells, and resident immune cells, such as airway macrophages (Macs). We developed an epithelial cell-Mac coculture model to investigate how epithelial cell-derived...

  16. Anti-Inflammatory Effects of Levalbuterol-Induced 11β-Hydroxysteroid Dehydrogenase Type 1 Activity in Airway Epithelial Cells

    PubMed Central

    Randall, Matthew J.; Kostin, Shannon F.; Burgess, Edward J.; Hoyt, Laura R.; Ather, Jennifer L.; Lundblad, Lennart K.; Poynter, Matthew E.

    2015-01-01

    Airway epithelial NF-κB activation is observed in asthmatic subjects and is a cause of airway inflammation in mouse models of allergic asthma. Combination therapy with inhaled short-acting β2-agonists and corticosteroids significantly improves lung function and reduces inflammation in asthmatic subjects. Corticosteroids operate through a number of mechanisms to potently inhibit NF-κB activity. Since β2-agonists can induce expression of 11β-HSD1, which converts inactive 11-keto corticosteroids into active 11-hydroxy corticosteroids, thereby potentiating the effects of endogenous glucocorticoids, we examined whether this mechanism is involved in the inhibition of NF-κB activation induced by the β-agonist albuterol in airway epithelial cells. Treatment of transformed murine Club cells (MTCC) with (R)-albuterol (levalbuterol), but not with (S)- or a mixture of (R + S)- (racemic) albuterol, augmented mRNA expression of 11β-HSD1. MTCC were stably transfected with luciferase (luc) reporter constructs under transcriptional regulation by NF-κB (NF-κB/luc) or glucocorticoid response element (GRE/luc) consensus motifs. Stimulation of NF-κB/luc MTCC with lipopolysaccharide (LPS) or tumor necrosis factor-α (TNFα) induced luc activity, which was inhibited by pretreatment with (R)-, but not (S)- or racemic albuterol. Furthermore, pretreatment of GRE/luc MTCC with (R)-, but not with (S)- or racemic albuterol, augmented 11-keto corticosteroid (cortisone) induced luc activity, which was diminished by the 11β-HSD inhibitor glycyrrhetinic acid (18β-GA), indicating that there was a conversion of inactive 11-keto to active 11-hydroxy corticosteroids. LPS- and TNFα-induced NF-κB/luc activity was diminished in MTCC cells treated with a combination of cortisone and (R)-albuterol, an effect that was inhibited by 18β-GA. Finally, pretreatment of MTCC cells with the combination of cortisone and (R)-albuterol diminished LPS- and TNFα-induced pro-inflammatory cytokine

  17. Anti-inflammatory effects of levalbuterol-induced 11β-hydroxysteroid dehydrogenase type 1 activity in airway epithelial cells.

    PubMed

    Randall, Matthew J; Kostin, Shannon F; Burgess, Edward J; Hoyt, Laura R; Ather, Jennifer L; Lundblad, Lennart K; Poynter, Matthew E

    2014-01-01

    Airway epithelial NF-κB activation is observed in asthmatic subjects and is a cause of airway inflammation in mouse models of allergic asthma. Combination therapy with inhaled short-acting β2-agonists and corticosteroids significantly improves lung function and reduces inflammation in asthmatic subjects. Corticosteroids operate through a number of mechanisms to potently inhibit NF-κB activity. Since β2-agonists can induce expression of 11β-HSD1, which converts inactive 11-keto corticosteroids into active 11-hydroxy corticosteroids, thereby potentiating the effects of endogenous glucocorticoids, we examined whether this mechanism is involved in the inhibition of NF-κB activation induced by the β-agonist albuterol in airway epithelial cells. Treatment of transformed murine Club cells (MTCC) with (R)-albuterol (levalbuterol), but not with (S)- or a mixture of (R + S)- (racemic) albuterol, augmented mRNA expression of 11β-HSD1. MTCC were stably transfected with luciferase (luc) reporter constructs under transcriptional regulation by NF-κB (NF-κB/luc) or glucocorticoid response element (GRE/luc) consensus motifs. Stimulation of NF-κB/luc MTCC with lipopolysaccharide (LPS) or tumor necrosis factor-α (TNFα) induced luc activity, which was inhibited by pretreatment with (R)-, but not (S)- or racemic albuterol. Furthermore, pretreatment of GRE/luc MTCC with (R)-, but not with (S)- or racemic albuterol, augmented 11-keto corticosteroid (cortisone) induced luc activity, which was diminished by the 11β-HSD inhibitor glycyrrhetinic acid (18β-GA), indicating that there was a conversion of inactive 11-keto to active 11-hydroxy corticosteroids. LPS- and TNFα-induced NF-κB/luc activity was diminished in MTCC cells treated with a combination of cortisone and (R)-albuterol, an effect that was inhibited by 18β-GA. Finally, pretreatment of MTCC cells with the combination of cortisone and (R)-albuterol diminished LPS- and TNFα-induced pro-inflammatory cytokine

  18. Airway inflammatory markers in individuals with cystic fibrosis and non-cystic fibrosis bronchiectasis

    PubMed Central

    Bergin, David A; Hurley, Killian; Mehta, Adwait; Cox, Stephen; Ryan, Dorothy; O’Neill, Shane J; Reeves, Emer P; McElvaney, Noel G

    2013-01-01

    Bronchiectasis is an airway disease characterized by thickening of the bronchial wall, chronic inflammation , and destruction of affected bronchi. Underlying etiologies include severe pulmonary infection and cystic fibrosis (CF); however, in a substantial number of patients with non-CF-related bronchiectasis (NCFB), no cause is found. The increasing armamentarium of therapies now available to combat disease in CF is in stark contrast to the limited tools employed in NCFB. Our study aimed to evaluate similarities and differences in airway inflammatory markers in patients with NCFB and CF, and to suggest potential common treatment options. The results of this study show that NCFB bronchoalveolar lavage fluid samples possessed significantly increased NE activity and elevated levels of matrix metalloproteinases 2 (MMP-2) and MMP-9 compared to healthy controls (P < 0.01); however, the levels detected were lower than in CF (P < 0.01). Interleukin-8 (IL-8) concentrations were significantly elevated in NCFB and CF compared to controls (P < 0.05), but in contrast, negligible levels of IL-18 were detected in both NCFB and CF. Analogous concentrations of IL-10 and IL-4 measured in NCFB and CF were statistically elevated above the healthy control values (P < 0.05 and P < 0.01, respectively). These results indicate high levels of important proinflammatory markers in both NCFB and CF and support the use of appropriate anti-inflammatory therapies already employed in the treatment of CF bronchiectasis in NCFB. PMID:23426081

  19. Morin Attenuates Ovalbumin-Induced Airway Inflammation by Modulating Oxidative Stress-Responsive MAPK Signaling

    PubMed Central

    Ma, Yuan; Ge, Ai; Zhu, Wen; Liu, Ya-Nan; Ji, Ning-Fei; Zha, Wang-Jian; Zhang, Jia-Xiang; Zeng, Xiao-Ning

    2016-01-01

    Asthma is one of the most common inflammatory diseases characterized by airway hyperresponsiveness, inflammation, and remodeling. Morin, an active ingredient obtained from Moraceae plants, has been demonstrated to have promising anti-inflammatory activities in a range of disorders. However, its impacts on pulmonary diseases, particularly on asthma, have not been clarified. This study was designed to investigate whether morin alleviates airway inflammation in chronic asthma with an emphasis on oxidative stress modulation. In vivo, ovalbumin- (OVA-) sensitized mice were administered with morin or dexamethasone before challenge. Bronchoalveolar lavage fluid (BALF) and lung tissues were obtained to perform cell counts, histological analysis, and enzyme-linked immunosorbent assay. In vitro, human bronchial epithelial cells (BECs) were challenged by tumor necrosis factor alpha (TNF-α). The supernatant was collected for the detection of the proinflammatory proteins, and the cells were collected for reactive oxygen species (ROS)/mitogen-activated protein kinase (MAPK) evaluations. Severe inflammatory responses and remodeling were observed in the airways of the OVA-sensitized mice. Treatment with morin dramatically attenuated the extensive trafficking of inflammatory cells into the BALF and inhibited their infiltration around the respiratory tracts and vessels. Morin administration also significantly suppressed goblet cell hyperplasia and collagen deposition/fibrosis and dose-dependently inhibited the OVA-induced increases in IgE, TNF-α, interleukin- (IL-) 4, IL-13, matrix metalloproteinase-9, and malondialdehyde. In human BECs challenged by TNF-α, the levels of proteins such as eotaxin-1, monocyte chemoattractant protein-1, IL-8 and intercellular adhesion molecule-1, were consistently significantly decreased by morin. Western blotting and the 2′,7′-dichlorofluorescein assay revealed that the increases in intracellular ROS and MAPK phosphorylation were abolished by

  20. Morin Attenuates Ovalbumin-Induced Airway Inflammation by Modulating Oxidative Stress-Responsive MAPK Signaling.

    PubMed

    Ma, Yuan; Ge, Ai; Zhu, Wen; Liu, Ya-Nan; Ji, Ning-Fei; Zha, Wang-Jian; Zhang, Jia-Xiang; Zeng, Xiao-Ning; Huang, Mao

    2016-01-01

    Asthma is one of the most common inflammatory diseases characterized by airway hyperresponsiveness, inflammation, and remodeling. Morin, an active ingredient obtained from Moraceae plants, has been demonstrated to have promising anti-inflammatory activities in a range of disorders. However, its impacts on pulmonary diseases, particularly on asthma, have not been clarified. This study was designed to investigate whether morin alleviates airway inflammation in chronic asthma with an emphasis on oxidative stress modulation. In vivo, ovalbumin- (OVA-) sensitized mice were administered with morin or dexamethasone before challenge. Bronchoalveolar lavage fluid (BALF) and lung tissues were obtained to perform cell counts, histological analysis, and enzyme-linked immunosorbent assay. In vitro, human bronchial epithelial cells (BECs) were challenged by tumor necrosis factor alpha (TNF-α). The supernatant was collected for the detection of the proinflammatory proteins, and the cells were collected for reactive oxygen species (ROS)/mitogen-activated protein kinase (MAPK) evaluations. Severe inflammatory responses and remodeling were observed in the airways of the OVA-sensitized mice. Treatment with morin dramatically attenuated the extensive trafficking of inflammatory cells into the BALF and inhibited their infiltration around the respiratory tracts and vessels. Morin administration also significantly suppressed goblet cell hyperplasia and collagen deposition/fibrosis and dose-dependently inhibited the OVA-induced increases in IgE, TNF-α, interleukin- (IL-) 4, IL-13, matrix metalloproteinase-9, and malondialdehyde. In human BECs challenged by TNF-α, the levels of proteins such as eotaxin-1, monocyte chemoattractant protein-1, IL-8 and intercellular adhesion molecule-1, were consistently significantly decreased by morin. Western blotting and the 2',7'-dichlorofluorescein assay revealed that the increases in intracellular ROS and MAPK phosphorylation were abolished by morin

  1. Chitin-Induced Airway Epithelial Cell Innate Immune Responses Are Inhibited by Carvacrol/Thymol.

    PubMed

    Khosravi, Ali Reza; Erle, David J

    2016-01-01

    Chitin is produced in large amounts by fungi, insects, and other organisms and has been implicated in the pathogenesis of asthma. Airway epithelial cells are in direct contact with environmental particles and serve as the first line of defense against inhaled allergens and pathogens. The potential contributions of airway epithelial cells to chitin-induced asthma remain poorly understood. We hypothesized that chitin directly stimulates airway epithelial cells to release cytokines that promote type 2 immune responses and to induce expression of molecules which are important in innate immune responses. We found that chitin exposure rapidly induced the expression of three key type 2-promoting cytokines, IL-25, IL-33 and TSLP, in BEAS-2B transformed human bronchial epithelial cells and in A549 and H292 lung carcinoma cells. Chitin also induced the expression of the key pattern recognition receptors TLR2 and TLR4. Chitin induced the expression of miR-155, miR-146a and miR-21, each of which is known to up-regulate the expression of pro-inflammatory cytokines. Also the expression of SOCS1 and SHIP1 which are known targets of miR-155 was repressed by chitin treatment. The monoterpene phenol carvacrol (Car) and its isomer thymol (Thy) are found in herbal essential oils and have been shown to inhibit allergic inflammation in asthma models. We found that Car/Thy inhibited the effects of chitin on type 2-promoting cytokine release and on the expression of TLRs, SOCS1, SHIP1, and miRNAs. Car/Thy could also efficiently reduce the protein levels of TLR4, inhibit the increase in TLR2 protein levels in chitin plus Car/Thy-treated cells and increase the protein levels of SHIP1 and SOCS1, which are negative regulators of TLR-mediated inflammatory responses. We conclude that direct effects of chitin on airway epithelial cells are likely to contribute to allergic airway diseases like asthma, and that Car/Thy directly inhibits epithelial cell pro-inflammatory responses to chitin. PMID

  2. Chitin-Induced Airway Epithelial Cell Innate Immune Responses Are Inhibited by Carvacrol/Thymol

    PubMed Central

    Erle, David J.

    2016-01-01

    Chitin is produced in large amounts by fungi, insects, and other organisms and has been implicated in the pathogenesis of asthma. Airway epithelial cells are in direct contact with environmental particles and serve as the first line of defense against inhaled allergens and pathogens. The potential contributions of airway epithelial cells to chitin-induced asthma remain poorly understood. We hypothesized that chitin directly stimulates airway epithelial cells to release cytokines that promote type 2 immune responses and to induce expression of molecules which are important in innate immune responses. We found that chitin exposure rapidly induced the expression of three key type 2-promoting cytokines, IL-25, IL-33 and TSLP, in BEAS-2B transformed human bronchial epithelial cells and in A549 and H292 lung carcinoma cells. Chitin also induced the expression of the key pattern recognition receptors TLR2 and TLR4. Chitin induced the expression of miR-155, miR-146a and miR-21, each of which is known to up-regulate the expression of pro-inflammatory cytokines. Also the expression of SOCS1 and SHIP1 which are known targets of miR-155 was repressed by chitin treatment. The monoterpene phenol carvacrol (Car) and its isomer thymol (Thy) are found in herbal essential oils and have been shown to inhibit allergic inflammation in asthma models. We found that Car/Thy inhibited the effects of chitin on type 2-promoting cytokine release and on the expression of TLRs, SOCS1, SHIP1, and miRNAs. Car/Thy could also efficiently reduce the protein levels of TLR4, inhibit the increase in TLR2 protein levels in chitin plus Car/Thy-treated cells and increase the protein levels of SHIP1 and SOCS1, which are negative regulators of TLR-mediated inflammatory responses. We conclude that direct effects of chitin on airway epithelial cells are likely to contribute to allergic airway diseases like asthma, and that Car/Thy directly inhibits epithelial cell pro-inflammatory responses to chitin. PMID

  3. Airway inflammation, airway responsiveness and cough before and after inhaled budesonide in patients with eosinophilic bronchitis.

    PubMed

    Brightling, C E; Ward, R; Wardlaw, A J; Pavord, I D

    2000-04-01

    Eosinophilic bronchitis is a common cause of chronic cough, characterized by sputum eosinophilia similar to that seen in asthma, but unlike asthma the patients have no objective evidence of variable airflow obstruction or airway hyperresponsiveness. The reason for the different functional associations is unclear. The authors have tested the hypothesis that in eosinophilic bronchitis the inflammation is mainly localized in the upper airway. In an open study the authors measured the lower (provocative concentration causing a 20% fall in forced expiratory volume in one second (PC20)) and upper (PC25 MIF50) airway responsiveness to histamine, lower and upper airway inflammation using induced sputum and nasal lavage, in II patients with eosinophilic bronchitis. The authors assessed changes in these measures and in cough reflex sensitivity to capsaicin and cough severity after 400 microg of inhaled budesonide for 4 weeks. A nasal eosinophilia was present in only three patients with one having upper airway hyperresponsiveness. Following treatment with inhaled corticosteroids the geometric mean sputum eosinophil count decreased from 12.8% to 2.9% (mean difference 4.4-fold, 95% confidence interval (CI) 2.14-10.02), the mean +/- sem cough visual analogue score on a 100 mm scale decreased from 27.2 +/- 6.6 mm to 12.6 +/- 5.7 mm (mean difference 14.6, 95% CI 9.1-20.1) and the cough sensitivity assessed as the capsaicin concentration required to cause two coughs (C2) and five coughs (C5) improved (C2 mean difference 0.75 doubling concentrations, 95% CI 0.36-1.1; C5 mean difference 1.3 doubling concentration, 95% CI 0.6-2.1). There was a significant positive correlation between the fold change in sputum eosinophil count and doubling dose change in C5 after inhaled budesonide (r=0.61). It is concluded that upper airway inflammation is not prominent in eosinophilic bronchitis and that inhaled budesonide improves the sputum eosinophilia, cough severity and sensitivity suggesting a

  4. Ovalbumin sensitization of guinea pig at birth prevents the ontogenetic decrease in airway smooth muscle responsiveness

    PubMed Central

    Chitano, Pasquale; Wang, Lu; Degan, Simone; Worthington, Charles L.; Pozzato, Valeria; Hussaini, Syed H.; Turner, Wesley C.; Dorscheid, Delbert R.; Murphy, Thomas M.

    2014-01-01

    Abstract Airway smooth muscle (ASM) displays a hyperresponsive phenotype at young age and becomes less responsive in adulthood. We hypothesized that allergic sensitization, which causes ASM hyperresponsiveness and typically occurs early in life, prevents the ontogenetic loss of the ASM hyperresponsive phenotype. We therefore studied whether neonatal allergic sensitization, not followed by later allergen challenges, alters the ontogenesis of ASM properties. We neonatally sensitized guinea pigs to ovalbumin and studied them at 1 week, 3 weeks, and 3 months (adult). A Schultz‐Dale response in isolated tracheal rings confirmed sensitization. The occurrence of inflammation was evaluated in the blood and in the submucosa of large airways. We assessed ASM function in tracheal strips as ability to produce force and shortening. ASM content of vimentin was also studied. A Schultz‐Dale response was observed in all 3‐week or older sensitized animals. A mild inflammatory process was characterized by eosinophilia in the blood and in the airway submucosa. Early life sensitization had no effect on ASM force generation, but prevented the ontogenetic decline of shortening velocity and the increase in resistance to shortening. Vimentin increased with age in control but not in sensitized animals. Allergic sensitization at birth without subsequent allergen exposures is sufficient to prevent normal ASM ontogenesis, inducing persistence to adulthood of an ASM hyperresponsive phenotype. PMID:25501429

  5. Intratracheal myriocin enhances allergen‐induced Th2 inflammation and airway hyper‐responsiveness

    PubMed Central

    Edukulla, Ramakrishna; Rehn, Kira Lee; Liu, Bo; McAlees, Jaclyn W.; Hershey, Gurjit K.; Wang, Yui Hsi; Lewkowich, Ian

    2016-01-01

    Introduction Ceramide is the central substrate of sphingolipid metabolism and plays a key role in cellular signal transduction pathways, regulating apoptosis, differentiation, and chemotaxis. Alterations in airway ceramide levels are observed in multiple pulmonary diseases and recent human genetic association studies have linked dysregulation of sphingolipid regulatory genes with asthma pathogenesis. Methods Utilizing myriocin, a potent inhibitor of sphingolipid synthesis, we evaluated the immune regulatory role of de novo ceramide generation in vitro and in vivo. Intratracheal myriocin was administered alone or during house dust mite sensitization (HDM) of BALB/C mice and airway hyper‐responsiveness (AHR) was evaluated by invasive plethysmography followed by bronchial lavage (BAL) cytology and cytokine quantification. Results Myriocin inhibits and HDM exposure activates de novo ceramide synthesis in bone marrow‐derived dendritic cells. Mice receiving intratracheal myriocin developed a mild airway neutrophilic infiltrate without inducing a significant increase in AHR. CXCL1 was elevated in the BAL fluid of myriocin‐treated mice while the neutrophilic chemotactic factors anaphylatoxin C5a, leukotriene B4, and IL‐17 were unaffected. HDM treatment combined with myriocin led to a dramatic enhancement of AHR (63% increase over HDM alone, p < 0.001) and increased granulocyte pulmonary infiltrates versus HDM or myriocin alone. Elevated Th2 T cell counts and Th2 cytokines/chemokines (IL5, IL13, CCL17) were observed in mice treated with combined HDM/myriocin compared to HDM alone. Myriocin‐treated pulmonary CD11c+ cells stimulated with HDM secreted significantly more CXCL1 than cells stimulated with HDM alone while HDM stimulated airway epithelial cells showed no change in CXCL1 secretion following myriocin treatment. Conclusions Intratracheal myriocin, likely acting via ceramide synthesis inhibition, enhances allergen‐induced airway inflammation

  6. Heightened airway responsiveness in normal female children compared with adults.

    PubMed

    Tepper, R S; Stevens, J; Eigen, H

    1994-03-01

    Studies have suggested that airway responsiveness declines with maturation; however, studies comparing infants, children, and adults are confounded by differences in size as well as maturation. Therefore, to determine whether maturation has a significant affect on airway responsiveness, we compared normal female children (n = 9; mean age = 13.6 yr) and adults (n = 7; mean age = 42.4 yr) who were matched for body size. Bronchial challenge tests were performed with increasing methacholine concentrations to a maximum of 30 mg/ml. At baseline, there were no significant differences between the two groups in lung volumes (TGV, RV, TLC) or flow-volume curves (FEV1, average forced expiratory flow rate between 25% and 75% of the vital capacity [FEF25-75], FVC). All subjects but one adolescent completed the challenge (30 mg/ml). The children had a greater percentage decline from baseline in FEV1 than the adults (17 versus 7%, p < 0.03). The percentage decline in FEF25-75 was greater for the children than for the adults, but the difference was not statistically significant (35 versus 20%, p < 0.10). Compared with the children, the adults more often demonstrated a plateau in their dose-response curves for FEV1 (22 versus 86%) and for FEF25-75 (33 versus 100%). We conclude that normal female children have a greater airway responsiveness to inhaled methacholine than do adults, and that this difference is not related to baseline lung size, airway caliber, or delivered methacholine dose. PMID:8118636

  7. EFFECT OF INHALED ENDOTOXIN ON AIRWAY AND CIRCULATING INFLAMMATORY CELL PHAGOCYTOSIS AND CD11B EXPRESSION IN ATOPIC ASTHMATIC SUBJECTS

    EPA Science Inventory

    Effect of inhaled endotoxin on airway and circulating inflammatory cell phagocytosis and CD11b expression in atopic asthmatic subjects

    Neil E. Alexis, PhD, Marlowe W. Eldridge, MD, David B. Peden, MD, MS

    Chapel Hill and Research Triangle Park, NC

    Backgrou...

  8. Hyperoxia promotes polarization of the immune response in ovalbumin-induced airway inflammation, leading to a TH17 cell phenotype

    PubMed Central

    Nagato, Akinori C; Bezerra, Frank S; Talvani, André; Aarestrup, Beatriz J; Aarestrup, Fernando M

    2015-01-01

    Previous studies have demonstrated that hyperoxia-induced stress and oxidative damage to the lungs of mice lead to an increase in IL-6, TNF-α, and TGF-β expression. Together, IL-6 and TGF-β have been known to direct T cell differentiation toward the TH17 phenotype. In the current study, we tested the hypothesis that hyperoxia promotes the polarization of T cells to the TH17 cell phenotype in response to ovalbumin-induced acute airway inflammation. Airway inflammation was induced in female BALB/c mice by intraperitoneal sensitization and intranasal introduction of ovalbumin, followed by challenge methacholine. After the methacholine challenge, animals were exposed to hyperoxic conditions in an inhalation chamber for 24 h. The controls were subjected to normoxia or aluminum hydroxide dissolved in phosphate buffered saline. After 24 h of hyperoxia, the number of macrophages and lymphocytes decreased in animals with ovalbumin-induced airway inflammation, whereas the number of neutrophils increased after ovalbumin-induced airway inflammation. The results showed that expression of Nrf2, iNOS, T-bet and IL-17 increased after 24 of hyperoxia in both alveolar macrophages and in lung epithelial cells, compared with both animals that remained in room air, and animals with ovalbumin-induced airway inflammation. Hyperoxia alone without the induction of airway inflammation lead to increased levels of TNF-α and CCL5, whereas hyperoxia after inflammation lead to decreased CCL2 levels. Histological evidence of extravasation of inflammatory cells into the perivascular and peribronchial regions of the lungs was observed after pulmonary inflammation and hyperoxia. Hyperoxia promotes polarization of the immune response toward the TH17 phenotype, resulting in tissue damage associated with oxidative stress, and the migration of neutrophils to the lung and airways. Elucidating the effect of hyperoxia on ovalbumin-induced acute airway inflammation is relevant to preventing or

  9. Airway reflexes, autonomic function, and cardiovascular responses.

    PubMed Central

    Widdicombe, J; Lee, L Y

    2001-01-01

    In this article, we review the cardiovascular responses to the inhalation of irritants and pollutants. Many sensory receptors in the respiratory system, from nose to alveoli, respond to these irritants and set up powerful reflex changes, including those in the cardiovascular system. Systemic hypotension or hypertension, pulmonary hypertension, bradycardia, tachycardia, and dysrhythmias have all been described previously. Most of the experiments have been acute and have been performed on anesthetized experimental animals. Experiments on humans suggest we have similar sensory systems and reflex responses. However, we must use caution when applying the animal results to humans. Most animal experiments, unlike those with humans, have been performed using general anesthesia, with irritants administered in high concentrations, and often to a restricted part of the respiratory tract. Species differences in the response to irritants are well established. We must be even more careful when applying the results of acute experiments in animals to the pathophysiologic changes observed in prolonged exposure to environmental pollution in humans. PMID:11544167

  10. Early interleukin 4-dependent response can induce airway hyperreactivity before development of airway inflammation in a mouse model of asthma.

    PubMed

    To, Y; Dohi, M; Tanaka, R; Sato, A; Nakagome, K; Yamamoto, K

    2001-10-01

    In experimental models of bronchial asthma with mice, airway inflammation and increase in airway hyperreactivity (AHR) are induced by a combination of systemic sensitization and airway challenge with allergens. In this report, we present another possibility: that systemic antigen-specific sensitization alone can induce AHR before the development of inflammation in the airway. Male BALB/c mice were sensitized with ovalbumin (OVA) by a combination of intraperitoneal injection and aerosol inhalation, and various parameters for airway inflammation and hyperreactivity were sequentially analyzed. Bronchial response measured by a noninvasive method (enhanced pause) and the eosinophil count and interleukin (IL)-5 concentration in bronchoalveolar lavage fluid (BALF) gradually increased following the sensitization, and significant increase was achieved after repeated OVA aerosol inhalation along with development of histologic changes of the airway. In contrast, AHR was already significantly increased by systemic sensitization alone, although airway inflammation hardly developed at that time point. BALF IL-4 concentration and the expression of IL-4 mRNA in the lung reached maximal values after the systemic sensitization, then subsequently decreased. Treatment of mice with anti-IL-4 neutralizing antibody during systemic sensitization significantly suppressed this early increase in AHR. In addition, IL-4 gene-targeted mice did not reveal this early increase in AHR by systemic sensitization. These results suggest that an immune response in the lung in an early stage of sensitization can induce airway hyperreactivity before development of an eosinophilic airway inflammation in BALB/c mice and that IL-4 plays an essential role in this process. If this early increase in AHR does occur in sensitized human infants, it could be another therapeutic target for early prevention of the future onset of asthma. PMID:11598151

  11. Pro- and Anti-Inflammatory Role of ChemR23 Signaling in Pollutant-Induced Inflammatory Lung Responses.

    PubMed

    Provoost, Sharen; De Grove, Katrien C; Fraser, Graeme L; Lannoy, Vincent J; Tournoy, Kurt G; Brusselle, Guy G; Maes, Tania; Joos, Guy F

    2016-02-15

    Inhalation of traffic-related particulate matter (e.g., diesel exhaust particles [DEPs]) is associated with acute inflammatory responses in the lung, and it promotes the development and aggravation of allergic airway diseases. We previously demonstrated that exposure to DEP was associated with increased recruitment and maturation of monocytes and conventional dendritic cells (DCs), resulting in TH2 polarization. Monocytes and immature DCs express the G-protein coupled receptor chemR23, which binds the chemoattractant chemerin. Using chemR23 knockout (KO) and corresponding wild-type (WT) mice, we determined the role of chemR23 signaling in response to acute exposure to DEPs and in response to DEP-enhanced house dust mite (HDM)-induced allergic airway inflammation. Exposure to DEP alone, as well as combined exposure to DEP plus HDM, elevated the levels of chemerin in the bronchoalveolar lavage fluid of WT mice. In response to acute exposure to DEPs, monocytes and monocyte-derived DCs accumulated in the lungs of WT mice, but this response was significantly attenuated in chemR23 KO mice. Concomitant exposure to DEP plus HDM resulted in allergic airway inflammation with increased eosinophilia, goblet cell metaplasia, and TH2 cytokine production in WT mice, which was further enhanced in chemR23 KO mice. In conclusion, we demonstrated an opposing role for chemR23 signaling depending on the context of DEP-induced inflammation. The chemR23 axis showed proinflammatory properties in a model of DEP-induced acute lung inflammation, in contrast to anti-inflammatory effects in a model of DEP-enhanced allergic airway inflammation. PMID:26773141

  12. Cistrome-based Cooperation between Airway Epithelial Glucocorticoid Receptor and NF-κB Orchestrates Anti-inflammatory Effects.

    PubMed

    Kadiyala, Vineela; Sasse, Sarah K; Altonsy, Mohammed O; Berman, Reena; Chu, Hong W; Phang, Tzu L; Gerber, Anthony N

    2016-06-10

    Antagonism of pro-inflammatory transcription factors by monomeric glucocorticoid receptor (GR) has long been viewed as central to glucocorticoid (GC) efficacy. However, the mechanisms and targets through which GCs exert therapeutic effects in diseases such as asthma remain incompletely understood. We previously defined a surprising cooperative interaction between GR and NF-κB that enhanced expression of A20 (TNFAIP3), a potent inhibitor of NF-κB. Here we extend this observation to establish that A20 is required for maximal cytokine repression by GCs. To ascertain the global extent of GR and NF-κB cooperation, we determined genome-wide occupancy of GR, the p65 subunit of NF-κB, and RNA polymerase II in airway epithelial cells treated with dexamethasone, TNF, or both using chromatin immunoprecipitation followed by deep sequencing. We found that GR recruits p65 to dimeric GR binding sites across the genome and discovered additional regulatory elements in which GR-p65 cooperation augments gene expression. GR targets regulated by this mechanism include key anti-inflammatory and injury response genes such as SERPINA1, which encodes α1 antitrypsin, and FOXP4, an inhibitor of mucus production. Although dexamethasone treatment reduced RNA polymerase II occupancy of TNF targets such as IL8 and TNFAIP2, we were unable to correlate specific binding sequences for GR or occupancy patterns with repressive effects on transcription. Our results suggest that cooperative anti-inflammatory gene regulation by GR and p65 contributes to GC efficacy, whereas tethering interactions between GR and p65 are not universally required for GC-based gene repression. PMID:27076634

  13. Residual oil fly ash amplifies allergic cytokines, airway responsiveness, and inflammation in mice.

    PubMed

    Gavett, S H; Madison, S L; Stevens, M A; Costa, D L

    1999-12-01

    Particulate matter (PM) air pollution may increase symptom severity in allergic asthmatics. To examine possible interaction, or greater than additive responses, between PM effects and allergic responses, an ovalbumin-sensitized and challenged (OVA) mouse model of allergic airways disease was utilized. After challenge, mice were intratracheally instilled with saline vehicle or 3 mg/kg (approximately 60 microg) residual oil fly ash (ROFA), a transition metal-rich emission source PM sample. Physiological and inflammatory responses were examined 1, 3, 8, and 15 d later. In response to intravenously administered methacholine, ROFA increased total respiratory system resistance and decreased compliance 1 d after exposure, whereas effects of OVA lasted at least 15 d after exposure. Significant interactions between OVA and ROFA were mainly observed 8 d after challenge and exposure, especially with respect to compliance. A strong interaction (p < 0.01) between OVA and ROFA exposure resulted in 8-fold (1 d) and 3-fold (3 d) increases in bronchoalveolar lavage (BAL) fluid eosinophil numbers. A similarly strong interaction (8-fold) was observed in BAL fluid interleukin-4 (IL-4) 1 d after challenge and exposure. Significant though less strong interactions were also found with respect to IL-4 and IL-5 by 3 d postchallenge/exposure. This study shows that allergen challenge and exposure to emission source particulate matter containing relatively high levels of transitions metals can interact to increase Th2 cytokine production, eosinophil recruitment, and airway hyperresponsiveness in previously sensitized mice. PMID:10588603

  14. Dendritic Cells and Monocytes with Distinct Inflammatory Responses Reside in Lung Mucosa of Healthy Humans.

    PubMed

    Baharom, Faezzah; Thomas, Saskia; Rankin, Gregory; Lepzien, Rico; Pourazar, Jamshid; Behndig, Annelie F; Ahlm, Clas; Blomberg, Anders; Smed-Sörensen, Anna

    2016-06-01

    Every breath we take contains potentially harmful pathogens or allergens. Dendritic cells (DCs), monocytes, and macrophages are essential in maintaining a delicate balance of initiating immunity without causing collateral damage to the lungs because of an exaggerated inflammatory response. To document the diversity of lung mononuclear phagocytes at steady-state, we performed bronchoscopies on 20 healthy subjects, sampling the proximal and distal airways (bronchial wash and bronchoalveolar lavage, respectively), as well as mucosal tissue (endobronchial biopsies). In addition to a substantial population of alveolar macrophages, we identified subpopulations of monocytes, myeloid DCs (MDCs), and plasmacytoid DCs in the lung mucosa. Intermediate monocytes and MDCs were highly frequent in the airways compared with peripheral blood. Strikingly, the density of mononuclear phagocytes increased upon descending the airways. Monocytes from blood and airways produced 10-fold more proinflammatory cytokines than MDCs upon ex vivo stimulation. However, airway monocytes were less inflammatory than blood monocytes, suggesting a more tolerant nature. The findings of this study establish how to identify human lung mononuclear phagocytes and how they function in normal conditions, so that dysregulations in patients with respiratory diseases can be detected to elucidate their contribution to immunity or pathogenesis. PMID:27183618

  15. Nasal airway responses to nasal continuous positive airway pressure breathing: An in-vivo pilot study.

    PubMed

    White, David E; Bartley, Jim; Shakeel, Muhammad; Nates, Roy J; Hankin, Robin K S

    2016-06-14

    The nasal cycle, through variation in nasal airflow partitioning, allows the upper airway to accommodate the contrasting demands of air conditioning and removal of entrapped air contaminants. The purpose of this study was to investigate the influence of nasal continuous positive airway pressure (nCPAP) breathing has on both nasal airflow partitioning and nasal geometry. Using a custom-made nasal mask, twenty healthy participants had the airflow in each naris measured during normal nasal breathing followed by nCPAP breathing. Eight participants also underwent magnetic resonance imaging (MRI) of the nasal region during spontaneous nasal breathing, and then nCPAP breathing over a range of air pressures. During nCPAP breathing, a simultaneous reduction in airflow through the patent airway together with a corresponding increase in airway flow within the congested nasal airway were observed in sixteen of the twenty participants. Nasal airflow resistance is inversely proportional to airway cross-sectional area. MRI data analysis during nCPAP breathing confirmed airway cross-sectional area reduced along the patent airway while the congested airway experienced an increase in this parameter. During awake breathing, nCPAP disturbs the normal inter-nasal airflow partitioning. This could partially explain the adverse nasal drying symptoms frequently reported by many users of this therapy. PMID:27173595

  16. The Compatible Solute Ectoine Reduces the Exacerbating Effect of Environmental Model Particles on the Immune Response of the Airways

    PubMed Central

    Gotić, Marijan

    2014-01-01

    Exposure of humans to particulate air pollution has been correlated with the incidence and aggravation of allergic airway diseases. In predisposed individuals, inhalation of environmental particles can lead to an exacerbation of immune responses. Previous studies demonstrated a beneficial effect of the compatible solute ectoine on lung inflammation in rats exposed to carbon nanoparticles (CNP) as a model of environmental particle exposure. In the current study we investigated the effect of such a treatment on airway inflammation in a mouse allergy model. Ectoine in nonsensitized animals significantly reduced the neutrophilic lung inflammation after CNP exposure. This effect was accompanied by a reduction of inflammatory factors in the bronchoalveolar lavage. Reduced IL-6 levels in the serum also indicate the effects of ectoine on systemic inflammation. In sensitized animals, an aggravation of the immune response was observed when animals were exposed to CNP prior to antigen provocation. The coadministration of ectoine together with the particles significantly reduced this exacerbation. The data indicate the role of neutrophilic lung inflammation in the exacerbation of allergic airway responses. Moreover, the data suggest to use ectoine as a preventive treatment to avoid the exacerbation of allergic airway responses induced by environmental air pollution. PMID:24822073

  17. Airway responsiveness to hypertonic saline: dose-response slope or PD15?

    PubMed

    de Meer, G; Marks, G B; de Jongste, J C; Brunekreef, B

    2005-01-01

    The result of airway challenge test with hypertonic saline (HS) is expressed as the dose causing a 15% fall in forced expiratory volume in one second (FEV1; PD15). A noncensored measure, such as the dose-response slope (DRS), allows the evaluation of the risk of asthma for subjects with a fall in FEV1 <15%. The aim of this study was to assess the relationship between airway responsiveness to HS by PD15 or DRS, asthma symptoms and markers of eosinophilic inflammation. Data on current wheeze and airway responsiveness were obtained for 1,107 children (aged 8-13 yrs). Blood eosinophils and serum eosinophil cationic protein (ECP) were assessed in subsets (n = 683 and 485). PD15 was assessed if FEV1 fell > or =15%, and the DRS was calculated for all tests. Graphs were constructed to visualise relationships with current wheeze, blood eosinophils and serum ECP. Odds ratios and Spearman's correlation coefficients were calculated to quantify these relationships. Children with features of asthma had lower PD15 and higher DRS, and separation was most pronounced for DRS. Prevalence of current wheeze increased continuously over the entire range of DRS values. Blood eosinophils were significantly higher only for the highest values of DRS. In conclusion, the continuous relationship between airway responsiveness and asthma symptoms is in favour of a noncensored measure of airway responsiveness, such as the dose-response slope. PMID:15640337

  18. Nicotine enhances murine airway contractile responses to kinin receptor agonists via activation of JNK- and PDE4-related intracellular pathways

    PubMed Central

    2010-01-01

    ), glucocorticoid (dexamethasone) or adenylcyclase activator (forskolin) suppressed the nicotine-enhanced airway contractile response to des-Arg9-bradykinin and bradykinin. Conclusions Nicotine induces airway hyperresponsiveness via transcriptional up-regulation of airway kinin B1 and B2 receptors, an effect mediated via neuronal nicotinic receptors. The underlying molecular mechanisms involve activation of JNK- and PDE4-mediated intracellular inflammatory signal pathways. Our results might be relevant to active and passive smokers suffering from airway hyperresponsiveness, and suggest new therapeutic targets for the treatment of smoke-associated airway disease. PMID:20113502

  19. Genome-Wide Association Study Identification of Novel Loci Associated with Airway Responsiveness in Chronic Obstructive Pulmonary Disease.

    PubMed

    Hansel, Nadia N; Paré, Peter D; Rafaels, Nicholas; Sin, Don D; Sandford, Andrew; Daley, Denise; Vergara, Candelaria; Huang, Lili; Elliott, W Mark; Pascoe, Chris D; Arsenault, Bryna A; Postma, Dirkje S; Boezen, H Marike; Bossé, Yohan; van den Berge, Maarten; Hiemstra, Pieter S; Cho, Michael H; Litonjua, Augusto A; Sparrow, David; Ober, Carole; Wise, Robert A; Connett, John; Neptune, Enid R; Beaty, Terri H; Ruczinski, Ingo; Mathias, Rasika A; Barnes, Kathleen C

    2015-08-01

    Increased airway responsiveness is linked to lung function decline and mortality in subjects with chronic obstructive pulmonary disease (COPD); however, the genetic contribution to airway responsiveness remains largely unknown. A genome-wide association study (GWAS) was performed using the Illumina (San Diego, CA) Human660W-Quad BeadChip on European Americans with COPD from the Lung Health Study. Linear regression models with correlated meta-analyses, including data from baseline (n = 2,814) and Year 5 (n = 2,657), were used to test for common genetic variants associated with airway responsiveness. Genotypic imputation was performed using reference 1000 Genomes Project data. Expression quantitative trait loci (eQTL) analyses in lung tissues were assessed for the top 10 markers identified, and immunohistochemistry assays assessed protein staining for SGCD and MYH15. Four genes were identified within the top 10 associations with airway responsiveness. Markers on chromosome 9p21.2 flanked by LINGO2 met a predetermined threshold of genome-wide significance (P < 9.57 × 10(-8)). Markers on chromosomes 3q13.1 (flanked by MYH15), 5q33 (SGCD), and 6q21 (PDSS2) yielded suggestive evidence of association (9.57 × 10(-8) < P ≤ 4.6 × 10(-6)). Gene expression studies in lung tissue showed single nucleotide polymorphisms on chromosomes 5 and 3 to act as eQTL for SGCD (P = 2.57 × 10(-9)) and MYH15 (P = 1.62 × 10(-6)), respectively. Immunohistochemistry confirmed localization of SGCD protein to airway smooth muscle and vessels and MYH15 to airway epithelium, vascular endothelium, and inflammatory cells. We identified novel loci associated with airway responsiveness in a GWAS among smokers with COPD. Risk alleles on chromosomes 5 and 3 acted as eQTLs for SGCD and MYH15 messenger RNA, and these proteins were expressed in lung cells relevant to the development of airway responsiveness. PMID:25514360

  20. 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. ...

  1. CRISPR-Cas9 mediated gene knockout in primary human airway epithelial cells reveals a pro-inflammatory role for MUC18

    PubMed Central

    Chu, Hong Wei; Rios, Cydney; Huang, Chunjian; Wesolowska-Andersen, Agata; Burchard, Esteban G.; O'Connor, Brian P.; Fingerlin, Tasha E.; Nichols, David; Reynolds, Susan D.; Seibold, Max A.

    2015-01-01

    Targeted knockout of genes in primary human cells using CRISPR-Cas9 mediated genome-editing represents a powerful approach to study gene function and to discern molecular mechanisms underlying complex human diseases. We used lentiviral delivery of CRISPR-Cas9 machinery and conditional reprogramming culture methods to knockout the MUC18 gene in human primary nasal airway epithelial cells (AECs). Massively parallel sequencing technology was used to confirm that the genome of essentially all cells in the edited AEC populations contained coding region insertions and deletions (indels). Correspondingly, we found mRNA expression of MUC18 was greatly reduced and protein expression was absent. Characterization of MUC18 knockout cell populations stimulated with TLR2, 3 and 4 agonists revealed that IL-8 (a pro-inflammatory chemokine) responses of AECs were greatly reduced in the absence of functional MUC18 protein. Our results show the feasibility of CRISPR-Cas9 mediated gene knockouts in AEC culture (both submerged and polarized), and suggest a pro-inflammatory role for MUC18 in airway epithelial response to bacterial and viral stimuli. PMID:26043872

  2. Divergent effects of urban particulate air pollution on allergic airway responses in experimental asthma: a comparison of field exposure studies

    PubMed Central

    2012-01-01

    Background Increases in ambient particulate matter of aerodynamic diameter of 2.5 μm (PM2.5) are associated with asthma morbidity and mortality. The overall objective of this study was to test the hypothesis that PM2.5 derived from two distinct urban U.S. communities would induce variable responses to aggravate airway symptoms during experimental asthma. Methods We used a mobile laboratory to conduct community-based inhalation exposures to laboratory rats with ovalbumin-induced allergic airways disease. In Grand Rapids exposures were conducted within 60 m of a major roadway, whereas the Detroit was located in an industrial area more than 400 m from roadways. Immediately after nasal allergen challenge, Brown Norway rats were exposed by whole body inhalation to either concentrated air particles (CAPs) or filtered air for 8 h (7:00 AM - 3:00 PM). Both ambient and concentrated PM2.5 was assessed for mass, size fractionation, and major component analyses, and trace element content. Sixteen hours after exposures, bronchoalveolar lavage fluid (BALF) and lung lobes were collected and evaluated for airway inflammatory and mucus responses. Results Similar CAPs mass concentrations were generated in Detroit (542 μg/m3) and Grand Rapids (519 μg/m3). Exposure to CAPs at either site had no effects in lungs of non-allergic rats. In contrast, asthmatic rats had 200% increases in airway mucus and had more BALF neutrophils (250% increase), eosinophils (90%), and total protein (300%) compared to controls. Exposure to Detroit CAPs enhanced all allergic inflammatory endpoints by 30-100%, whereas inhalation of Grand Rapids CAPs suppressed all allergic responses by 50%. Detroit CAPs were characterized by high sulfate, smaller sized particles and were derived from local combustion sources. Conversely Grand Rapids CAPs were derived primarily from motor vehicle sources. Conclusions Despite inhalation exposure to the same mass concentration of urban PM2.5, disparate health

  3. The immunomodulatory actions of prostaglandin E2 on allergic airway responses in the rat.

    PubMed

    Martin, James G; Suzuki, Masaru; Maghni, Karim; Pantano, Rosa; Ramos-Barbón, David; Ihaku, Daizo; Nantel, François; Denis, Danielle; Hamid, Qutayba; Powell, William S

    2002-10-01

    PGE(2) has been reported to inhibit allergen-induced airway responses in sensitized human subjects. The aim of this study was to investigate the mechanism of anti-inflammatory actions of PGE(2) in an animal model of allergic asthma. BN rats were sensitized to OVA using Bordetella pertussis as an adjuvant. One week later, an aerosol of OVA was administered. After a further week, animals were anesthetized with urethan, intubated, and subjected to measurements of pulmonary resistance (R(L)) for a period of 8 h after OVA challenge. PGE(2) (1 and 3 micro g in 100 micro l of saline) was administered by insufflation intratracheally 30 min before OVA challenge. The early response was inhibited by PGE(2) (3 micro g). The late response was inhibited by both PGE(2) (1 and 3 micro g). Bronchoalveolar lavage fluid from OVA-challenged rats showed eosinophilia and an increase in the number of cells expressing IL-4 and IL-5 mRNA. These responses were inhibited by PGE(2). Bronchoalveolar lavage fluid levels of cysteinyl-leukotrienes were elevated after OVA challenge and were reduced after PGE(2) to levels comparable with those of sham challenged animals. We conclude that PGE(2) is a potent anti-inflammatory agent that may act by reducing allergen-induced Th2 cell activation and cysteinyl-leukotriene synthesis in the rat. PMID:12244197

  4. Mucosal Inflammatory Response to Salmonella typhimurium Infection

    PubMed Central

    Patel, Samir; McCormick, Beth A.

    2014-01-01

    The human intestinal epithelium consists of a single layer of epithelial cells that forms a barrier against food antigens and the resident microbiota within the lumen. This delicately balanced organ functions in a highly sophisticated manner to uphold the fidelity of the intestinal epithelium and to eliminate pathogenic microorganisms. On the luminal side, this barrier is fortified by a thick mucus layer, and on the serosal side exists the lamina propria containing a resident population of immune cells. Pathogens that are able to breach this barrier disrupt the healthy epithelial lining by interfering with the regulatory mechanisms that govern the normal balance of intestinal architecture and function. This disruption results in a coordinated innate immune response deployed to eliminate the intruder that includes the release of antimicrobial peptides, activation of pattern-recognition receptors, and recruitment of a variety of immune cells. In the case of Salmonella enterica serovar typhimurium (S. typhimurium) infection, induction of an inflammatory response has been linked to its virulence mechanism, the type III secretion system (T3SS). The T3SS secretes protein effectors that exploit the host’s cell biology to facilitate bacterial entry and intracellular survival, and to modulate the host immune response. As the role of the intestinal epithelium in initiating an immune response has been increasingly realized, this review will highlight recent research that details progress made in understanding mechanisms underlying the mucosal inflammatory response to Salmonella infection, and how such inflammatory responses impact pathogenic fitness of this organism. PMID:25071772

  5. Carbon Nanofibers Have IgE Adjuvant Capacity but Are Less Potent Than Nanotubes in Promoting Allergic Airway Responses

    PubMed Central

    Samuelsen, Mari; Marioara, Calin Daniel; Løvik, Martinus

    2013-01-01

    There is a growing concern for the possible health impact of nanoparticles. The main objective of this study was to investigate the allergy-promoting capacity of four different carbon nanofiber (CNF) samples in an injection and an airway mouse model of allergy. Secondly, the potency of the CNF was compared to the previously reported allergy-promoting capacity of carbon nanotubes (CNT) in the airway model. Ultrafine carbon black particles (ufCBP) were used as a positive control. Particles were given together with the allergen ovalbumin (OVA) either by subcutaneous injection into the footpad or intranasally to BALB/cA mice. After allergen booster, OVA-specific IgE, IgG1, and IgG2a in serum were measured. In the airway model, inflammation was determined as influx of inflammatory cells (eosinophils, neutrophils, lymphocytes, and macrophages) and by mediators (MCP-1 and TNF-α present in bronchoalveolar fluid (BALF)). CNF and CNT both increased OVA-specific IgE levels in the two models, but in the airway model, the CNT gave a significantly stronger IgE response than the CNF. Furthermore, the CNT and not the CNF promoted eosinophil lung inflammation. Our data therefore suggest that nanotube-associated properties are particularly potent in promoting allergic responses. PMID:24024193

  6. Natural Products: Insights into Leishmaniasis Inflammatory Response

    PubMed Central

    Rodrigues, Igor A.; Mazotto, Ana Maria; Cardoso, Verônica; Alves, Renan L.; Amaral, Ana Claudia F.; Silva, Jefferson Rocha de Andrade; Pinheiro, Anderson S.; Vermelho, Alane B.

    2015-01-01

    Leishmaniasis is a vector-borne disease that affects several populations worldwide, against which there are no vaccines available and the chemotherapy is highly toxic. Depending on the species causing the infection, the disease is characterized by commitment of tissues, including the skin, mucous membranes, and internal organs. Despite the relevance of host inflammatory mediators on parasite burden control, Leishmania and host immune cells interaction may generate an exacerbated proinflammatory response that plays an important role in the development of leishmaniasis clinical manifestations. Plant-derived natural products have been recognized as bioactive agents with several properties, including anti-protozoal and anti-inflammatory activities. The present review focuses on the antileishmanial activity of plant-derived natural products that are able to modulate the inflammatory response in vitro and in vivo. The capability of crude extracts and some isolated substances in promoting an anti-inflammatory response during Leishmania infection may be used as part of an effective strategy to fight the disease. PMID:26538837

  7. Regulation of inflammatory responses by IL-17F

    PubMed Central

    Yang, Xuexian O.; Chang, Seon Hee; Park, Heon; Nurieva, Roza; Shah, Bhavin; Acero, Luis; Wang, Yi-Hong; Schluns, Kimberly S.; Broaddus, Russell R.; Zhu, Zhou; Dong, Chen

    2008-01-01

    Although interleukin (IL) 17 has been extensively characterized, the function of IL-17F, which has an expression pattern regulated similarly to IL-17, is poorly understood. We show that like IL-17, IL-17F regulates proinflammatory gene expression in vitro, and this requires IL-17 receptor A, tumor necrosis factor receptor–associated factor 6, and Act1. In vivo, overexpression of IL-17F in lung epithelium led to infiltration of lymphocytes and macrophages and mucus hyperplasia, similar to observations made in IL-17 transgenic mice. To further understand the function of IL-17F, we generated and analyzed mice deficient in IL-17F or IL-17. IL-17, but not IL-17F, was required for the initiation of experimental autoimmune encephalomyelitis. Mice deficient in IL-17F, but not IL-17, had defective airway neutrophilia in response to allergen challenge. Moreover, in an asthma model, although IL-17 deficiency reduced T helper type 2 responses, IL-17F–deficient mice displayed enhanced type 2 cytokine production and eosinophil function. In addition, IL-17F deficiency resulted in reduced colitis caused by dextran sulfate sodium, whereas IL-17 knockout mice developed more severe disease. Our results thus demonstrate that IL-17F is an important regulator of inflammatory responses that seems to function differently than IL-17 in immune responses and diseases. PMID:18411338

  8. Regulation of inflammatory responses by IL-17F.

    PubMed

    Yang, Xuexian O; Chang, Seon Hee; Park, Heon; Nurieva, Roza; Shah, Bhavin; Acero, Luis; Wang, Yi-Hong; Schluns, Kimberly S; Broaddus, Russell R; Zhu, Zhou; Dong, Chen

    2008-05-12

    Although interleukin (IL) 17 has been extensively characterized, the function of IL-17F, which has an expression pattern regulated similarly to IL-17, is poorly understood. We show that like IL-17, IL-17F regulates proinflammatory gene expression in vitro, and this requires IL-17 receptor A, tumor necrosis factor receptor-associated factor 6, and Act1. In vivo, overexpression of IL-17F in lung epithelium led to infiltration of lymphocytes and macrophages and mucus hyperplasia, similar to observations made in IL-17 transgenic mice. To further understand the function of IL-17F, we generated and analyzed mice deficient in IL-17F or IL-17. IL-17, but not IL-17F, was required for the initiation of experimental autoimmune encephalomyelitis. Mice deficient in IL-17F, but not IL-17, had defective airway neutrophilia in response to allergen challenge. Moreover, in an asthma model, although IL-17 deficiency reduced T helper type 2 responses, IL-17F-deficient mice displayed enhanced type 2 cytokine production and eosinophil function. In addition, IL-17F deficiency resulted in reduced colitis caused by dextran sulfate sodium, whereas IL-17 knockout mice developed more severe disease. Our results thus demonstrate that IL-17F is an important regulator of inflammatory responses that seems to function differently than IL-17 in immune responses and diseases. PMID:18411338

  9. Mitochondrial Ca2+-dependent NLRP3 activation exacerbates the Pseudomonas aeruginosa-driven inflammatory response in cystic fibrosis.

    PubMed

    Rimessi, Alessandro; Bezzerri, Valentino; Patergnani, Simone; Marchi, Saverio; Cabrini, Giulio; Pinton, Paolo

    2015-01-01

    The common pathological manifestation of cystic fibrosis (CF) is associated with an excessive lung inflammatory response characterized by interleukin-1β accumulation. CF airway epithelial cells show an exacerbated pro-inflammatory response to Pseudomonas aeruginosa; however, it is unclear whether this heightened inflammatory response is intrinsic to cells lacking CF transmembrane conductance regulator (CFTR). Here we demonstrate that the degree and quality of the inflammatory response in CF are supported by P. aeruginosa-dependent mitochondrial perturbation, in which flagellin is the inducer and mitochondrial Ca(2+) uniporter (MCU) is a signal-integrating organelle member for NLRP3 activation and IL-1β and IL-18 processing. Our work elucidates the regulation of the NLRP3 inflammasome by mitochondrial Ca(2+) in the P. aeruginosa-dependent inflammatory response and deepens our understanding of the significance of mitochondria in the Ca(2+)-dependent control of inflammation. PMID:25648527

  10. Effect of heparin and a low-molecular weight heparinoid on PAF-induced airway responses in neonatally immunized rabbits.

    PubMed Central

    Sasaki, M.; Herd, C. M.; Page, C. P.

    1993-01-01

    1. We have investigated the effect of an unfractionated heparin preparation, a low-molecular weight heparinoid (Org 10172) and the polyanionic molecule polyglutamic acid against PAF-induced airway hyperresponsiveness and pulmonary cell infiltration in neonatally immunized rabbits in vivo. 2. Exposure of neonatally immunized rabbits to aerosolized platelet activating factor (PAF) (80 micrograms ml-1 for 60 min) elicited an increase in airway responsiveness to inhaled histamine 24 h and 72 h following challenge which was associated with an infiltration of inflammatory cells into the airways, as assessed by bronchoalveolar lavage (BAL). 3. A significant increase in the total numbers of cells recovered from BAL fluid was associated with significantly increased cell numbers of neutrophils, eosinophils and mononuclear cells 24 h following PAF exposure. The numbers of eosinophils and neutrophils in the airways remained elevated 72 h after challenge. 4. The intravenous administration of an unfractionated preparation of heparin (100 units kg-1) or Org 10172 (100 micrograms kg-1) 30 min prior to PAF exposure significantly inhibited the airway hyperresponsiveness induced by PAF, 24 h and 72 h following challenge. PAF-induced hyperresponsiveness was not significantly affected by prior intravenous administration of polyglutamic acid (100 micrograms kg-1). 5. The intravenous administration of unfractionated heparin (100 units kg-1), Org 10172 (100 micrograms kg-1) or polyglutamic acid (100 micrograms kg-1) 30 min prior to PAF exposure significantly inhibited the expected increase in total cell infiltration. 6. This study shows that unfractionated heparin and a low-molecular weight heparinoid, Org 10172, are capable of inhibiting both the airway hyperresponsiveness and pulmonary cell infiltration induced by PAF in the rabbit. PMID:7693273

  11. Effect of an inhaled neutral endopeptidase inhibitor, phosphoramidon, on baseline airway calibre and bronchial responsiveness to bradykinin in asthma.

    PubMed Central

    Crimi, N.; Polosa, R.; Pulvirenti, G.; Magrì, S.; Santonocito, G.; Prosperini, G.; Mastruzzo, C.; Mistretta, A.

    1995-01-01

    BACKGROUND--Bradykinin is a potent vasoactive peptide which has been proposed as an important inflammatory mediator in asthma since it provokes potent bronchoconstriction in asthmatic subjects. Little is known at present about the potential role of lung peptidases in modulating bradykinin-induced airway dysfunction in vivo in man. The change in bronchial reactivity to bradykinin was therefore investigated after treatment with inhaled phosphoramidon, a potent neutral endopeptidase (NEP) inhibitor, in a double blind, placebo controlled, randomised study of 10 asthmatic subjects. METHODS--Subjects attended on six separate occasions at the same time of day during which concentration-response studies with inhaled bradykinin and histamine were carried out, without treatment and after each test drug. Subjects received nebulised phosphoramidon sodium salt (10(-5) M, 3 ml) or matched placebo for 5-7 minutes using an Inspiron Mini-neb nebuliser 5 minutes before the bronchoprovocation test with bradykinin or histamine. Agonists were administered in increasing concentrations as an aerosol generated from a starting volume of 3 ml in a nebuliser driven by compressed air at 8 1/min. Changes in airway calibre were measured as forced expiratory volume in one second (FEV1) and responsiveness as the provocative concentration causing a 20% fall in FEV1 (PC20). RESULTS--Phosphoramidon administration caused a transient fall in FEV1 from baseline, FEV1 values decreasing 6.3% and 5.3% on the bradykinin and histamine study days, respectively. When compared with placebo, phosphoramidon elicited a small enhancement of the airways response to bradykinin, the geometric mean PC20 value (range) decreasing from 0.281 (0.015-5.575) to 0.136 (0.006-2.061) mg/ml. In contrast, NEP blockade failed to alter the airways response to a subsequent inhalation with histamine, the geometric mean (range) PC20 histamine value of 1.65 (0.17-10.52) mg/ml after placebo being no different from that of 1.58 (0

  12. A GM-CSF/IL-33 pathway facilitates allergic airway responses to sub-threshold house dust mite exposure.

    PubMed

    Llop-Guevara, Alba; Chu, Derek K; Walker, Tina D; Goncharova, Susanna; Fattouh, Ramzi; Silver, Jonathan S; Moore, Cheryl Lynn; Xie, Juliana L; O'Byrne, Paul M; Coyle, Anthony J; Kolbeck, Roland; Humbles, Alison A; Stämpfli, Martin R; Jordana, Manel

    2014-01-01

    Allergic asthma is a chronic immune-inflammatory disease of the airways. Despite aeroallergen exposure being universal, allergic asthma affects only a fraction of individuals. This is likely related, at least in part, to the extent of allergen exposure. Regarding house dust mite (HDM), we previously identified the threshold required to elicit allergic responses in BALB/c mice. Here, we investigated the impact of an initial immune perturbation on the response to sub-threshold HDM exposure. We show that transient GM-CSF expression in the lung facilitated robust eosinophilic inflammation, long-lasting antigen-specific Th2 responses, mucus production and airway hyperresponsiveness. This was associated with increased IL-33 levels and activated CD11b(+) DCs expressing OX40L. GM-CSF-driven allergic responses were significantly blunted in IL-33-deficient mice. IL-33 was localized on alveolar type II cells and in vitro stimulation of human epithelial cells with GM-CSF enhanced intracellular IL-33 independently of IL-1α. Likewise, GM-CSF administration in vivo resulted in increased levels of IL-33 but not IL-1α. These findings suggest that exposures to environmental agents associated with GM-CSF production, including airway infections and pollutants, may decrease the threshold of allergen responsiveness and, hence, increase the susceptibility to develop allergic asthma through a GM-CSF/IL-33/OX40L pathway. PMID:24551140

  13. A GM-CSF/IL-33 Pathway Facilitates Allergic Airway Responses to Sub-Threshold House Dust Mite Exposure

    PubMed Central

    Llop-Guevara, Alba; Chu, Derek K.; Walker, Tina D.; Goncharova, Susanna; Fattouh, Ramzi; Silver, Jonathan S.; Moore, Cheryl Lynn; Xie, Juliana L.; O’Byrne, Paul M.; Coyle, Anthony J.; Kolbeck, Roland; Humbles, Alison A.; Stämpfli, Martin R.; Jordana, Manel

    2014-01-01

    Allergic asthma is a chronic immune-inflammatory disease of the airways. Despite aeroallergen exposure being universal, allergic asthma affects only a fraction of individuals. This is likely related, at least in part, to the extent of allergen exposure. Regarding house dust mite (HDM), we previously identified the threshold required to elicit allergic responses in BALB/c mice. Here, we investigated the impact of an initial immune perturbation on the response to sub-threshold HDM exposure. We show that transient GM-CSF expression in the lung facilitated robust eosinophilic inflammation, long-lasting antigen-specific Th2 responses, mucus production and airway hyperresponsiveness. This was associated with increased IL-33 levels and activated CD11b+ DCs expressing OX40L. GM-CSF-driven allergic responses were significantly blunted in IL-33-deficient mice. IL-33 was localized on alveolar type II cells and in vitro stimulation of human epithelial cells with GM-CSF enhanced intracellular IL-33 independently of IL-1α. Likewise, GM-CSF administration in vivo resulted in increased levels of IL-33 but not IL-1α. These findings suggest that exposures to environmental agents associated with GM-CSF production, including airway infections and pollutants, may decrease the threshold of allergen responsiveness and, hence, increase the susceptibility to develop allergic asthma through a GM-CSF/IL-33/OX40L pathway. PMID:24551140

  14. [Comparison of respiratory control responses in bronchial and external airway stenosis].

    PubMed

    Marek, W; Rasche, K; Mailänder, A; Hoffarth, H P; Ulmer, W T

    1989-11-01

    Respiratory responses during allergen-induced airway obstruction and external airway stenosis were investigated in anaesthetised sheep. The results were compared to those obtained from healthy subjects during external airway stenosis. Allergen-induced increase in airway resistance results in an increased respiratory frequency, mainly due to a shortening of expiration (TE) and only partially due to a shortening of inspiration (TI). Tidal volume is diminished while respiratory changes in oesophageal pressure (delta Poes) are increased. Both results in an increase of dynamic elastance (Edyn) representing airway resistance. Based on the increase in the slope and amplitude of inspiratory pressure (delta Poes/TI), the mean inspiratory airflow (VT/TI) remains almost unchanged. In spite of an increased ventilation PaO2 decreases, whereas PaCO2 increases only slightly. External airway stenosis, however, results in a decrease of respiratory frequency, mainly depending on a prolongation of inspiration. Changes in Poes and VT are similar to those of allergen-induced airway obstruction. delta Poes/TI, however, increases less than during allergen application and results in a decrease of mean inspiratory airflow, tidal volume and ventilation. Respiratory responses of healthy subjects during external airway stenosis were similar to those described in experimental animals. The results of our investigation show a different pattern in the control of breathing during bronchial and external stenosis-induced airway obstruction and thus indicate different vagal reflex mechanisms. PMID:2608647

  15. Relationship between sputum inflammatory markers and osmotic airway hyperresponsiveness during induction of sputum in asthmatic patients.

    PubMed Central

    Jang, A. S.; Choi, I. S.

    2001-01-01

    Hypertonic saline aerosols are being used increasingly for bronchial provocation testing and induction of sputum. The aims of this study were to assess the response to challenge with 3% hypertonic saline administered via a ultrasonic nebulizer in patients with asthma, and to evaluate relationship between % fall of FEV1 during induction of sputum (osmotic airway hyperresponsiveness; osmotic AHR) and biochemical markers of induced sputum. We investigated changes in FEV1 in response to inhaling ultrasonically nebulized 3% saline in 25 patients with asthma and 10 control subjects. FEV1 was measured before, during, and after induction of sputum. We used fluoroimmunoassay to detect eosinophil cationic protein (ECP), immunohistochemical staining to detect EG2+ (secretory form of ECP) eosinophils, and a sandwich ELISA to detect interleukin (IL)-5. Protein concentration was determined by using bicinchoninic acid protein assay reagent. Asthmatics, compared with controls, had significantly higher osmotic AHR. Moderate to severe asthmatics had significantly higher osmotic AHR compared to mild asthmatics. Osmotic AHR was significantly correlated with the proportion of eosinophils, the levels of ECP, EG2+ eosinophils, IL-5, and proteins. These data suggest that osmotic AHR is closely related to the clinical status and biochemical markers of sputum supernatant in asthmatic patients. PMID:11511785

  16. LPS exacerbates functional and inflammatory responses to ovalbumin and decreases sensitivity to inhaled fluticasone propionate in a guinea pig model of asthma

    PubMed Central

    Lowe, A P P; Thomas, R S; Nials, A T; Kidd, E J; Broadley, K J; Ford, W R

    2015-01-01

    Background and Purpose Asthma exacerbations contribute to corticosteroid insensitivity. LPS is ubiquitous in the environment. It causes bronchoconstriction and airway inflammation and may therefore exacerbate allergen responses. This study examined whether LPS and ovalbumin co-administration could exacerbate the airway inflammatory and functional responses to ovalbumin in conscious guinea pigs and whether these exacerbated responses were insensitive to inhaled corticosteroid treatment with fluticasone propionate (FP). Experimental Approach Guinea pigs were sensitized and challenged with ovalbumin and airway function recorded as specific airway conductance by whole body plethysmography. Airway inflammation was measured from lung histology and bronchoalveolar lavage. Airway hyper-reactivity (AHR) to inhaled histamine was examined 24 h after ovalbumin. LPS was inhaled alone or 24 or 48 h before ovalbumin and combined with ovalbumin. FP (0.05–1 mg·mL−1) or vehicle was nebulized for 15 min twice daily for 6 days before ovalbumin or LPS exposure. Key Results Ovalbumin inhalation caused early (EAR) and late asthmatic response (LAR), airway hyper-reactivity to histamine and influx of inflammatory cells into the lungs. LPS 48 h before and co-administered with ovalbumin exacerbated the response with increased length of the EAR, prolonged response to histamine and elevated inflammatory cells. FP 0.5 and 1 mg·mL−1 reduced the LAR, AHR and cell influx with ovalbumin alone, but was ineffective when guinea pigs were exposed to LPS before and with ovalbumin. Conclusions and Implications LPS exposure exacerbates airway inflammatory and functional responses to allergen inhalation and decreases corticosteroid sensitivity. Its widespread presence in the environment could contribute to asthma exacerbations and corticosteroid insensitivity in humans. PMID:25586266

  17. MicroRNA Mediated Chemokine Responses in Human Airway Smooth Muscle Cells

    PubMed Central

    Dileepan, Mythili; Sarver, Anne E.; Rao, Savita P.; Panettieri, Reynold A.; Subramanian, Subbaya; Kannan, Mathur S.

    2016-01-01

    Airway smooth muscle (ASM) cells play a critical role in the pathophysiology of asthma due to their hypercontractility and their ability to proliferate and secrete inflammatory mediators. microRNAs (miRNAs) are gene regulators that control many signaling pathways and thus serve as potential therapeutic alternatives for many diseases. We have previously shown that miR-708 and miR-140-3p regulate the MAPK and PI3K signaling pathways in human ASM (HASM) cells following TNF-α exposure. In this study, we investigated the regulatory effect of these miRNAs on other asthma-related genes. Microarray analysis using the Illumina platform was performed with total RNA extracted from miR-708 (or control miR)-transfected HASM cells. Inhibition of candidate inflammation-associated gene expression was further validated by qPCR and ELISA. The most significant biologic functions for the differentially expressed gene set included decreased inflammatory response, cytokine expression and signaling. qPCR revealed inhibition of expression of CCL11, CXCL10, CCL2 and CXCL8, while the release of CCL11 was inhibited in miR-708-transfected cells. Transfection of cells with miR-140-3p resulted in inhibition of expression of CCL11, CXCL12, CXCL10, CCL5 and CXCL8 and of TNF-α-induced CXCL12 release. In addition, expression of RARRES2, CD44 and ADAM33, genes known to contribute to the pathophysiology of asthma, were found to be inhibited in miR-708-transfected cells. These results demonstrate that miR-708 and miR-140-3p exert distinct effects on inflammation-associated gene expression and biological function of ASM cells. Targeting these miRNA networks may provide a novel therapeutic mechanism to down-regulate airway inflammation and ASM proliferation in asthma. PMID:26998837

  18. MicroRNA Mediated Chemokine Responses in Human Airway Smooth Muscle Cells.

    PubMed

    Dileepan, Mythili; Sarver, Anne E; Rao, Savita P; Panettieri, Reynold A; Subramanian, Subbaya; Kannan, Mathur S

    2016-01-01

    Airway smooth muscle (ASM) cells play a critical role in the pathophysiology of asthma due to their hypercontractility and their ability to proliferate and secrete inflammatory mediators. microRNAs (miRNAs) are gene regulators that control many signaling pathways and thus serve as potential therapeutic alternatives for many diseases. We have previously shown that miR-708 and miR-140-3p regulate the MAPK and PI3K signaling pathways in human ASM (HASM) cells following TNF-α exposure. In this study, we investigated the regulatory effect of these miRNAs on other asthma-related genes. Microarray analysis using the Illumina platform was performed with total RNA extracted from miR-708 (or control miR)-transfected HASM cells. Inhibition of candidate inflammation-associated gene expression was further validated by qPCR and ELISA. The most significant biologic functions for the differentially expressed gene set included decreased inflammatory response, cytokine expression and signaling. qPCR revealed inhibition of expression of CCL11, CXCL10, CCL2 and CXCL8, while the release of CCL11 was inhibited in miR-708-transfected cells. Transfection of cells with miR-140-3p resulted in inhibition of expression of CCL11, CXCL12, CXCL10, CCL5 and CXCL8 and of TNF-α-induced CXCL12 release. In addition, expression of RARRES2, CD44 and ADAM33, genes known to contribute to the pathophysiology of asthma, were found to be inhibited in miR-708-transfected cells. These results demonstrate that miR-708 and miR-140-3p exert distinct effects on inflammation-associated gene expression and biological function of ASM cells. Targeting these miRNA networks may provide a novel therapeutic mechanism to down-regulate airway inflammation and ASM proliferation in asthma. PMID:26998837

  19. Effect of subchronic in vivo exposure to nitrogen dioxide on lung tissue inflammation, airway microvascular leakage, and in vitro bronchial muscle responsiveness in rats.

    PubMed Central

    Chitano, P; Rado, V; Di Stefano, A; Papi, A; Boniotti, A; Zancuoghi, G; Boschetto, P; Romano, M; Salmona, M; Ciaccia, A; Fabbri, L M; Mapp, C E

    1996-01-01

    OBJECTIVES: In a previous study on bronchoalveolar lavage fluid from rats exposed in vivo for seven days to 10 ppm nitrogen dioxide (NO2), it has been shown that there is an influx of macrophages into the airways. The present study investigated the effect of seven day exposure to 10 ppm NO2, on: (a) lung tissue inflammation and morphology; (b) airway microvascular leakage; (c) in vitro contractile response of main bronchi. METHODS: Lung tissue was studied by light microscopy, after fixing the lungs by inflation with 4% formalin at a pressure of 20 cm H2O. Microvascular leakage was measured by extravasation of Evans blue dye in the larynx, trachea, main bronchi, and intrapulmonary airways. Smooth muscle responsiveness was evaluated by concentration-responses curves to acetylcholine (10(-9)-10(-3) M), serotonin (10(-9)-10(-4) M), and voltage-response curves (12-28 V) to electrical field stimulation. RESULTS: Histology showed an increased total inflammation at the level of respiratory bronchioles and alveoli. No influx of inflammatory cells was found in the main bronchi. A loss of cilia in the epithelium of small airways and ectasia of alveolar capillaries was also found. By contrast, no alterations to microvascular permeability or modification of bronchial smooth muscle responsiveness was found. CONCLUSIONS: Subchronic exposure to 10 ppm NO2 causes airway inflammation and structural damage, but does not cause any persistent alteration to microvascular permeability or bronchial smooth muscle responsiveness in rats. Images Figure 1 PMID:8758032

  20. Analyzing inflammatory response as excitable media

    NASA Astrophysics Data System (ADS)

    Yde, Pernille; Høgh Jensen, Mogens; Trusina, Ala

    2011-11-01

    The regulatory system of the transcription factor NF-κB plays a great role in many cell functions, including inflammatory response. Interestingly, the NF-κB system is known to up-regulate production of its own triggering signal—namely, inflammatory cytokines such as TNF, IL-1, and IL-6. In this paper we investigate a previously presented model of the NF-κB, which includes both spatial effects and the positive feedback from cytokines. The model exhibits the properties of an excitable medium and has the ability to propagate waves of high cytokine concentration. These waves represent an optimal way of sending an inflammatory signal through the tissue as they create a chemotactic signal able to recruit neutrophils to the site of infection. The simple model displays three qualitatively different states; low stimuli leads to no or very little response. Intermediate stimuli leads to reoccurring waves of high cytokine concentration. Finally, high stimuli leads to a sustained high cytokine concentration, a scenario which is toxic for the tissue cells and corresponds to chronic inflammation. Due to the few variables of the simple model, we are able to perform a phase-space analysis leading to a detailed understanding of the functional form of the model and its limitations. The spatial effects of the model contribute to the robustness of the cytokine wave formation and propagation.

  1. Collective cell migration during inflammatory response

    NASA Astrophysics Data System (ADS)

    Wu, Di; Stroka, Kimberly; Aranda-Espinoza, Helim

    2012-02-01

    Wound scratch healing assays of endothelial cell monolayers is a simple model to study collective cell migration as a function of biological signals. A signal of particular interest is the immune response, which after initial wounding in vivo causes the release of various inflammatory factors such as tumor necrosis alpha (TNF-α). TNF-α is an innate inflammatory cytokine that can induce cell growth, cell necrosis, and change cell morphology. We studied the effects of TNF-α on collective cell migration using the wound healing assays and measured several migration metrics, such as rate of scratch closure, velocities of leading edge and bulk cells, closure index, and velocity correlation functions between migrating cells. We observed that TNF-α alters all migratory metrics as a function of the size of the scratch and TNF-α content. The changes observed in migration correlate with actin reorganization upon TNF-α exposure.

  2. CULTURE CONDITIONS AFFECT HUMAN AIRWAY EPITHELIAL CELL RESPONSE TO DIESEL PARTICLE EXPOSURE IN VITRO

    EPA Science Inventory

    Diesel exhaust particles (DEP) are a ubiquitous ambient air contaminant that may contribute to the health effects of particulate matter inhalation. In vitro studies have shown that DEP exposure induces pro-inflammatory proteins in human airway epithelial cells (HAEC) with varying...

  3. Curine inhibits eosinophil activation and airway hyper-responsiveness in a mouse model of allergic asthma.

    PubMed

    Ribeiro-Filho, Jaime; Calheiros, Andrea Surrage; Vieira-de-Abreu, Adriana; de Carvalho, Katharinne Ingrid Moraes; da Silva Mendes, Diego; Melo, Christianne Bandeira; Martins, Marco Aurélio; da Silva Dias, Celidarque; Piuvezam, Márcia Regina; Bozza, Patrícia T

    2013-11-15

    Allergic asthma is a chronic inflammatory airway disease with increasing prevalence around the world. Current asthma therapy includes drugs that usually cause significant side effects, justifying the search for new anti-asthmatic drugs. Curine is a bisbenzylisoquinoline alkaloid that modulates calcium influx in many cell types; however, its anti-allergic and putative toxic effects remain to be elucidated. Our aim was to investigate the effects of curine on eosinophil activation and airway hyper-responsiveness (AHR) and to characterize its potential toxic effects. We used a mouse model of allergic asthma induced by sensitization and challenge with ovalbumin (OVA) to evaluate the anti-allergic effects of oral treatment with curine. The oral administration of curine significantly inhibited eosinophilic inflammation, eosinophil lipid body formation and AHR in animals challenged with OVA compared with animals in the untreated group. The curine treatment also reduced eotaxin and IL-13 production triggered by OVA. Verapamil, a calcium channel antagonist, had similar anti-allergic properties, and curine pre-treatment inhibited the calcium-induced tracheal contractile response ex-vivo, suggesting that the mechanism by which curine exerts its effects is through the inhibition of a calcium-dependent response. A toxicological evaluation showed that orally administered curine did not significantly alter the biochemical, hematological, behavioral and physical parameters measured in the experimental animals compared with saline-treated animals. In conclusion, curine showed anti-allergic activity through mechanisms that involve inhibition of IL-13 and eotaxin and of Ca(++) influx, without inducing evident toxicity and as such, has the potential for the development of anti-asthmatic drugs. PMID:23994558

  4. Curine inhibits eosinophil activation and airway hyper-responsiveness in a mouse model of allergic asthma

    SciTech Connect

    Ribeiro-Filho, Jaime; Calheiros, Andrea Surrage; Vieira-de-Abreu, Adriana; Moraes de Carvalho, Katharinne Ingrid; Silva Mendes, Diego da; Melo, Christianne Bandeira; Martins, Marco Aurélio; Silva Dias, Celidarque da; Piuvezam, Márcia Regina; and others

    2013-11-15

    Allergic asthma is a chronic inflammatory airway disease with increasing prevalence around the world. Current asthma therapy includes drugs that usually cause significant side effects, justifying the search for new anti-asthmatic drugs. Curine is a bisbenzylisoquinoline alkaloid that modulates calcium influx in many cell types; however, its anti-allergic and putative toxic effects remain to be elucidated. Our aim was to investigate the effects of curine on eosinophil activation and airway hyper-responsiveness (AHR) and to characterize its potential toxic effects. We used a mouse model of allergic asthma induced by sensitization and challenge with ovalbumin (OVA) to evaluate the anti-allergic effects of oral treatment with curine. The oral administration of curine significantly inhibited eosinophilic inflammation, eosinophil lipid body formation and AHR in animals challenged with OVA compared with animals in the untreated group. The curine treatment also reduced eotaxin and IL-13 production triggered by OVA. Verapamil, a calcium channel antagonist, had similar anti-allergic properties, and curine pre-treatment inhibited the calcium-induced tracheal contractile response ex-vivo, suggesting that the mechanism by which curine exerts its effects is through the inhibition of a calcium-dependent response. A toxicological evaluation showed that orally administered curine did not significantly alter the biochemical, hematological, behavioral and physical parameters measured in the experimental animals compared with saline-treated animals. In conclusion, curine showed anti-allergic activity through mechanisms that involve inhibition of IL-13 and eotaxin and of Ca{sup ++} influx, without inducing evident toxicity and as such, has the potential for the development of anti-asthmatic drugs. - Highlights: • Curine is a bisbenzylisoquinoline alkaloid from Chondrodendron platyphyllum. • Curine inhibits eosinophil influx and activation and airway hyper-responsiveness. • Curine

  5. Responses of well-differentiated nasal epithelial cells exposed to particles: Role of the epithelium in airway inflammation

    SciTech Connect

    Auger, Floriane; Gendron, Marie-Claude; Chamot, Christophe; Marano, Francelyne; Dazy, Anne-Catherine . E-mail: dazy@paris7.jussieu.fr

    2006-09-15

    Numerous epidemiological studies support the contention that ambient air pollution particles can adversely affect human health. To explain the acute inflammatory process in airways exposed to particles, a number of in vitro studies have been performed on cells grown submerged on plastic and poorly differentiated, and on cell lines, the physiology of which is somewhat different from that of well-differentiated cells. In order to obtain results using a model system in which epithelial cells are similar to those of the human airway in vivo, apical membranes of well-differentiated human nasal epithelial (HNE) cells cultured in an air-liquid interface (ALI) were exposed for 24 h to diesel exhaust particles (DEP) and Paris urban air particles (PM{sub 2.5}). DEP and PM{sub 2.5} (10-80 {mu}g/cm{sup 2}) stimulated both IL-8 and amphiregulin (ligand of EGFR) secretion exclusively towards the basal compartment. In contrast, there was no IL-1{beta} secretion and only weak non-reproducible secretion of TNF-{alpha}. IL-6 and GM-CSF were consistently stimulated towards the apical compartment and only when cells were exposed to PM{sub 2.5}. ICAM-1 protein expression on cell surfaces remained low after particle exposure, although it increased after TNF-{alpha} treatment. Internalization of particles, which is believed to initiate oxidative stress and proinflammatory cytokine expression, was restricted to small nanoparticles ({<=} 40 nm). Production of reactive oxygen species (ROS) was detected, and DEP were more efficient than PM{sub 2.5}. Collectively, our results suggest that airway epithelial cells exposed to particles augment the local inflammatory response in the lung but cannot alone initiate a systemic inflammatory response.

  6. Astragalin inhibits airway eotaxin-1 induction and epithelial apoptosis through modulating oxidative stress-responsive MAPK signaling

    PubMed Central

    2014-01-01

    Background Eotaxin proteins are a potential therapeutic target in treating the peribronchial eosinophilia associated with allergic airway diseases. Since inflammation is often associated with an increased generation of reactive oxygen species (ROS), oxidative stress is a mechanistically imperative factor in asthma. Astragalin (kaempferol-3-O-glucoside) is a flavonoid with anti-inflammatory activity and newly found in persimmon leaves and green tea seeds. This study elucidated that astragalin inhibited endotoxin-induced oxidative stress leading to eosinophilia and epithelial apoptosis in airways. Methods Airway epithelial BEAS-2B cells were exposed to lipopolysaccharide (LPS) in the absence and presence of 1–20 μM astragalin. Western blot and immunocytochemical analyses were conducted to determine induction of target proteins. Cell and nuclear staining was also performed for ROS production and epithelial apoptosis. Results When airway epithelial cells were exposed to 2 μg/ml LPS, astragalin nontoxic at ≤20 μM suppressed cellular induction of Toll-like receptor 4 (TLR4) and ROS production enhanced by LPS. Both LPS and H2O2 induced epithelial eotaxin-1 expression, which was blocked by astragalin. LPS activated and induced PLCγ1, PKCβ2, and NADPH oxidase subunits of p22phox and p47phox in epithelial cells and such activation and induction were demoted by astragalin or TLR4 inhibition antagonizing eotaxin-1 induction. H2O2-upregulated phosphorylation of JNK and p38 MAPK was dampened by adding astragalin to epithelial cells, while this compound enhanced epithelial activation of Akt and ERK. H2O2 and LPS promoted epithelial apoptosis concomitant with nuclear condensation or caspase-3 activation, which was blunted by astragalin. Conclusions Astragalin ameliorated oxidative stress-associated epithelial eosinophilia and apoptosis through disturbing TLR4-PKCβ2-NADPH oxidase-responsive signaling. Therefore, astragalin may be a potent agent antagonizing endotoxin

  7. Regulator of G-protein signaling 2 repression exacerbates airway hyper-responsiveness and remodeling in asthma.

    PubMed

    Jiang, Haihong; Xie, Yan; Abel, Peter W; Wolff, Dennis W; Toews, Myron L; Panettieri, Reynold A; Casale, Thomas B; Tu, Yaping

    2015-07-01

    G protein-coupled receptors (GPCRs) are important regulators of cell functions in asthma. We recently reported that regulator of G-protein signaling (RGS) 2, a selective modulator of Gq-coupled GPCRs, is a key regulator of airway hyper-responsiveness (AHR), the pathophysiologic hallmark of asthma. Because RGS2 protein levels in airway cells were significantly lower in patients with asthma compared with patients without asthma, we further investigated the potential pathological importance of RGS2 repression in asthma. The human RGS2 gene maps to chromosome 1q31. We first screened patients with asthma for RGS2 gene promoter single-nucleotide polymorphisms (SNPs) and found significant differences in the distribution of two RGS2 SNPs (A638G, rs2746071 and C395G, rs2746072) between patients with asthma and nonasthmatic subjects. These two SNPs are always associated with each other and have the same higher prevalence in patients with asthma (65%) as compared with nonasthmatic subjects (35%). Point mutations corresponding to these SNPs decrease RGS2 promoter activity by 44%. The importance of RGS2 down-regulation was then determined in an acute IL-13 mouse model of asthma. Intranasal administration of IL-13 in mice also decreased RGS2 expression in lungs by ∼50% and caused AHR. Although naive RGS2 knockout (KO) mice exhibit spontaneous AHR, acute IL-13 exposure further increased AHR in RGS2 KO mice. Loss of RGS2 also significantly enhanced IL-13-induced mouse airway remodeling, including peribronchial smooth muscle thickening and fibrosis, without effects on goblet cell hyperplasia or airway inflammation in mice. Thus, genetic variations and increased inflammatory cytokines can lead to RGS2 repression, which exacerbates AHR and airway remodeling in asthma. PMID:25368964

  8. Airway response to ultra short-term exposure to ozone

    SciTech Connect

    Fouke, J.M.; Delemos, R.A.; McFadden, E.R. Jr.

    1988-02-01

    To determine whether acute short-term exposure to oxidant pollutants can cause changes in respiratory mechanics, we gave 0.5 ppm ozone for 5 min to 7 baboons. We measured pulmonary resistance (RL) and obtained dose response curves to methacholine before and after the exposures. This brief insult increased resistance (control RL = 1.53 +/- 0.21 cm H/sub 2/O.L-1 s; post-ozone RL = 3.53 +/- 0.54 cm H/sub 2/O.L-1 s). On a second occasion, 6 of these animals were restudied before and after the administration of cromolyn sodium. Although this drug had no effect on the measurements of mechanics made in the control period, it significantly reduced the ozone-induced changes in mechanics. The increase in RL was 52% of that produced in the first study. The results demonstrated that the ozone injury with its acute and subacute airway sequelae occurs quite rapidly and after very brief exposure. The time course of the change in mechanics and the effects of cromolyn suggest the hypothesis that surface epithelial cells are disrupted, causing subsequent release of bronchoconstricting agents.

  9. Pneumocystis Elicits a STAT6-Dependent, Strain-Specific Innate Immune Response and Airway Hyperresponsiveness

    PubMed Central

    Meissner, Nicole N.; Siemsen, Dan W.; McInnerney, Kate; Harmsen, Allen G.

    2012-01-01

    It is widely held that exposure to pathogens such as fungi can be an agent of comorbidity, such as exacerbation of asthma or chronic obstructive pulmonary disease. Although many studies have examined allergic responses to fungi and their effects on pulmonary function, the possible pathologic implications of the early innate responses to fungal pathogens have not been explored. We examined early responses to the atypical fungus Pneumocystis in two common strains of mice in terms of overall immunological response and related pathology, such as cell damage and airway hyperresponsiveness (AHR). We found a strong strain-specific response in BALB/c mice that included recruitment of neutrophils, NK, NKT, and CD4 T cells. This response was accompanied by elevated indicators of lung damage (bronchoalveolar lavage fluid albumin and LDH) and profound AHR. This early response was absent in C57BL/6 mice, although both strains exhibited a later response associated with the clearance of Pneumocystis. We found that this AHR could not be attributed exclusively to the presence of recruited neutrophils, NKT, NK, or CD4 cells or to the actions of IFN-γ or IL-4. However, in the absence of STAT6 signaling, AHR and inflammatory cell recruitment were virtually absent. Gene expression analysis indicated that this early response included activation of several transcription factors that could be involved in pulmonary remodeling. These results show that exposure to a fungus such as Pneumocystis can elicit pulmonary responses that may contribute to morbidity, even without prior sensitization, in the context of certain genetic backgrounds. PMID:21960549

  10. BLOCKADE OF TRKA OR P75 NEUROTROPHIN RECEPTORS ATTENUATES DIESEL PARTICULATE-INDUCED ENHANCEMENT OF ALLERGIC AIRWAYS RESPONSES IN BALB/C MICE

    EPA Science Inventory

    Neurotrophins, including nerve growth factor (NGF) partially mediate many features of allergic airways disease including airway resistance. Exposure to diesel exhaust particles (DEP) associated with the combustion of diesel fuel exacerbates allergic airways responses. We tested t...

  11. Inflammatory responses to infection: the Dutch contribution.

    PubMed

    Nolte, Martijn A; van der Meer, Jos W M

    2014-12-01

    At any given moment, our body is under attack by a large variety of pathogens, which aim to enter and use our body to propagate and disseminate. The extensive cellular and molecular complexity of our immune system enables us to efficiently eliminate invading pathogens or at least develop a condition in which propagation of the microorganism is reduced to a minimum. Yet, the evolutionary pressure on pathogens to circumvent our immune defense mechanisms is immense, which continuously leads to the development of novel pathogenic strains that challenge the health of mankind. Understanding this battle between pathogen and the immune system has been a fruitful area of immunological research over the last century and will continue to do so for many years. In this review, which has been written on the occasion of the 50th anniversary of the Dutch Society for Immunology, we provide an overview of the major contributions that Dutch immunologists and infection biologists have made in the last decades on the inflammatory response to viral, bacterial, fungal or parasitic infections. We focus on those studies that have addressed both the host and the pathogen, as these are most interesting from an immunological point of view. Although it is not possible to completely cover this comprehensive research field, this review does provide an interesting overview of Dutch research on inflammatory responses to infection. PMID:25455597

  12. Scorpion venom and the inflammatory response.

    PubMed

    Petricevich, Vera L

    2010-01-01

    Scorpion venoms consist of a complex of several toxins that exhibit a wide range of biological properties and actions, as well as chemical compositions, toxicity, and pharmacokinetic and pharmacodynamic characteristics. These venoms are associated with high morbility and mortality, especially among children. Victims of envenoming by a scorpion suffer a variety of pathologies, involving mainly both sympathetic and parasympathetic stimulation as well as central manifestations such as irritability, hyperthermia, vomiting, profuse salivation, tremor, and convulsion. The clinical signs and symptoms observed in humans and experimental animals are related with an excessive systemic host inflammatory response to stings and stings, respectively. Although the pathophysiology of envenomation is complex and not yet fully understood, venom and immune responses are known to trigger the release of inflammatory mediators that are largely mediated by cytokines. In models of severe systemic inflammation produced by injection of high doses of venom or venoms products, the increase in production of proinflammatory cytokines significantly contributes to immunological imbalance, multiple organ dysfunction and death. The cytokines initiate a cascade of events that lead to illness behaviors such as fever, anorexia, and also physiological events in the host such as activation of vasodilatation, hypotension, and increased of vessel permeability. PMID:20300540

  13. Scorpion Venom and the Inflammatory Response

    PubMed Central

    Petricevich, Vera L.

    2010-01-01

    Scorpion venoms consist of a complex of several toxins that exhibit a wide range of biological properties and actions, as well as chemical compositions, toxicity, and pharmacokinetic and pharmacodynamic characteristics. These venoms are associated with high morbility and mortality, especially among children. Victims of envenoming by a scorpion suffer a variety of pathologies, involving mainly both sympathetic and parasympathetic stimulation as well as central manifestations such as irritability, hyperthermia, vomiting, profuse salivation, tremor, and convulsion. The clinical signs and symptoms observed in humans and experimental animals are related with an excessive systemic host inflammatory response to stings and stings, respectively. Although the pathophysiology of envenomation is complex and not yet fully understood, venom and immune responses are known to trigger the release of inflammatory mediators that are largely mediated by cytokines. In models of severe systemic inflammation produced by injection of high doses of venom or venoms products, the increase in production of proinflammatory cytokines significantly contributes to immunological imbalance, multiple organ dysfunction and death. The cytokines initiate a cascade of events that lead to illness behaviors such as fever, anorexia, and also physiological events in the host such as activation of vasodilatation, hypotension, and increased of vessel permeability. PMID:20300540

  14. Dual PDE3/4 and PDE4 inhibitors: novel treatments for COPD and other inflammatory airway diseases.

    PubMed

    Abbott-Banner, Katharine H; Page, Clive P

    2014-05-01

    Selective phosphodiesterase (PDE) 4 and dual PDE3/4 inhibitors have attracted considerable interest as potential therapeutic agents for the treatment of respiratory diseases, largely by virtue of their anti-inflammatory (PDE4) and bifunctional bronchodilator/anti-inflammatory (PDE3/4) effects. Many of these agents have, however, failed in early development for various reasons, including dose-limiting side effects when administered orally and lack of sufficient activity when inhaled. Indeed, only one selective PDE4 inhibitor, the orally active roflumilast-n-oxide, has to date received marketing authorization. The majority of the compounds that have failed were, however, orally administered and non-selective for either PDE3 (A,B) or PDE4 (A,B,C,D) subtypes. Developing an inhaled dual PDE3/4 inhibitor that is rapidly cleared from the systemic circulation, potentially with subtype specificity, may represent one strategy to improve the therapeutic index and also exhibit enhanced efficacy versus inhibition of either PDE3 or PDE4 alone, given the potential positive interactions with regard to anti-inflammatory and bronchodilator effects that have been observed pre-clinically with dual inhibition of PDE3 and PDE4 compared with inhibition of either isozyme alone. This MiniReview will summarize recent clinical data obtained with PDE inhibitors and the potential for these drugs to treat COPD and other inflammatory airways diseases such as asthma and cystic fibrosis. PMID:24517491

  15. 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

  16. Increase in passive stiffness at reduced airway smooth muscle length: potential impact on airway responsiveness.

    PubMed

    Bossé, Ynuk; Solomon, Dennis; Chin, Leslie Y M; Lian, Kevin; Paré, Peter D; Seow, Chun Y

    2010-03-01

    The amplitude of strain in airway smooth muscle (ASM) produced by oscillatory perturbations such as tidal breathing or deep inspiration (DI) influences the force loss in the muscle and is therefore a key determinant of the bronchoprotective and bronchodilatory effects of these breathing maneuvers. The stiffness of unstimulated ASM (passive stiffness) directly influences the amplitude of strain. The nature of the passive stiffness is, however, not clear. In this study, we measured the passive stiffness of ovine ASM at different muscle lengths (relative to in situ length, which was used as a reference length, L(ref)) and states of adaptation to gain insights into the origin of this muscle property. The results showed that the passive stiffness was relatively independent of muscle length, possessing a constant plateau value over a length range from 0.62 to 1.25 L(ref). Following a halving of ASM length, passive stiffness decreased substantially (by 71%) but redeveloped over time ( approximately 30 min) at the shorter length to reach 65% of the stiffness value at L(ref), provided that the muscle was stimulated to contract at least once over a approximately 30-min period. The redevelopment and maintenance of passive stiffness were dependent on the presence of Ca(2+) but unaffected by latrunculin B, an inhibitor of actin filament polymerization. The maintenance of passive stiffness was also not affected by blocking myosin cross-bridge cycling using a myosin light chain kinase inhibitor or by blocking the Rho-Rho kinase (RhoK) pathway using a RhoK inhibitor. Our results suggest that the passive stiffness of ASM is labile and capable of redevelopment following length reduction. Redevelopment and maintenance of passive stiffness following muscle shortening could contribute to airway hyperresponsiveness by attenuating the airway wall strain induced by tidal breathing and DI. PMID:20008114

  17. Analysis of the Sputum and Inflammatory Alterations of the Airways in Patients with Common Variable Immunodeficiency and Bronchiectasis

    PubMed Central

    Pereira, Andrea Cristina; Kokron, Cristina M.; Romagnolo, Beatriz Mangueira Saraiva; Yagi, Claudia Simeire Albertini; Saldiva, Paulo Hilário Nascimento; Filho, Geraldo Lorenzi; Negri, Elnara Marcia

    2009-01-01

    INTRODUCTION: Common variable immunodeficiency is characterized by defective antibody production and recurrent pulmonary infections. Intravenous immunoglobulin is the treatment of choice, but the effects of Intravenous immunoglobulin on pulmonary defense mechanisms are poorly understood. OBJECTIVE: The aim of this study was to verify the impact of intravenous immunoglobulin on the physical properties of the sputum and on inflammatory alterations in the airways of patients with Common variable immunodeficiency associated with bronchiectasis. METHOD: The present study analyzed sputum physical properties, exhaled NO, inflammatory cells in the sputum, and IG titers in 7 patients with Common variable immunodeficiency and bronchiectasis with secretion, immediately before and 15 days after Intravenous immunoglobulin. A group of 6 patients with Common variable immunodeficiency and bronchiectasis but no sputum was also studied for comparison of the basal IgG level and blood count. The 13 patients were young (age=36±17 years) and comprised predominantly of females (n=11). RESULTS: Patients with secretion presented significantly decreased IgG and IgM levels. Intravenous immunoglobulin was associated with a significant decrease in exhaled NO (54.7 vs. 40.1 ppb, p<0.05), sputum inflammatory cell counts (28.7 vs. 14.6 cells/mm3, p<0.05), and a significant increase in respiratory mucus transportability by cough (42.5 vs. 65.0 mm, p < 0.05). CONCLUSION: We concluded that immunoglobulin administration in Common variable immunodeficiency patients results in significant improvement in indexes of inflammation of the airways with improvement in the transportability of the respiratory mucus by cough. PMID:20037702

  18. Anti-inflammatory properties of the monoterpene 1.8-cineole: current evidence for co-medication in inflammatory airway diseases.

    PubMed

    Juergens, U R

    2014-12-01

    1,8-cineole is a natural monoterpene, also known as eucalyptol. It is a major compound of many plant essential oils, mainly extracted from Eucalyptus globulus oil. As an isolated compound, 1,8-cineole is known for its mucolytic and spasmolytic action on the respiratory tract, with proven clinical efficacy. 1,8-cineole has also shown therapeutic benefits in inflammatory airway diseases, such as asthma and chronic obstructive pulmonary disease (COPD). This clinical evidence refers to its anti-inflammatory and anti-oxidant mode of action, which has been proven in numerous pre-clinical studies. In vitro studies found strong evidence that 1,8-cineole controls inflammatory processes and mediator production of infection- or inflammation-induced mucus hypersecretion by its action as anti-inflammatory modifier rather than a simple mucolytic agent. The aim of this review is to present these preclinical studies performed with the pure monoterpene, and to summarize the current knowledge on the mode of action of 1,8-cineole. The actual understanding of the pure 1,8-cineole compared to mixtures of natural volatile oils containing 1,8-cineole as a major compound and to mixtures of natural terpenes, known as essential oils, will be discussed. Based on the anti-oxidative and anti-inflammatory properties, recent clinical trials with 1,8-cineole have shown first evidence for the beneficial use of 1,8-cineole as long-term therapy in the prevention of COPD-exacerbations and to improve asthma control. PMID:24831245

  19. Associations of airway inflammation and responsiveness markers in non asthmatic subjects at start of apprenticeship

    PubMed Central

    2010-01-01

    Background Bronchial Hyperresponsiveness (BHR) is considered a hallmark of asthma. Other methods are helpful in epidemiological respiratory health studies including Fractional Exhaled Nitric Oxide (FENO) and Eosinophils Percentage (EP) in nasal lavage fluid measuring markers for airway inflammation along with the Forced Oscillatory Technique measuring Airway resistance (AR). Can their outcomes discriminate profiles of respiratory health in healthy subjects starting apprenticeship in occupations with a risk of asthma? Methods Rhinoconjunctivitis, asthma-like symptoms, FEV1 and AR post-Methacholine Bronchial Challenge (MBC) test results, FENO measurements and EP were all investigated in apprentice bakers, pastry-makers and hairdressers not suffering from asthma. Multiple Correspondence Analysis (MCA) was simultaneously conducted in relation to these groups and this generated a synthetic partition (EI). Associations between groups of subjects based on BHR and EI respectively, as well as risk factors, symptoms and investigations were also assessed. Results Among the 441 apprentice subjects, 45 (10%) declared rhinoconjunctivitis-like symptoms, 18 (4%) declared asthma-like symptoms and 26 (6%) suffered from BHR. The mean increase in AR post-MBC test was 21% (sd = 20.8%). The median of FENO values was 12.6 ppb (2.6-132 range). Twenty-six subjects (6.7%) had EP exceeding 14%. BHR was associated with atopy (p < 0.01) and highest FENO values (p = 0.09). EI identified 39 subjects with eosinophilic inflammation (highest values of FENO and eosinophils), which was associated with BHR and atopy. Conclusions Are any of the identified markers predictive of increased inflammatory responsiveness or of development of symptoms caused by occupational exposures? Analysis of population follow-up will attempt to answer this question. PMID:20604945

  20. Polyhexamethylene guanidine phosphate aerosol particles induce pulmonary inflammatory and fibrotic responses.

    PubMed

    Kim, Ha Ryong; Lee, Kyuhong; Park, Chang We; Song, Jeong Ah; Shin, Da Young; Park, Yong Joo; Chung, Kyu Hyuck

    2016-03-01

    Polyhexamethylene guanidine (PHMG) phosphate was used as a disinfectant for the prevention of microorganism growth in humidifiers, without recognizing that a change of exposure route might cause significant health effects. Epidemiological studies reported that the use of humidifier disinfectant containing PHMG-phosphate can provoke pulmonary fibrosis. However, the pulmonary toxicity of PHMG-phosphate aerosol particles is unknown yet. This study aimed to elucidate the toxicological relationship between PHMG-phosphate aerosol particles and pulmonary fibrosis. An in vivo nose-only exposure system and an in vitro air-liquid interface (ALI) co-culture model were applied to confirm whether PHMG-phosphate induces inflammatory and fibrotic responses in the respiratory tract. Seven-week-old male Sprague-Dawley rats were exposed to PHMG-phosphate aerosol particles for 3 weeks and recovered for 3 weeks in a nose-only exposure chamber. In addition, three human lung cells (Calu-3, differentiated THP-1 and HMC-1 cells) were cultured at ALI condition for 12 days and were treated with PHMG-phosphate at set concentrations and times. The reactive oxygen species (ROS) generation, airway barrier injuries and inflammatory and fibrotic responses were evaluated in vivo and in vitro. The rats exposed to PHMG-phosphate aerosol particles in nanometer size showed pulmonary inflammation and fibrosis including inflammatory cytokines and fibronectin mRNA increase, as well as histopathological changes. In addition, PHMG-phosphate triggered the ROS generation, airway barrier injuries and inflammatory responses in a bronchial ALI co-culture model. Those results demonstrated that PHMG-phosphate aerosol particles cause pulmonary inflammatory and fibrotic responses. All features of fibrogenesis by PHMG-phosphate aerosol particles closely resembled the pathology of fibrosis that was reported in epidemiological studies. Finally, we expected that PHMG-phosphate infiltrated into the lungs in the form

  1. [Influence of nanosize particles of cobalt ferrite on contractile responses of smooth muscle segment of airways].

    PubMed

    Kapilevich, L V; Zaĭtseva, T N; Nosarev, A V; D'iakova, E Iu; Petlina, Z R; Ogorodova, L M; Ageev, B G; Magaeva, A A; Itin, V I; Terekhova, O G; Medvedev, M A

    2012-02-01

    Contractile responses of airways segments of porpoises inhaling nanopowder CoFe2O4 were stidued by means of a mechanographic method. Inhalation of the nanosize particles of CoFe2O4 in vivo and in vitro testing the nanomaterial on isolated smooth muscles led to potentiation histaminergic, cholinergic contractile activity in airways of porpoises and to strengthening of adrenergic relaxing answers. Nanosize particles vary amplitude of hyperpotassium reductions in smooth muscle segments of airways similarly to the effect of depolymerizing drug colchicine. PMID:22650066

  2. Dose-response relationship of ozone-induced airway hyperresponsiveness in unanesthetized guinea pigs

    SciTech Connect

    Nishikawa, M.; Suzuki, S.; Ikeda, H.; Fukuda, T.; Suzuki, J.; Okubo, T. )

    1990-06-01

    The effect of ozone dose (the product of ozone concentration and exposure time) on airway responsiveness was examined in unanesthetized, spontaneously breathing guinea pigs. Airway responsiveness was assessed by measuring specific airway resistance (sRaw) as a function of increasing concentration of inhaled methacholine (Mch) aerosol (the concentration of Mch required in order to double the baseline sRaw: PC200Mch). The airway responsiveness was measured before and at 5 min, 5 h, and 24 h after exposure. A 30-min exposure to 1 ppm ozone (dose 30 ppm.min) did not change PC200Mch at any time after exposure. Both a 90-min exposure to 1 ppm ozone and a 30-min exposure to 3 ppm ozone, which are identical in terms of ozone dose (90 ppm.min), decreased PC200Mch to a similar degree. A 120-min exposure to 3 ppm ozone (360 ppm.min) produced a much greater decrease of PC200Mch at 5 min and 5 h after exposure, compared with low-dose exposure. There was a significant correlation between ozone dose and the change in airway responsiveness. In all groups, the baseline sRaw was increased by approximately 50% at 5 min after exposure, but there was no correlation between the changes in PC200Mch and the baseline sRaw. This study suggests that ozone-induced airway hyperresponsiveness in guinea pigs is closely related to ozone dose.

  3. Transport induced inflammatory responses in horses.

    PubMed

    Wessely-Szponder, J; Bełkot, Z; Bobowiec, R; Kosior-Korzecka, U; Wójcik, M

    2015-01-01

    Deleterious response to road transport is an important problem in equine practice. It determines different physiological, immunological and metabolic changes which lead to increased susceptibility to several disorders such as pneumonia, diarrhea, colics, laminitis, injuries and rhabdomyolisis. The aim of our study was to look for possible relationships between transportation of female young and older horses over a long and short distance and an inflammatory state reflected by an increase of acute phase protein concentration, oxidative stress and muscle injury. The study was conducted on 24 cold-blooded female horses divided into four groups. Six fillies aged 6-18 months and six mares aged 10-12 years were transported over the distance of about 550 km, six fillies aged 6-18 months and six mares aged 10-12 years were transported over the distance of about 50 km. Plasma and serum were obtained from blood samples taken before transportation (T0), immediately after transportation (T1) and at an abattoir during slaughter (T2). In these samples fibrinogen, MDA, AST and CK were assessed. Fibrinogen increased in all studied groups especially in fillies after long distance transportation, where it reached 205±7.07 mg/dl before transportation, 625±35.35 mg/dl after transportation, and 790±14.14 mg/dl during slaughter. MDA concentrations rose after transportation and reached the maximal level during slaughter. CK activity was more elevated after short transportation in younger horses, whereas initial activity of AST was higher in older horses. We estimated that intensified responses from acute phase, oxidative stress and muscle injury parameters indicated an inflammatory state. PMID:26172192

  4. Mechanical Strain Causes Adaptive Change in Bronchial Fibroblasts Enhancing Profibrotic and Inflammatory Responses

    PubMed Central

    Manuyakorn, Wiparat; Smart, David E.; Noto, Antonio; Bucchieri, Fabio; Haitchi, Hans Michael; Holgate, Stephen T.; Howarth, Peter H.; Davies, Donna E.

    2016-01-01

    Asthma is characterized by periodic episodes of bronchoconstriction and reversible airway obstruction; these symptoms are attributable to a number of factors including increased mass and reactivity of bronchial smooth muscle and extracellular matrix (ECM) in asthmatic airways. Literature has suggested changes in cell responses and signaling can be elicited via modulation of mechanical stress acting upon them, potentially affecting the microenvironment of the cell. In this study, we hypothesized that mechanical strain directly affects the (myo)fibroblast phenotype in asthma. Therefore, we characterized responses of bronchial fibroblasts, from 6 normal and 11 asthmatic non-smoking volunteers, exposed to cyclical mechanical strain using flexible silastic membranes. Samples were analyzed for proteoglycans, α-smooth muscle actin (αSMA), collagens I and III, matrix metalloproteinase (MMP) 2 & 9 and interleukin-8 (IL-8) by qRT-PCR, Western blot, zymography and ELISA. Mechanical strain caused a decrease in αSMA mRNA but no change in either αSMA protein or proteoglycan expression. In contrast the inflammatory mediator IL-8, MMPs and interstitial collagens were increased at both the transcriptional and protein level. The results demonstrate an adaptive response of bronchial fibroblasts to mechanical strain, irrespective of donor. The adaptation involves cytoskeletal rearrangement, matrix remodelling and inflammatory cytokine release. These results suggest that mechanical strain could contribute to disease progression in asthma by promoting inflammation and remodelling responses. PMID:27101406

  5. Adoptive transfer of allergic airway responses with sensitized lymphocytes in BN rats.

    PubMed

    Watanabe, A; Rossi, P; Renzi, P M; Xu, L J; Guttmann, R D; Martin, J G

    1995-07-01

    To evaluate the role of lymphocytes in the pathogenesis of allergic bronchoconstriction, we investigated whether allergic airway responses are adoptively transferred by antigen-primed lymphocytes in Brown Norway (BN) rats. Animals were actively sensitized to ovalbumin (OA) or sham sensitized, and 14 d later mononuclear cells (MNCs) were isolated from intrathoracic lymph nodes, passed through a nylon wool column, and transferred to naive syngeneic rats. Recipients were challenged with aerosolized OA or bovine serum albumin (BSA) (5% wt/vol) and analyzed for changes in lung resistance (RL), airway responsiveness to inhaled methacholine (MCh), and bronchoalveolar lavage (BAL) cells. Recipients of MNCs from sensitized rats responded to OA inhalation and exhibited sustained increases in RL throughout the 8-h observation period, but without usual early airway responses. Recipients of sham-sensitized MNCs or BSA-challenged recipients failed to respond to antigen challenge. At 32 h after OA exposure, airway responsiveness to MCh was increased in four of seven rats that had received sensitized MNCs (p = 0.035). BAL eosinophils increased at 32 h in the recipients of both sensitized and sham-sensitized MNCs. However, eosinophil numbers in BAL were inversely correlated with airway responsiveness in the recipients of sensitized MNCs (r = -0.788, p = 0.036). OA-specific immunoglobulin E (IgE) was undetectable by enzyme-linked immunosorbent assay (ELISA) or passive cutaneous anaphylaxis (PCA) in recipient rats following adoptive transfer. In conclusion, allergic late airway responses (LAR) and cholinergic airway hyperresponsiveness, but not antigen-specific IgE and early responses, were adoptively transferred by antigen-primed lymphocytes in BN rats.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7599864

  6. Curcumin regulates airway epithelial cell cytokine responses to the pollutant cadmium

    SciTech Connect

    Rennolds, Jessica; Malireddy, Smitha; Hassan, Fatemat; Tridandapani, Susheela; Parinandi, Narasimham; Boyaka, Prosper N.; Cormet-Boyaka, Estelle

    2012-01-06

    Highlights: Black-Right-Pointing-Pointer Cadmium induces secretion of IL-6 and IL-8 by two distinct pathways. Black-Right-Pointing-Pointer Cadmium increases NAPDH oxidase activity leading to Erk activation and IL-8 secretion. Black-Right-Pointing-Pointer Curcumin prevents cadmium-induced secretion of both IL-6 and IL-8 by airway cells. Black-Right-Pointing-Pointer Curcumin could be use to suppress lung inflammation due to cadmium inhalation. -- Abstract: Cadmium is a toxic metal present in the environment and its inhalation can lead to pulmonary disease such as lung cancer and chronic obstructive pulmonary disease. These lung diseases are characterized by chronic inflammation. Here we show that exposure of human airway epithelial cells to cadmium promotes a polarized apical secretion of IL-6 and IL-8, two pivotal pro-inflammatory cytokines known to play an important role in pulmonary inflammation. We also determined that two distinct pathways controlled secretion of these proinflammatory cytokines by human airway epithelial cells as cadmium-induced IL-6 secretion occurs via an NF-{kappa}B dependent pathway, whereas IL-8 secretion involves the Erk1/2 signaling pathway. Interestingly, the natural antioxidant curcumin could prevent both cadmium-induced IL-6 and IL-8 secretion by human airway epithelial cells. In conclusion, curcumin could be used to prevent airway inflammation due to cadmium inhalation.

  7. Gene Expression Changes Associated with the Airway Wall Response to Injury

    PubMed Central

    Yahaya, Badrul; McLachlan, Gerry; McCorquodale, Caroline; Collie, David

    2013-01-01

    Background Understanding the way in which the airway heals in response to injury is fundamental to dissecting the mechanisms underlying airway disease pathology. As only limited data is available in relation to the in vivo characterisation of the molecular features of repair in the airway we sought to characterise the dynamic changes in gene expression that are associated with the early response to physical injury in the airway wall. Methodology/Principal Findings We profiled gene expression changes in the airway wall using a large animal model of physical injury comprising bronchial brush biopsy in anaesthetised sheep. The experimental design featured sequential studies in the same animals over the course of a week and yielded data relating to the response at 6 hours, and 1, 3 and 7 days after injury. Notable features of the transcriptional response included the early and sustained preponderance of down-regulated genes associated with angiogenesis and immune cell activation, selection and differentiation. Later features of the response included the up-regulation of cell cycle genes at d1 and d3, and the latter pronounced up-regulation of extracellular matrix-related genes at d3 and d7. Conclusions/Significance It is possible to follow the airway wall response to physical injury in the same animal over the course of time. Transcriptional changes featured coordinate expression of functionally related genes in a reproducible manner both within and between animals. This characterisation will provide a foundation against which to assess the perturbations that accompany airway disease pathologies of comparative relevance. PMID:23593124

  8. In vivo exposure to hyperoxia increases airway responsiveness in rats. Demonstration in vivo and in vitro.

    PubMed

    Szarek, J L

    1989-10-01

    Studies regarding O2-induced lung injury have concentrated on damage to alveolar structures and pulmonary vasculature without consideration of alterations that may be occurring in airways. This study was undertaken to determine the effects of in vivo hyperoxic exposure on airway responses to excitatory stimuli in intact, anesthetized rats and in intrapulmonary bronchi isolated from hyperoxia-exposed rats. Using lung conductance (G1) as an index of bronchoconstriction, intravenously administered 5-hydroxytryptamine (5HT) elicited greater bronchoconstrictor responses in anesthetized, mechanically ventilated rats that had been exposed to 85% O2 for 7 days rather than to air. Further, airways of hyperoxia-exposed rats were more sensitive to the effects of intravenously administered 5HT as evidenced by the lower log dose of 5HT required to decrease G1 30%. Cylindrical segments of intrapulmonary bronchi isolated from hyperoxia-exposed rats were more responsive to the contractile effects of 5HT and electrical field stimulation. However, no differences in responsiveness to bethanechol or KCl were observed between the two groups. The log concentration of 5HT and the log frequency of electrical field stimulation that elicited half-maximal responses were smaller in bronchi isolated from hyperoxia-exposed animals, indicating an increase in sensitivity of the airways to these stimuli. These results suggest that prolonged exposure to greater than ambient levels of O2 can alter airway function; however, the mechanism responsible for these changes remains to be determined. PMID:2802379

  9. Bile Acids Repress Hypoxia-Inducible Factor 1 Signaling and Modulate the Airway Immune Response

    PubMed Central

    Legendre, Claire; Reen, F. Jerry; Woods, David F.; Mooij, Marlies J.; Adams, Claire

    2014-01-01

    Gastroesophageal reflux (GER) frequently occurs in patients with respiratory disease and is particularly prevalent in patients with cystic fibrosis. GER is a condition in which the duodenogastric contents of the stomach leak into the esophagus, in many cases resulting in aspiration into the respiratory tract. As such, the presence of GER-derived bile acids (BAs) has been confirmed in the bronchoalveolar lavage fluid and sputum of affected patients. We have recently shown that bile causes cystic fibrosis-associated bacterial pathogens to adopt a chronic lifestyle and may constitute a major host trigger underlying respiratory infection. The current study shows that BAs elicit a specific response in humans in which they repress hypoxia-inducible factor 1α (HIF-1α) protein, an emerging master regulator in response to infection and inflammation. HIF-1α repression was shown to occur through the 26S proteasome machinery via the prolyl hydroxylase domain (PHD) pathway. Further analysis of the downstream inflammatory response showed that HIF-1α repression by BAs can significantly modulate the immune response of airway epithelial cells, correlating with a decrease in interleukin-8 (IL-8) production, while IL-6 production was strongly increased. Importantly, the effects of BAs on cytokine production can also be more dominant than the bacterium-mediated effects. However, the effect of BAs on cytokine levels cannot be fully explained by their ability to repress HIF-1α, which is not surprising, given the complexity of the immune regulatory network. The suppression of HIF-1 signaling by bile acids may have a significant influence on the progression and outcome of respiratory disease, and the molecular mechanism underpinning this response warrants further investigation. PMID:24914220

  10. Airway Inflammation and Hypersensitivity Induced by Chronic Smoking

    PubMed Central

    Kou, Yu Ru; Kwong, Kevin; Lee, Lu-Yuan

    2011-01-01

    Airway hypersensitivity, characterized by enhanced excitability of airway sensory nerves, is a prominent pathophysiological feature in patients with airway inflammatory diseases. Although the underlying pathogenic mechanism is not fully understood, chronic airway inflammation is believed to be primarily responsible. Cigarette smoking is known to cause chronic airway inflammation, accompanied by airway hyperresponsiveness. Experimental evidence indicates that enhanced excitability of vagal bronchopulmonary sensory nerves and increased tachykinin synthesis in these nerves resulting from chronic inflammation are important contributing factors to the airway hyperresponsiveness. Multiple inflammatory mediators released from various types of structural and inflammatory cells are involved in the smoking-induced airway inflammation, which is mainly regulated by redox-sensitive signaling pathways and transcription factors. Furthermore, recent studies have reported potent sensitizing and stimulatory effects of these inflammatory mediators such as prostanoids and reactive oxygen species on these sensory nerves. In summary, these studies using cigarette smoking as an experimental approach have identified certain potentially important cell signaling pathways and underlying mechanisms of the airway hypersensitivity induced by chronic airway inflammation. PMID:21397052

  11. Protective Effects of the Polyphenol Sesamin on Allergen-Induced TH2 Responses and Airway Inflammation in Mice

    PubMed Central

    Lin, Ching-Huei; Shen, Mei-Lin; Zhou, Ning; Lee, Chen-Chen; Kao, Shung-Te; Wu, Dong Chuan

    2014-01-01

    Allergic asthma is a lifelong airway condition that affects people of all ages. In recent decades, asthma prevalence continues to increase globally, with an estimated number of 250,000 annual deaths attributed to the disease. Although inhaled corticosteroids and β-adrenergic receptor agonists are the primary therapeutic avenues that effectively reduce asthma symptoms, profound side effects may occur in patients with long-term treatments. Therefore, development of new therapeutic strategies is needed as alternative or supplement to current asthma treatments. Sesamin is a natural polyphenolic compound with strong anti-oxidative effects. Several studies have reported that sesamin is effective in preventing hypertension, thrombotic tendency, and neuroinflammation. However, it is still unknown whether sesamin can reduce asthma-induced allergic inflammation and airway hyperresponsiveness (AHR). Our study has revealed that sesamin exhibited significant anti-inflammatory effects in ovalbumin (OVA)-induced murine asthma model. We found that treatments with sesamin after OVA sensitization and challenge significantly decreased expression levels of interleukin-4 (IL-4), IL-5, IL-13, and serum IgE. The numbers of total inflammatory cells and eosinophils in BALF were also reduced in the sesamin-treated animals. Histological results demonstrated that sesamin attenuated OVA-induced eosinophil infiltration, airway goblet cell hyperplasia, mucus occlusion, and MUC5AC expression in the lung tissue. Mice administered with sesamin showed limited increases in AHR compared with mice receiving vehicle after OVA challenge. OVA increased phosphorylation levels of IκB-α and nuclear expression levels of NF-κB, both of which were reversed by sesamin treatments. These data indicate that sesamin is effective in treating allergic asthma responses induced by OVA in mice. PMID:24755955

  12. Airway hyper-responsiveness in lipopolysaccharide-challenged common marmosets (Callithrix jacchus)

    PubMed Central

    Curths, Christoph; Wichmann, Judy; Dunker, Sarah; Windt, Horst; Hoymann, Heinz-Gerd; Lauenstein, Hans D.; Hohlfeld, Jens; Becker, Tamara; Kaup, Franz-Josef; Braun, Armin; Knauf, Sascha

    2013-01-01

    Animal models with a high predictive value for human trials are needed to develop novel human-specific therapeutics for respiratory diseases. The aim of the present study was to examine lung-function parameters in marmoset monkeys (Callithrix jacchus) that can be used to detect pharmacologically or provocation-induced AHR (airway hyper-responsiveness). Therefore a custom-made lung-function device that allows application of defined aerosol doses during measurement was developed. It was hypothesized that LPS (lipopolysaccharide)-challenged marmosets show AHR compared with non-challenged healthy subjects. Invasive plethysmography was performed in 12 anaesthetized orotracheally intubated and spontaneously breathing marmosets. Pulmonary data of RL (lung resistance), Cdyn (dynamic compliance), EF50 (mid-expiratory flow), Poes (oesophageal pressure), MV (minute volume), respiratory frequency (f) and VT (tidal volume) were collected. Measurements were conducted under baseline conditions and under MCh (methacholine)-induced bronchoconstriction. The measurement was repeated with the same group of animals after induction of an acute lung inflammation by intratracheal application of LPS. PDs (provocative doses) of MCh to achieve a certain increase in RL were significantly lower after LPS administration. AHR was demonstrated in the LPS treated compared with the naïve animals. The recorded lung-function data provide ground for pre-clinical efficacy and safety testing of anti-inflammatory substances in the common marmoset, a new translational NHP (non-human primate) model for LPS-induced lung inflammation. PMID:23879175

  13. Apoptosis and the Airway Epithelium

    PubMed Central

    White, Steven R.

    2011-01-01

    The airway epithelium functions as a barrier and front line of host defense in the lung. Apoptosis or programmed cell death can be elicited in the epithelium as a response to viral infection, exposure to allergen or to environmental toxins, or to drugs. While apoptosis can be induced via activation of death receptors on the cell surface or by disruption of mitochondrial polarity, epithelial cells compared to inflammatory cells are more resistant to apoptotic stimuli. This paper focuses on the response of airway epithelium to apoptosis in the normal state, apoptosis as a potential regulator of the number and types of epithelial cells in the airway, and the contribution of epithelial cell apoptosis in important airways diseases. PMID:22203854

  14. Airway blood flow response to dry air hyperventilation in sheep

    SciTech Connect

    Parsons, G.H.; Baile, E.M.; Pare, P.D.

    1986-03-01

    Airway blood flow (Qaw) may be important in conditioning inspired air. To determine the effect of eucapneic dry air hyperventilation (hv) on Qaw in sheep the authors studied 7 anesthetized open-chest sheep after 25 min. of warm dry air hv. During each period of hv the authors have recorded vascular pressures, cardiac output (CO), and tracheal mucosal and inspired air temperature. Using a modification of the reference flow technique radiolabelled microspheres were injected into the left atrium to make separate measurements after humid air and dry air hv. In 4 animals a snare around the left main pulmonary artery was used following microsphere injection to prevent recirculation (entry into L lung of microspheres from the pulmonary artery). Qaw to the trachea and L lung as measured and Qaw for the R lung was estimated. After the final injection the sheep were killed and bronchi (Br) and lungs removed. Qaw (trachea plus L lung plus R lung) in 4 sheep increased from a mean of 30.8 to 67.0 ml/min. Airway mucosal temp. decreased from 39/sup 0/ to 33/sup 0/C. The authors conclude that dry air hv cools airway mucosa and increases Qaw in sheep.

  15. EFFECTS OF TITANIUM DIOXIDE NANOPARTICLE EXPOSURE ON NEUROIMMUNE RESPONSES IN RAT AIRWAYS

    PubMed Central

    Scuri, Mario; Chen, Bean T.; Castranova, Vincent; Reynolds, Jeffrey S.; Johnson, Victor J.; Samsell, Lennie; Walton, Cheryl; Piedimonte, Giovanni

    2013-01-01

    Exposure to ambient nanoparticles (defined as particulate matter [PM] having one dimension < 100 nm) is associated with increased risk of childhood and adult asthma. Nanomaterials feature a smaller aerodynamic diameter and a higher surface area per unit mass ratio compared to fine or coarse-sized particles, resulting in greater lung deposition efficiency and an increased potential for biological interaction. The neurotrophins nerve growth factor and brain-derived neurotrophic factor are key regulatory elements of neuronal development and responsiveness of airway sensory neurons. Changes in their expression are associated with bronchoconstriction, airway hyperresponsiveness, and airway inflammation. The neurogenic-mediated control of airway responses is a key pathophysiological mechanism of childhood asthma. However, the effects of nanoparticle exposure on neurotrophin-driven airway responses and their potential role as a predisposing factor for developing asthma have not been clearly elucidated. In this study, in vivo inhalation exposure to titanium dioxide nanoparticles (12 mg/m13; 5.6 h/d for 3 d) produced upregulation of lung neurotrophins in weanling (2-wk-old) and newborn (2-d-old) rats but not in adult (12-wk-old) animals compared to controls. This effect was associated with increased airway responsiveness and upregulation of growth-related oncogene/keratine-derived chemokine (GRO/KC; CXCL1, rat equivalent of human interleukin [IL]-8) in bronchoalveolar lavage fluid. These data show for the first time that exposure to nanoparticulate upregulates the expression of lung neurotrophins in an age-dependent fashion and that this effect is associated with airway hyperresponsiveness and inflammation. These results suggest the presence of a critical window of vulnerability in earlier stages of lung development, which may lead to a higher risk of developing asthma. PMID:20818535

  16. Alert cell strategy: mechanisms of inflammatory response and organ protection.

    PubMed

    Hatakeyama, Noboru; Matsuda, Naoyuki

    2014-01-01

    Systemic inflammatory response syndrome (SIRS) is triggered by various factors such as surgical operation, trauma, burn injury, ischemia, pancreatitis and bacterial translocation. Sepsis is a SIRS associated with bacterial infection. SIRS and sepsis tend to trigger excessive production of inflammatory cytokines and other inflammatory molecules and induce multiple organ failure, such as acute lung injury, acute kidney injury and inflammatory cardiac injury. Epithelial and endothelial cells in some major organs express inflammatory receptors on the plasma membrane and work as alert cells for inflammation, and regulation of these alert cells could have a relieving effect on the inflammatory response. In inflammatory conditions, initial cardiac dysfunction is mediated by decreased preload and adequate infusion therapy is required. Tachyarrhythmia is a complication of inflammatory conditions and early control of the inflammatory reaction would prevent the structural remodeling that is resistant to therapies. Furthermore, there seems to be crosstalk between major organs with a central focus on the kidneys in inflammatory conditions. As an alert cell strategy, volatile anesthetics, sevoflurane and isoflurane, seem to have anti-inflammatory effects, and both experimental and clinical studies have shown the beneficial effects of these drugs in various settings of inflammatory conditions. On the other hand, in terms of intravenous anesthetics, propofol and ketamine, their current status is still controversial as there is a lack of confirmatory evidence on whether they have an organ-protective effect in inflammatory conditions. The local anesthetic lidocaine suppressed inflammatory responses upon both systemic and local administration. For the control of inflammatory conditions, anesthetic agents may be a target of drug development in accordance with other treatments and drugs. PMID:25229471

  17. Induction of cyclo-oxygenase-2 by cytokines in human cultured airway smooth muscle cells: novel inflammatory role of this cell type

    PubMed Central

    Belvisi, Maria G; Saunders, Michael A; Haddad, El-Bdaoui; Hirst, Stuart J; Yacoub, Magdi H; Barnes, Peter J; Mitchell, Jane A

    1997-01-01

    Cyclo-oxygenase (COX) is the enzyme that converts arachidonic acid to prostaglandin H2 (PGH2) which can then be further metabolized to prostanoids which modulate various airway functions. COX exists in at least two isoforms. COX-1 is expressed constitutively, whereas COX-2 is expressed in response to pro-inflammatory stimuli. Prostanoids are produced under physiological and pathophysiological conditions by many cell types in the lung. However, the regulation of the different COX isoforms in human airway smooth muscle (HASM) cells has not yet been determined.COX-1 and COX-2 protein were measured by Western blot analysis with specific antibodies for COX-1 and COX-2. COX-2 mRNA levels were assessed by Northern blot analysis by use of a COX-2 cDNA probe. COX activity was determined by measuring conversion of either endogenous or exogenous arachidonic acid to three metabolites, PGE2, thromboxane B2 or 6-ketoPGF1α by radioimmunoassay.Under control culture conditions HASM cells expressed COX-1, but not COX-2, protein. However, a mixture of cytokines (interleukin-1β (IL-1β), tumour necrosis factor α (TNFα) and interferon γ (IFNγ) each at 10 ng ml−1) induced COX-2 mRNA expression, which was maximal at 12 h and inhibited by dexamethasone (1 μM; added 30 min before the cytokines). Furthermore, COX-2 protein was detected 24 h after the cytokine treatment and the expression of this protein was also inhibited by dexamethasone (1 μM) and cyclohexamide (10 μg ml−1; added 30 min before the cytokines).Untreated HASM cells released low or undetectable amounts of all COX metabolites measured over a 24 h period. Incubation of the cells with the cytokine mixture (IL-1β, TNFα, IFNγ each at 10 ng ml−1 for 24 h) caused the accumulation of PGE2 and 6-keto-PGF1α.In experiments where COX-2 metabolized endogenous stores of arachidonic acid, treatment of HASM cells with IL-1β in combination with TNFα caused a similar release of PGE2 to that when

  18. S-nitrosothiols regulate cell-surface pH buffering by airway epithelial cells during the human immune response to rhinovirus.

    PubMed

    Carraro, Silvia; Doherty, Joseph; Zaman, Khalequz; Gainov, Iain; Turner, Ronald; Vaughan, John; Hunt, John F; Márquez, Javier; Gaston, Benjamin

    2006-05-01

    Human rhinovirus infection is a common trigger for asthma exacerbations. Asthma exacerbations and rhinovirus infections are both associated with markedly decreased pH and ammonium levels in exhaled breath condensates. This observation is thought to be related, in part, to decreased activity of airway epithelial glutaminase. We studied whether direct rhinovirus infection and/or the host immune response to the infection decreased airway epithelial cell surface pH in vitro. Interferon-gamma and tumor necrosis factor-alpha, but not direct rhinovirus infection, decreased pH, an effect partly associated with decreased ammonium concentrations. This effect was 1) prevented by nitric oxide synthase inhibition; 2) independent of cyclic GMP; 3) associated with an increase in endogenous airway epithelial cell S-nitrosothiol concentration; 4) mimicked by the exogenous S-nitrosothiol, S-nitroso-N-acetyl cysteine; and 5) independent of glutaminase expression and activity. We then confirmed that decreased epithelial pH inhibits human rhinovirus replication in airway epithelial cells. These data suggest that a nitric oxide synthase-dependent host response to viral infection mediated by S-nitrosothiols, rather than direct infection itself, plays a role in decreased airway surface pH during human rhinovirus infection. This host immune response may serve to protect the lower airways from direct infection in the normal host. In patients with asthma, however, this fall in pH could be associated with the increased mucus production, augmented inflammatory cell degranulation, bronchoconstriction, and cough characteristic of an asthma exacerbation. PMID:16603595

  19. Assessing mucus and airway morphology in response to a segmental allergen challenge using OCT (Conference Presentation)

    NASA Astrophysics Data System (ADS)

    Adams, David C.; Miller, Alyssa J.; Holz, Jasmin A.; Szabari, Margit V.; Hariri, Lida P.; Harris, R. Scott; Cho, Jocelyn L.; Hamilos, Daniel L.; Luster, Andrew D.; Medoff, Benjamin D.; Suter, Melissa J.

    2016-03-01

    Asthma affects hundreds of millions of people worldwide, and the prevalence of the disease appears to be increasing. One of the most important aspects of asthma is the excessive bronchoconstriction that results in many of the symptoms experienced by asthma sufferers, but the relationship between bronchoconstriction and airway morphology is not clearly established. We present the imaging results of a study involving a segmental allergen challenge given to both allergic asthmatic (n = 12) and allergic non-asthmatic (n = 19) human volunteers. Using OCT, we have imaged and assessed baseline morphology in a right upper lobe (RUL) airway, serving as the control, and a right middle lobe (RML) airway, in which the allergen was to be administered. After a period of 24 hours had elapsed following the administration of the allergen, both airways were again imaged and the response morphology assessed. A number of airway parameters were measured and compared, including epithelial thickness, mucosal thickness and buckling, lumen area, and mucus content. We found that at baseline epithelial thickness, mucosal thickness, and mucosal buckling were greater in AAs than ANAs. We also observed statistically significant increases in these values 24 hours after the allergen had been administered for both the ANA and AA sets. In comparison, the control airway which received a diluent showed no statistically significant change.

  20. Novel small airway bronchodilator responses to rosiglitazone in mouse lung slices.

    PubMed

    Bourke, Jane E; Bai, Yan; Donovan, Chantal; Esposito, James G; Tan, Xiahui; Sanderson, Michael J

    2014-04-01

    There is a need to identify novel agents that elicit small airway relaxation when β2-adrenoceptor agonists become ineffective in difficult-to-treat asthma. Because chronic treatment with the synthetic peroxisome proliferator activated receptor (PPAR)γ agonist rosiglitazone (RGZ) inhibits airway hyperresponsiveness in mouse models of allergic airways disease, we tested the hypothesis that RGZ causes acute airway relaxation by measuring changes in small airway size in mouse lung slices. Whereas the β-adrenoceptor agonists albuterol (ALB) and isoproterenol induced partial airway relaxation, RGZ reversed submaximal and maximal contraction to methacholine (MCh) and was similarly effective after precontraction with serotonin or endothelin-1. Concentration-dependent relaxation to RGZ was not altered by the β-adrenoceptor antagonist propranolol and was enhanced by ALB. RGZ-induced relaxation was mimicked by other synthetic PPARγ agonists but not by the putative endogenous agonist 15-deoxy-PGJ2 and was not prevented by the PPARγ antagonist GW9662. To induce airway relaxation, RGZ inhibited the amplitude and frequency of MCh-induced Ca(2+) oscillations of airway smooth muscle cells (ASMCs). In addition, RGZ reduced MCh-induced Ca(2+) sensitivity of the ASMCs. Collectively, these findings demonstrate that acute bronchodilator responses induced by RGZ are PPARγ independent, additive with ALB, and occur by the inhibition of ASMC Ca(2+) signaling and Ca(2+) sensitivity. Because RGZ continues to elicit relaxation when β-adrenoceptor agonists have a limited effect, RGZ or related compounds may have potential as bronchodilators for the treatment of difficult asthma. PMID:24188042

  1. Preventive and therapeutic anti-inflammatory properties of the sesquiterpene α-humulene in experimental airways allergic inflammation

    PubMed Central

    Rogerio, Alexandre P; Andrade, Edinéia L; Leite, Daniela FP; Figueiredo, Cláudia P; Calixto, João B

    2009-01-01

    Background and purpose: α-Humulene and trans-caryophyllene are plant sesquiterpenes with pronounced anti-inflammatory properties. Here, we evaluated the effects of these compounds in an experimental model of airways allergic inflammation. Experimental approach: Female BALB/c mice, sensitized to and challenged with ovalbumin received daily α-humulene or trans-caryophyllene (50 mg·kg−1, orally) or α-humulene (1 mg·mL−1, by aerosol) as either a preventive (for 22 days) or therapeutic (from the 18th to the 22nd day) treatment. Dexamethasone or budesonide was used as a positive control drug. Inflammation was determined on day 22 post-immunization by leukocyte recruitment, interleukin-5 (IL-5), CCL11, interferon-γ (IFN-γ) and leukotriene (LT)B4 levels in bronchoalveolar lavage fluid (BALF). In addition, transcription factors [nuclear factor κB (NF-κB), activator protein 1 (AP-1)] and P-selectin in lung tissue were measured by immunohistochemistry and mucus secretion by histochemistry. Key results: Preventive or therapeutic treatments with α-humulene, but not with trans-caryophyllene, significantly reduced the eosinophil recruitment to the BALF. In addition, α-humulene recovery INF-γ and reduced the IL-5, CCL11 and LTB4 levels in BALF, as well as the IL-5 production in mediastinal lymph nodes (in vitro assay). Furthermore, α-humulene decreased the NF-kB and the AP-1 activation, the expression of P-selectin and the increased mucus secretion in the lung. Conclusions and implications: α-Humulene, given either orally or by aerosol, exhibited marked anti-inflammatory properties in a murine model of airways allergic inflammation, an effect that seemed to be mediated via reduction of inflammatory mediators, adhesion molecule expression and transcription factors activation. This article is part of a themed issue on Mediators and Receptors in the Resolution of Inflammation. To view this issue visit http://www3.interscience.wiley.com/journal/121548564/issueyear

  2. Airway responses to methacholine and exercise at high altitude in healthy lowlanders.

    PubMed

    Pellegrino, Riccardo; Pompilio, Pasquale; Quaranta, Marco; Aliverti, Andrea; Kayser, Bengt; Miserocchi, Giuseppe; Fasano, Valter; Cogo, Annalisa; Milanese, Manlio; Cornara, Giuseppe; Brusasco, Vito; Dellacà, Raffaele

    2010-02-01

    Peribronchial edema has been proposed as a mechanism enhancing airway responses to constrictor stimuli. Acute exposure to altitude in nonacclimatized lowlanders leads to subclinical interstitial pulmonary edema that lasts for several days after ascent, as suggested by changes in lung mechanics. We, therefore, investigated whether changes in lung mechanics consistent with fluid accumulation at high altitude within the lungs are associated with changes in airway responses to methacholine or exercise. Fourteen healthy subjects were studied at 4,559 and at 120 m above sea level. At high altitude, both static and dynamic lung compliances and respiratory reactance at 5 Hz significantly decreased, suggestive of interstitial pulmonary edema. Resting minute ventilation significantly increased by approximately 30%. Compared with sea level, inhalation of methacholine at high altitude caused a similar reduction of partial forced expiratory flow but less reduction of maximal forced expiratory flow, less increments of pulmonary resistance and respiratory resistance at 5 Hz, and similar effects of deep breath on pulmonary and respiratory resistance. During maximal incremental exercise at high altitude, partial forced expiratory flow gradually increased with the increase in minute ventilation similarly to sea level but both achieved higher values at peak exercise. In conclusion, airway responsiveness to methacholine at high altitude is well preserved despite the occurrence of interstitial pulmonary edema. We suggest that this may be the result of the increase in resting minute ventilation opposing the effects and/or the development of airway smooth muscle force, reduced gas density, and well preserved airway-to-parenchyma interdependence. PMID:19940099

  3. Inflammatory and oxidative stress airway markers in premature newborns of hypertensive mothers.

    PubMed

    Madoglio, R J; Rugolo, L M S S; Kurokawa, C S; Sá, M P A; Lyra, J C; Antunes, L C O

    2016-01-01

    Although oxidative stress and inflammation are important mechanisms in the pathophysiology of preeclampsia and preterm diseases, their contribution to the respiratory prognosis of premature infants of hypertensive mothers is not known. Our objective was to determine the levels of oxidative stress and inflammation markers in the airways of premature infants born to hypertensive and normotensive mothers, in the first 72 h of life, and to investigate whether they are predictors of bronchopulmonary dysplasia (BPD)/death. This was a prospective study with premature infants less than 34 weeks' gestation on respiratory support who were stratified into 2 groups: 32 premature infants of hypertensive mothers and 41 of normotensive women, with a mean gestational age of 29 weeks. Exclusion criteria were as follows: diabetes mellitus, chorioamnionitis, malformation, congenital infection, and death within 24 h after birth. The outcome of interest was BPD/death. Malondialdehyde (MDA), nitric oxide (NO), and interleukin 8 (IL-8) were measured in airway aspirates from the first and third days of life and did not differ between the groups. Univariate and multivariate statistical analyses were performed. The concentrations of MDA, NO, and IL-8 were not predictors of BPD/death. Premature infants who developed BPD/death had higher levels of IL-8 in the first days of life. The gestational age, mechanical ventilation, and a small size for gestational age were risk factors for BPD/death. In conclusion, the biomarkers evaluated were not increased in premature infants of hypertensive mothers and were not predictors of BPD/death. PMID:27533763

  4. Inflammatory and oxidative stress airway markers in premature newborns of hypertensive mothers

    PubMed Central

    Madoglio, R.J.; Rugolo, L.M.S.S.; Kurokawa, C.S.; Sá, M.P.A.; Lyra, J.C.; Antunes, L.C.O.

    2016-01-01

    Although oxidative stress and inflammation are important mechanisms in the pathophysiology of preeclampsia and preterm diseases, their contribution to the respiratory prognosis of premature infants of hypertensive mothers is not known. Our objective was to determine the levels of oxidative stress and inflammation markers in the airways of premature infants born to hypertensive and normotensive mothers, in the first 72 h of life, and to investigate whether they are predictors of bronchopulmonary dysplasia (BPD)/death. This was a prospective study with premature infants less than 34 weeks’ gestation on respiratory support who were stratified into 2 groups: 32 premature infants of hypertensive mothers and 41 of normotensive women, with a mean gestational age of 29 weeks. Exclusion criteria were as follows: diabetes mellitus, chorioamnionitis, malformation, congenital infection, and death within 24 h after birth. The outcome of interest was BPD/death. Malondialdehyde (MDA), nitric oxide (NO), and interleukin 8 (IL-8) were measured in airway aspirates from the first and third days of life and did not differ between the groups. Univariate and multivariate statistical analyses were performed. The concentrations of MDA, NO, and IL-8 were not predictors of BPD/death. Premature infants who developed BPD/death had higher levels of IL-8 in the first days of life. The gestational age, mechanical ventilation, and a small size for gestational age were risk factors for BPD/death. In conclusion, the biomarkers evaluated were not increased in premature infants of hypertensive mothers and were not predictors of BPD/death. PMID:27533763

  5. Functional Roles of Syk in Macrophage-Mediated Inflammatory Responses

    PubMed Central

    Yi, Young-Su; Son, Young-Jin; Ryou, Chongsuk; Sung, Gi-Ho; Kim, Jong-Hoon; Cho, Jae Youl

    2014-01-01

    Inflammation is a series of complex biological responses to protect the host from pathogen invasion. Chronic inflammation is considered a major cause of diseases, such as various types of inflammatory/autoimmune diseases and cancers. Spleen tyrosine kinase (Syk) was initially found to be highly expressed in hematopoietic cells and has been known to play crucial roles in adaptive immune responses. However, recent studies have reported that Syk is also involved in other biological functions, especially in innate immune responses. Although Syk has been extensively studied in adaptive immune responses, numerous studies have recently presented evidence that Syk has critical functions in macrophage-mediated inflammatory responses and is closely related to innate immune response. This review describes the characteristics of Syk-mediated signaling pathways, summarizes the recent findings supporting the crucial roles of Syk in macrophage-mediated inflammatory responses and diseases, and discusses Syk-targeted drug development for the therapy of inflammatory diseases. PMID:25045209

  6. Piperazine-induced airway symptoms: exposure-response relationships and selection in an occupational setting

    SciTech Connect

    Hagmar, L.; Bellander, T.; Ranstam, J.; Skerfving, S.

    1984-01-01

    The heterocyclic secondary amine piperazine is known to cause asthma. In a cohort of 602 workers, employed during the period 1942-1979, at a chemical industry where piperazine is handled, a study conducted by means of a mailed questionnaire showed a strong exposure-response relationship as to frequency of work-related airway symptoms indicating asthma. In the most exposed group about a third of the workers had experienced such symptoms. Age, length of employment, smoking habits, and previous work-related asthmatic symptoms, but not atopy, modified the response. Further, there was an association between piperazine exposure and chronic bronchitis. In the most exposed group every fourth subject had chronic bronchitis. The frequency was modified by smoking habits; atopy was a confounder. Although many subjects, especially high-exposed ones, left work because of airway symptoms, there was no difference in occurrence of airway symptoms between former and present employees.

  7. The effect of smoke inhalation on lung function and airway responsiveness in wildland fire fighters

    SciTech Connect

    Liu, D.; Tager, I.B.; Balmes, J.R.; Harrison, R.J. )

    1992-12-01

    The current study was undertaken to evaluate the effect of smoke on forced expiratory volumes and airway responsiveness in wildland fire fighters during a season of active fire fighting. Sixty-three seasonal and full-time wildland fire fighters from five U.S. Department of Agriculture Forest Service (USDAFS) Hotshot crews in Northern California and Montana completed questionnaires, spirometry, and methacholine challenge testing before and after an active season of fire fighting in 1989. There were significant mean individual declines of 0.09, 0.15, and 0.44 L/s in postseason values of FVC, FEV1, and FEF25-75, respectively, compared with preseason values. There were no consistent significant relationships between mean individual declines of the spirometric parameters and the covariates: sex, smoking history, history of asthma or allergies, years as a fire fighter, upper/lower respiratory symptoms, or membership in a particular Hotshot crew. There was a statistically significant increase in airway responsiveness when comparing preseason methacholine dose-response slopes (DRS) with postseason dose-response slopes (p = 0.02). The increase in airway responsiveness appeared to be greatest in fire fighters with a history of lower respiratory symptoms or asthma, but it was not related to smoking history. These data suggest that wildland fire fighting is associated with decreases in lung function and increases in airway responsiveness independent of a history of cigarette smoking. Our findings are consistent with the results of previous studies of municipal fire fighters.

  8. The effect of smoke inhalation on lung function and airway responsiveness in wildland fire fighters.

    PubMed

    Liu, D; Tager, I B; Balmes, J R; Harrison, R J

    1992-12-01

    The current study was undertaken to evaluate the effect of smoke on forced expiratory volumes and airway responsiveness in wildland fire fighters during a season of active fire fighting. Sixty-three seasonal and full-time wildland fire fighters from five U.S. Department of Agriculture Forest Service (USDAFS) Hotshot crews in Northern California and Montana completed questionnaires, spirometry, and methacholine challenge testing before and after an active season of fire fighting in 1989. There were significant mean individual declines of 0.09, 0.15, and 0.44 L/s in postseason values of FVC, FEV1, and FEF25-75, respectively, compared with preseason values. There were no consistent significant relationships between mean individual declines of the spirometric parameters and the covariates: sex, smoking history, history of asthma or allergies, years as a fire fighter, upper/lower respiratory symptoms, or membership in a particular Hotshot crew. There was a statistically significant increase in airway responsiveness when comparing preseason methacholine dose-response slopes (DRS) with postseason dose-response slopes (p = 0.02). The increase in airway responsiveness appeared to be greatest in fire fighters with a history of lower respiratory symptoms or asthma, but it was not related to smoking history. These data suggest that wildland fire fighting is associated with decreases in lung function and increases in airway responsiveness independent of a history of cigarette smoking. Our findings are consistent with the results of previous studies of municipal fire fighters. PMID:1456562

  9. Airway epithelial cells initiate the allergen response through transglutaminase 2 by inducing IL-33 expression and a subsequent Th2 response

    PubMed Central

    2013-01-01

    Background Transglutaminase 2 (TG2) is a post-translational protein-modifying enzyme that catalyzes the transamidation reaction, producing crosslinked or polyaminated proteins. Increased TG2 expression and activity have been reported in various inflammatory conditions, such as rheumatoid arthritis, inflammation-associated pulmonary fibrosis, and autoimmune encephalitis. In particular, TG2 from epithelial cells is important during the initial inflammatory response in the lung. In this study, we evaluated the role of TG2 in the pathogenesis of allergic asthma, particularly whether TG2 affects initial activation signaling leading to Th2 differentiation against antigens. Methods We induced allergic asthma by ovalbumin sensitization and intranasal challenge in wild-type (WT) BALB/c and TG2-deficient mice. Broncheoalveolar lavage fluid cells and intracellular cytokine production were analyzed by flow cytometry. Interleukin (IL)-33 and TG2 expression in lung epithelial cells was detected by confocal microscopy. Results Airway responsiveness was attenuated in TG2-deficient mice compared to that in the WT control. In addition, recruitment of eosinophils and Th2 and Th17 differentiation decreased in TG2-deficient mice. Treatment with cysteamine, a transglutaminase inhibitor, also reduced airway hypersensitivity, inflammatory cell recruitment, and T helper cell differentiation. TG2-deficient mice showed reduced IL-33 expression following induction of allergic asthma compared to those in the WT control. Conclusions We found that pulmonary epithelial cells damaged by allergens triggered TG2-mediated IL-33 expression leading to type 2 responses by recruiting both innate and adaptive arms of the immune system. PMID:23496815

  10. Bronchial Epithelial Cells Produce IL-5: Implications for Local Immune Responses in the Airways

    PubMed Central

    Wu, Carol A.; Peluso, John J.; Zhu, Li; Lingenheld, Elizabeth G.; Walker, Sharale T.; Puddington, Lynn

    2010-01-01

    IL-5 is a pleiotropic cytokine that promotes eosinophil differentiation and survival. While naïve bronchial epithelial cells (BEC) produce low levels of IL-5, the role of BEC-derived IL-5 in allergic airway inflammation is unknown. We now show that BEC, isolated from mice with OVA-induced allergic airway disease (AAD), produced elevated levels of IL-5 mRNA and protein as compared to BEC from naïve mice. To determine the contribution of BEC-derived IL-5 to effector responses in the airways, IL-5 deficient bone marrow chimeric mice were generated in which IL-5 expression was restricted to stromal (e.g. BEC) or hematopoietic cells. When subjected to AAD, IL-5 produced by BECs contributed to mucous metaplasia, airway eosinophilia, and OVA-specific IgA levels. Thus, IL-5 production by BEC can impact the microenvironment of the lung, modifying pathologic and protective immune responses in the airways. PMID:20494340

  11. Importance of airway inflammation for hyperresponsiveness induced by ozone. [Dogs

    SciTech Connect

    Holtzman, M.J.; Fabbri, L.M.; O'Byrne, P.M.; Gold, B.D.; Aizawa, H.; Walters, E.H.; Alpert, S.E.; Nadel, J.A.

    1983-06-01

    We studied whether ozone-induced airway hyperresponsiveness correlates with the development of airway inflammation in dogs. To assess airway responsiveness, we determined increases in pulmonary resistance produced by delivering acetylcholine aerosol to the airways. To assess airway inflammation, we biopsied the airway mucosa and counted the number of neutrophils present in the epithelium. Airway responsiveness and inflammation were assessed in anesthetized dogs before ozone exposure and then 1 h and 1 wk after ozone (2.1 ppm, 2 h). Airway responsiveness increased markedly at 1 h after ozone and returned to control levels 1 wk later in each of 6 dogs, but it did not change after ozone in another 4 dogs. Furthermore, dogs that became hyperresponsive also developed a marked and reversible increase in the number of neutrophils in the epithelium, whereas dogs that did not become hyperresponsive had no change in the number of neutrophils. For the group of dogs, the level of airway responsiveness before and after ozone exposure correlated closely with the number of epithelial neutrophils. The results suggest that ozone-induced airway hyperresponsiveness may depend on the development of an acute inflammatory response in the airways.

  12. Upper airway response in workers exposed to fuel oil ash: nasal lavage analysis.

    PubMed Central

    Hauser, R; Elreedy, S; Hoppin, J A; Christiani, D C

    1995-01-01

    non-smokers but not smokers was found. This suggests that in non-smokers, exposure to fuel oil ash is associated with upper airway inflammation manifested as increased polymorphonuclear cell counts. The lack of an increase in polymorphonuclear cells in smokers may reflect either a diminished inflammatory response or may indicate that smoking masks the effect of exposure to fuel oil ash. PMID:7795759

  13. Airway wall thickness is increased in COPD patients with bronchodilator responsiveness

    PubMed Central

    2014-01-01

    Rationale Bronchodilator responsiveness (BDR) is a common but variable phenomenon in COPD. The CT characteristics of airway dimensions that differentiate COPD subjects with BDR from those without BDR have not been well described. We aimed to assess airway dimensions in COPD subjects with and without BDR. Methods We analyzed subjects with GOLD 1–4 disease in the COPDGene® study who had CT airway analysis. We divided patients into two groups: BDR + (post bronchodilator ΔFEV1 ≥ 10%) and BDR-(post bronchodilator ΔFEV1 < 10%). The mean wall area percent (WA%) of six segmental bronchi in each subject was quantified using VIDA. Using 3D SLICER, airway wall thickness was also expressed as the square root wall area of an airway of 10 mm (Pi10) and 15 mm (Pi15) diameter. %Emphysema and %gas trapping were also calculated. Results 2355 subjects in the BDR-group and 1306 in the BDR + group formed our analysis. The BDR + group had a greater Pi10, Pi15, and mean segmental WA% compared to the BDR-group. In multivariate logistic regression using gender, race, current smoking, history of asthma, %emphysema, %gas trapping, %predicted FEV1, and %predicted FVC, airway wall measures remained independent predictors of BDR. Using a threshold change in FEV1 ≥ 15% and FEV1 ≥ 12% and 200 mL to divide patients into groups, the results were similar. Conclusion BDR in COPD is independently associated with CT evidence of airway pathology. This study provides us with greater evidence of changes in lung structure that correlate with physiologic manifestations of airflow obstruction in COPD. PMID:25248436

  14. CXCR4 inhibitor attenuates ovalbumin-induced airway inflammation and hyperresponsiveness by inhibiting Th17 and Tc17 cell immune response

    PubMed Central

    CHEN, HUILONG; XU, XIANGQIN; TENG, JIEMING; CHENG, SHENG; BUNJHOO, HANSVIN; CAO, YONG; LIU, JIN; XIE, JUNGANG; WANG, CONGYI; XU, YONGJIAN; XIONG, WEINING

    2016-01-01

    Accumulating evidence suggests that chemokine (C-X-C motif) ligand 12 (CXCL12) and its receptor chemokine (C-X-C motif) receptor 4 (CXCR4) may contribute to the pathogenesis of allergic asthma. However, the underlying molecular mechanisms remain to be fully understood. T-helper 17 cells (Th17) and T-cytotoxic 17 cells (Tc17) have been implicated in the development of several allergic disorders, including asthma. The present study aimed to explore the association between CXCL12 signaling and Th17/Tc17 cells in the development of asthma. Ovalbumin (OVA)-sensitized BALB/c mice were treated with AMD3100, a specific CXCR4 antagonist, prior to OVA challenge. Following the final allergen (OVA) challenge, airway responsiveness to methacholine, influx of inflammatory cells to the airway, and cytokine levels in the bronchoalveolar lavage fluids (BALF) and lung homogenate were assessed. Interleukin (IL)-17-expressing CD3+CD8− lymphocytes (Th17 cells) and IL-17+CD3+CD8+ lymphocytes (Tc17 cells) isolated from lung tissue samples were detected by flow cytometry. The results of the present study demonstrated that administration of AMD3100 significantly decreased airway responsiveness to methacholine, attenuated the influx of inflammatory cells to the airway and reduced the levels of IL-4, IL-5 and IL-13 in the BALF. Furthermore, AMD3100 significantly reduced the increased number of lung Th17 and Tc17 cells as well as the levels of IL-17 in the lung homogenate induced by OVA challenge. In conclusion, the CXCR4 inhibitor suppresses the asthmatic response, which is associated with attenuation of the Th17 and Tc17 cell immune response. PMID:27168818

  15. ROLE OF NEPRILYSIN IN AIRWAY INFLAMMATION INDUCED BY DIESEL EXHAUST EMISSIONS

    EPA Science Inventory

    The investigators intend to evaluate airway inflammatory responses and expression of the enzyme neprilysin in response to diesel exhaust particle exposure. Dr. Wong and colleagues anticipate that their research will reveal that components of diesel exhaust decrease neprilys...

  16. [Treatment of acute inflammatory pathology of the upper airway with morniflumate].

    PubMed

    Marchioni, C F; Livi, E; Oliani, C; Guerzoni, P; Corona, M

    1990-12-01

    Sixty patients, 33 men and 27 women (mean age about 45 years; range 25-60), affected by acute influenza syndrome of the upper airways were admitted to a controlled single-blind study with three drugs under parallel conditions. According to a balanced randomized sequence, the subjects were treated over a 7-10 day period with morniflumate sachets (700 mg bid) or with tiaprofenic acid sachets (300 mg bid) or with paracetamol (10 ml syrup equivalent to 500 mg tid). The efficacy of the test drugs was assessed by determining the local and general signs and symptoms before starting the treatments, in basal conditions, and on the 3rd, 5th and last day of treatment. At the doses and formulations used, morniflumate proved to be equivalent to paracetamol and more effective than tiaprofenic acid as for its antipyretic action in the first days of treatment. On the other hand, both morniflumate and tiaprofenic acid showed a significantly higher antiinflammatory effect compared to paracetamol. Pain was effectively and equally controlled in all the treatment groups. The drugs administered were generally well tolerated. A greater incidence of adverse GI events was reported in the group treated with tiaprofenic acid. PMID:2132289

  17. Recent insights into the relationship between airway inflammation and asthma.

    PubMed

    Siva, R; Berry, M; Pavord, I D

    2003-01-01

    There have been important recent advances in our understanding of the relationship between eosinophilic airway inflammation and airway dysfunction. Observational studies have shown that eosinophilic airway inflammation is not always present in asthma nor is it an exclusive feature of asthma. Its presence seems to be more closely linked to the presence of corticosteroid responsive airways disease and the occurrence of severe exacerbations than the presence of symptoms or the extent of airway dysfunction--indeed recent evidence suggests that in asthma these features may be more closely linked to the site of localisation of mast cells in the airway wall. One implication of this new understanding of the significance of eosinophilic airway inflammation is that it predicts that measuring airway inflammation might provide information that it is not readily available from a more traditional clinical assessment, and that patients might do better if this information is available. Recent studies support this view, showing a marked reduction in asthma exacerbation in patients with moderate to severe disease who are managed with reference to markers of airway inflammation as well as symptoms and simple tests of airway function. The development of new agents that have the potential to modulate specific aspects of airway inflammation, together with refinements in non-invasive techniques to assess the efficacy of these agents offers the prospect of further refining our understanding of the role of this aspect of the inflammatory response in asthma and other airway diseases. PMID:15148839

  18. Allergic airways disease develops after an increase in allergen capture and processing in the airway mucosa.

    PubMed

    von Garnier, Christophe; Wikstrom, Matthew E; Zosky, Graeme; Turner, Debra J; Sly, Peter D; Smith, Miranda; Thomas, Jennifer A; Judd, Samantha R; Strickland, Deborah H; Holt, Patrick G; Stumbles, Philip A

    2007-11-01

    Airway mucosal dendritic cells (AMDC) and other airway APCs continuously sample inhaled Ags and regulate the nature of any resulting T cell-mediated immune response. Although immunity develops to harmful pathogens, tolerance arises to nonpathogenic Ags in healthy individuals. This homeostasis is thought to be disrupted in allergic respiratory disorders such as allergic asthma, such that a potentially damaging Th2-biased, CD4(+) T cell-mediated inflammatory response develops against intrinsically nonpathogenic allergens. Using a mouse model of experimental allergic airways disease (EAAD), we have investigated the functional changes occurring in AMDC and other airway APC populations during disease onset. Onset of EAAD was characterized by early and transient activation of airway CD4(+) T cells coinciding with up-regulation of CD40 expression exclusively on CD11b(-) AMDC. Concurrent enhanced allergen uptake and processing occurred within all airway APC populations, including B cells, macrophages, and both CD11b(+) and CD11b(-) AMDC subsets. Immune serum transfer into naive animals recapitulated the enhanced allergen uptake observed in airway APC populations and mediated activation of naive allergen-specific, airway CD4(+) T cells following inhaled allergen challenge. These data suggest that the onset of EAAD is initiated by enhanced allergen capture and processing by a number of airway APC populations and that allergen-specific Igs play a role in the conversion of normally quiescent AMDC subsets into those capable of inducing airway CD4(+) T cell activation. PMID:17947647

  19. I-gel Laryngeal Mask Airway Combined with Tracheal Intubation Attenuate Systemic Stress Response in Patients Undergoing Posterior Fossa Surgery

    PubMed Central

    Tang, Chaoliang; Chai, Xiaoqing; Kang, Fang; Huang, Xiang; Hou, Tao; Tang, Fei; Li, Juan

    2015-01-01

    Background. The adverse events induced by intubation and extubation may cause intracranial hemorrhage and increase of intracranial pressure, especially in posterior fossa surgery patients. In this study, we proposed that I-gel combined with tracheal intubation could reduce the stress response of posterior fossa surgery patients. Methods. Sixty-six posterior fossa surgery patients were randomly allocated to receive either tracheal tube intubation (Group TT) or I-gel facilitated endotracheal tube intubation (Group TI). Hemodynamic and respiratory variables, stress and inflammatory response, oxidative stress, anesthesia recovery parameters, and adverse events during emergence were compared. Results. Mean arterial pressure and heart rate were lower in Group TI during intubation and extubation (P < 0.05 versus Group TT). Respiratory variables including peak airway pressure and end-tidal carbon dioxide tension were similar intraoperative, while plasma β-endorphin, cortisol, interleukin-6, tumor necrosis factor-alpha, malondialdehyde concentrations, and blood glucose were significantly lower in Group TI during emergence relative to Group TT. Postoperative bucking and serious hypertensions were seen in Group TT but not in Group TI. Conclusion. Utilization of I-gel combined with endotracheal tube in posterior fossa surgery patients is safe which can yield more stable hemodynamic profile during intubation and emergence and lower inflammatory and oxidative response, leading to uneventful recovery. PMID:26273146

  20. SYNTHETIC PARTICLES ENHANCE AIRWAY RESPONSES TO OVALBUMIN ANTIGEN IN BALB/C MICE

    EPA Science Inventory

    SYNTHETIC PARTICLES ENHANCE AIRWAY RESPONSES TO OVALBUMIN ANTIGEN IN BALB/CJ MICE. S H Gavett, N Haykal-Coates, and M I Gilmour. Experimental Toxicology Division, NHEERL, ORD, USEPA, Research Triangle Park, NC

    Levels of airborne particulate matter (PM) are positively c...

  1. Secretory response induced by essential oils on airway surface fluid: a pharmacological MRI study.

    PubMed

    Nicolato, Elena; Boschi, Federico; Marzola, Pasquina; Sbarbati, Andrea

    2009-07-30

    Using pharmacological magnetic resonance imaging, we have performed an in vivo evaluation of the secretory response induced by essential oils in the rat airway. Aim of the work was to establish a computerized method to assess the efficacy of volatile compounds in spatially localized areas without the bias derived by subjective evaluation. Magnetic resonance experiments were carried out using a 4.7 T horizontal magnet. In the trachea, airway surface fluid was easily identified for its high intensity signal. The tracheal glands were also easily visible. The oesophageal lumen was usually collapsed and was identifiable only in the presence of intraluminal liquid. Scotch pine essential oil inhalation significantly increased the surface fluid in the middle portion of the trachea and the increase was visible at both 5 and 10 min. A lesser secretory response was detected after rosemary essential oil inhalation even though the response was significant with respect to the control in particular at 10 min. No secretory response was detected after peppermint essential oil inhalation both at 5 and 10 min. The data obtained in the present work demonstrate a chemically induced airway secretion. The availability of a pharmacological magnetic resonance imaging approach opens new perspectives to test the action of volatile compounds on the airway. PMID:19422906

  2. SYNTHETIC COPPER-CONTAINING PARTICLES ENHANCE ALLERGIC AIRWAY RESPONSES IN MICE

    EPA Science Inventory

    SYNTHETIC COPPER-CONTAINING PARTICLES ENHANCE ALLERGIC AIRWAY RESPONSES IN MICE. SH Gavett, MI Gilmour, and N Haykal-Coates. National Health and Environ Effects Research Lab, USEPA, Res Triangle Park, NC USA
    Respiratory morbidity and mortality associated with increases in ...

  3. Preexposure to ozone blocks the antigen-induced late asthmatic response of the canine peripheral airways

    SciTech Connect

    Turner, C.R.; Kleeberger, S.R.; Spannhake, E.W. )

    1989-01-01

    The influence of exposure of the airways to ozone on acute allergic responsiveness has been investigated in several species. Little is known, however, about the effect of this environmental pollutant on the late asthmatic response (LAR) in animals in which it is exhibited. The purpose of this study was to evaluate this effect in the canine peripheral airways and to assess the potential role of mast cells in modulating the effect. A series of experiments on seven mongrel dogs demonstrated that the numbers of mast cells at the base of the epithelial region of small subsegmental airways exposed to 1 ppm ozone for 5 min were significantly (p less than .01) increased 3 h following exposure compared to air exposed or nonexposed control airways. In a second series of experiments performed on eight additional mongrel dogs with inherent sensitivity to Ascaris suum antigen, antigen aerosol was administered to the sublobar segment 3 h following ozone preexposure when mast cell numbers were presumed to be increased. These experiments were performed to determine whether ozone preexposure could enhance the late-phase response to antigen by virtue of acutely increasing the number of mast cells available to bind the antigen. Four of the eight dogs tested displayed a late-phase response to antigen following air-sham preexposure. In these four dogs, simultaneous ozone preexposure of a contralateral lobe completely blocked the late-phase response to antigen. These results indicate that the consequences of a single exposure to ozone persist beyond its effects on acute antigen-induced bronchoconstriction and extend to the complex processes involved with the late response. This attenuating effect of ozone is seen under conditions where mast-cell numbers in the airways are increased above baseline levels.

  4. Effect of thromboxane antagonists on ozone-induced airway responses in dogs

    SciTech Connect

    Jones, G.L.; Lane, C.G.; O'Byrne, P.M. )

    1990-09-01

    Airway hyperresponsiveness after inhaled ozone in dogs may occur as a result of thromboxane release in the airway. In this study, two thromboxane receptor antagonists, L-655,240 and L-670,596, were used in doses that inhibit the response to an inhaled thromboxane mimetic, U-46619, to determine further the role of thromboxane in ozone-induced airway hyperresponsiveness. Dogs were studied on 2 days separated by 1 wk. On each day, the dogs inhaled ozone (3 ppm) for 30 min. On one randomly assigned day, 10 dogs received an infusion of L-655,240 (5 mg.kg-1.h-1) and 5 dogs received an infusion of L-670,596 (1 mg.kg-1.h-1); on the other day dogs received a control infusion. Airway responses to doubling doses of acetylcholine were measured before and after inhalation of ozone and were expressed as the concentration of acetylcholine giving a rise in resistance of 5 cmH2O.l-1.s from baseline (acetylcholine provocation concentration). The development of airway hyperresponsiveness after ozone was not inhibited by the thromboxane antagonists. The mean log difference in the acetylcholine provocative concentration before and after ozone on the L-655,240 treatment day was 0.62 +/- 0.12 (SE) and on the control day was 0.71 +/- 0.12 (P = 0.48); on the L-670,596 treatment day the mean log difference was 0.68 +/- 0.15 (SE) and on the control day it was 0.75 +/- 0.19 (P = 0.45). These results do not support an important role for thromboxane in causing ozone-induced airway hyperresponsiveness.

  5. Bronchoconstriction and airway biology: potential impact and therapeutic opportunities.

    PubMed

    Gosens, Reinoud; Grainge, Chris

    2015-03-01

    Recent work has demonstrated that mechanical forces occurring in the airway as a consequence of bronchoconstriction are sufficient to not only induce symptoms but also influence airway biology. Animal and human in vitro and in vivo work demonstrates that the airways are structurally and functionally altered by mechanical stress induced by bronchoconstriction. Compression of the airway epithelium and mechanosensing by the airway smooth muscle trigger the activation and release of growth factors, causing cell proliferation, extracellular matrix protein accumulation, and goblet cell differentiation. These effects of bronchoconstriction are of major importance to asthma pathophysiology and appear sufficient to induce remodeling independent of the inflammatory response. We review these findings in detail and discuss previous studies in light of this new evidence regarding the influence of mechanical forces in the airways. Furthermore, we highlight potential impacts of therapies influencing mechanical forces on airway structure and function in asthma. PMID:25732446

  6. Ventilatory response to helium-oxygen breathing during exercise: effect of airway anesthesia.

    PubMed

    Krishnan, B S; Clemens, R E; Zintel, T A; Stockwell, M J; Gallagher, C G

    1997-07-01

    The substitution of a normoxic helium mixture (HeO2) for room air (Air) during exercise results in a sustained hyperventilation, which is present even in the first breath. We hypothesized that this response is dependent on intact airway afferents; if so, airway anesthesia (Anesthesia) should affect this response. Anesthesia was administered to the upper airways by topical application and to lower central airways by aerosol inhalation and was confirmed to be effective for over 15 min. Subjects performed constant work-rate exercise (CWE) at 69 +/- 2 (SE) % maximal work rate on a cycle ergometer on three separate days: twice after saline inhalation (days 1 and 3) and once after Anesthesia (day 2). CWE commenced after a brief warm-up, with subjects breathing Air for the first 5 min (Air-1), HeO2 for the next 3 min, and Air again until the end of CWE (Air-2). The resistance of the breathing circuit was matched for Air and HeO2. Breathing HeO2 resulted in a small but significant increase in minute ventilation (VI) and decrease in alveolar PCO2 in both the Saline (average of 2 saline tests; not significant) and Anesthesia tests. Although Anesthesia had no effect on the sustained hyperventilatory response to HeO2 breathing, the VI transients within the first six breaths of HeO2 were significantly attenuated with Anesthesia. We conclude that the VI response to HeO2 is not simply due to a reduction in external tubing resistance and that, in humans, airway afferents mediate the transient but not the sustained hyperventilatory response to HeO2 breathing during exercise. PMID:9216948

  7. Dendritic cell-derived tumor necrosis factor α modifies airway epithelial cell responses.

    PubMed

    Lutfi, R; Ledford, J R; Zhou, P; Lewkowich, I P; Page, K

    2012-01-01

    Mucosal dendritic cells (DC) are intimately associated with the airway epithelium and thus are ideally situated to be first responders to pathogens. We hypothesize that DC drive innate immune responses through early release of tumor necrosis factor (TNF) α, which drives airway epithelial cell responses. In a mouse model, TNFα release was significantly increased following a single exposure to German cockroach (GC) frass, an event independent of neutrophil recruitment into the airways. While lung epithelial cells and alveolar macrophages failed to release TNFα following GC frass exposure, bone marrow-derived DC (BMDC) produced substantial amounts of TNFα suggesting their importance as early responding cells. This was confirmed by flow cytometry of pulmonary myeloid DC. Addition of GC frass-pulsed BMDC or conditioned media from GC frass-pulsed BMDC to primary mouse tracheal epithelial cells (MTEC) or MLE-15 cells induced chemokine (C-C) motif ligand (CCL) 20 and granulocyte macrophage (GM) colony-stimulating factor (CSF), both of which are important for DC recruitment, survival and differentiation. Importantly, DC do not produce CCL20 or GM-CSF following allergen exposure. Blocking TNFα receptor 1 (TNFR1) completely abolished chemokine production, suggesting that BMDC-derived TNFα induced airway epithelial cell activation and enhancement of the innate immune response. Lastly, blocking TNFR1 in vivo resulted in significantly decreased CCL20 and GM-CSF production in the lungs of mice. Together, our data strongly suggest that DC-derived TNFα plays a crucial role in the initiation of innate immune responses through the modification of airway epithelial cell responses. PMID:22517116

  8. Airway irritation and cough evoked by acid: from human to ion channel

    PubMed Central

    Gu, Qihai; Lee, Lu-Yuan

    2011-01-01

    Inhalation or aspiration of acid solution evokes airway defense responses such as cough and reflex bronchoconstriction, resulting from activation of vagal bronchopulmonary C-fibers and Aδ afferents. The stimulatory effect of hydrogen ion on these sensory nerves is generated by activation of two major types of ion channels expressed in these neurons: a rapidly activating and inactivating current mediated through ASICs, and a slow sustaining current via activation of TRPV1. Recent studies have shown that these acid-evoked responses are elevated during airway inflammatory reaction, revealing the potential convergence of a wide array of inflammatory signaling on these ion channels. Since pH in the airway fluid drops substantially in patients with inflammatory airway diseases, these heightened stimulatory effects of acid on airway sensory nerves may play a part in the manifestation of airway irritation and excessive cough under those pathophysiological conditions. PMID:21543258

  9. Differential effects of endogenous and exogenous interferon-gamma on immunoglobulin E, cellular infiltration, and airway responsiveness in a murine model of allergic asthma.

    PubMed

    Hofstra, C L; Van Ark, I; Hofman, G; Nijkamp, F P; Jardieu, P M; Van Oosterhout, A J

    1998-11-01

    The inflammatory response as seen in human allergic asthma is thought to be regulated by Th2 cells. It has been shown that interferon-gamma (IFN-gamma) can downregulate the proliferation of Th2 cells and therefore might be of therapeutic use. In the present study we have investigated the in vivo role of endogenous and exogenous IFN-gamma in a murine model with features reminiscent of human allergic asthma. IFN-gamma gene knockout (GKO) and wild-type mice were sensitized with ovalbumin and exposed to repeated ovalbumin aerosol challenges. In addition, wild-type mice were treated with intraperitoneal or nebulized recombinant murine IFN-gamma during the challenge period. Sensitized wild-type mice exhibited upregulated ovalbumin-specific IgE in serum, and airway hyperresponsiveness and infiltration of eosinophils and mononuclear cells in the bronchoalveolar lavage fluid (BALF) after ovalbumin challenge. In contrast, in GKO mice only reduced eosinophilic infiltration in the BALF was observed after ovalbumin challenge. In wild-type mice, parenteral IFN-gamma treatment downregulated ovalbumin-specific IgE levels in serum, and airway hyperresponsiveness and cellular infiltration in the BALF, whereas aerosolized IFN-gamma treatment only suppressed airway hyperresponsiveness. In vitro experiments showed that these effects of IFN-gamma appear not to be mediated via a direct effect on the cytokine production of antigen-specific Th2 cells. These data indicate that airway hyperresponsiveness can be downregulated by IFN-gamma locally in the airways, whereas for downregulation of IgE and cellular infiltration systemic IFN-gamma is needed. The present study shows that exogenous IFN-gamma can downregulate the allergic response via an antigen-specific T-cell independent mechanism, but at the same time endogenous IFN-gamma plays a role in an optimal response. PMID:9806748

  10. Anti-Inflammatory Activity of a Novel Family of Aryl Ureas Compounds in an Endotoxin-Induced Airway Epithelial Cell Injury Model

    PubMed Central

    Cabrera-Benitez, Nuria E.; Pérez-Roth, Eduardo; Casula, Milena; Ramos-Nuez, Ángela; Ríos-Luci, Carla; Rodríguez-Gallego, Carlos; Sologuren, Ithaisa; Jakubkiene, Virginija; Slutsky, Arthur S.; Padrón, José M.; Villar, Jesús

    2012-01-01

    Background Despite our increased understanding of the mechanisms involved in acute lung injury (ALI) and the acute respiratory distress syndrome (ARDS), there is no specific pharmacological treatment of proven benefit. We used a novel screening methodology to examine potential anti-inflammatory effects of a small structure-focused library of synthetic carbamate and urea derivatives in a well established cell model of lipopolysaccharide (LPS)-induced ALI/ARDS. Methodology/Principal Findings After a pilot study to develop an in vitro LPS-induced airway epithelial cell injury model, a library of synthetic carbamate and urea derivates was screened against representative panels of human solid tumor cell lines and bacterial and fungal strains. Molecules that were non-cytotoxic and were inactive in terms of antiproliferative and antimicrobial activities were selected to study the effects on LPS-induced inflammatory response in an in vitro cell culture model using A549 human alveolar and BEAS-2B human bronchial cells. These cells were exposed for 18 h to LPS obtained from Escherichia coli, either alone or in combination with the test compounds. The LPS antagonists rhein and emodin were used as reference compounds. The most active compound (CKT0103) was selected as the lead compound and the impact of CKT0103 on pro-inflammatory IL-6 and IL-8 cytokine levels, expression of toll-like receptor-4 (TLR4) and nuclear factor kappa B inhibitor alpha (IκBα) was measured. CKT0103 significantly inhibited the synthesis and release of IL-6 and IL-8 induced by LPS. This suppression was associated with inhibition of TLR4 up-regulation and IκBα down-regulation. Immunocytochemical staining for TLR4 and IκBα supported these findings. Conclusions/Significance Using a novel screening methodology, we identified a compound – CKT0103 – with potent anti-inflammatory effects. These findings suggest that CKT0103 is a potential target for the treatment of the acute phase of sepsis and

  11. Macrophage Expression of Inflammatory Genes in Response to EMCV Infection

    PubMed Central

    Shaheen, Zachary R.; Corbett, John A.

    2015-01-01

    The expression and production of type 1 interferon is the classic cellular response to virus infection. In addition to this antiviral response, virus infection also stimulates the production of proinflammatory mediators. In this review, the pathways controlling the induction of inflammatory genes and the roles that these inflammatory mediators contribute to host defense against viral pathogens will be discussed. Specific focus will be on the role of the chemokine receptor CCR5, as a signaling receptor controlling the activation of pathways leading to virus-induced inflammatory gene expression. PMID:26295266

  12. The systemic inflammatory response in heart failure.

    PubMed

    Anderson

    2000-09-01

    The physiologic diagnosis of heart failure has changed very little over the past several decades: heart failure is the inability of the cardiac output to meet the metabolic demands of the organism. The clinical definition of heart failure (also relatively unchanged) describes it as ventricular dysfunction that is accompanied by reduced exercise tolerance. Our understanding of the true pathophysiologic processes involved in heart failure have, however, changed. We have moved from thinking of heart failure as primarily a circulatory phenomenon to seeing it as a pathophysiologic state under the control of multiple complex systems. Over the past several years the dramatic explosion of research in the fields of immunology and immunopathology have added an additional piece to the puzzle that defines heart failure and have lead to an understanding of heart failure, at least in some part, as an 'inflammatory disease'. In this review we will examine several of the key inflammatory mediators as they relate to heart failure while at the same time attempting to define the source(s) of these mediators. We will examine key elements of the inflammatory cascade as they relate to heart failure such as: cytokines, 'proximal mediators' (e.g. NF-kappaB), and distal mediators (e.g. nitric oxide). We will end with a discussion of the potential therapeutic role of anti-inflammatory strategies in the future treatment of heart failure. Also, throughout the review we will examine the potential pitfalls encountered in applying bench discoveries to the bedside as have been learned in the field of septic shock research. PMID:10978715

  13. The Endogenous Th17 Response in NO2-Promoted Allergic Airway Disease Is Dispensable for Airway Hyperresponsiveness and Distinct from Th17 Adoptive Transfer

    PubMed Central

    Martin, Rebecca A.; Ather, Jennifer L.; Daggett, Rebecca; Hoyt, Laura; Alcorn, John F.; Suratt, Benjamin T.; Weiss, Daniel J.; Lundblad, Lennart K. A.; Poynter, Matthew E.

    2013-01-01

    Severe, glucocorticoid-resistant asthma comprises 5-7% of patients with asthma. IL-17 is a biomarker of severe asthma, and the adoptive transfer of Th17 cells in mice is sufficient to induce glucocorticoid-resistant allergic airway disease. Nitrogen dioxide (NO2) is an environmental toxin that correlates with asthma severity, exacerbation, and risk of adverse outcomes. Mice that are allergically sensitized to the antigen ovalbumin by exposure to NO2 exhibit a mixed Th2/Th17 adaptive immune response and eosinophil and neutrophil recruitment to the airway following antigen challenge, a phenotype reminiscent of severe clinical asthma. Because IL-1 receptor (IL-1R) signaling is critical in the generation of the Th17 response in vivo, we hypothesized that the IL-1R/Th17 axis contributes to pulmonary inflammation and airway hyperresponsiveness (AHR) in NO2-promoted allergic airway disease and manifests in glucocorticoid-resistant cytokine production. IL-17A neutralization at the time of antigen challenge or genetic deficiency in IL-1R resulted in decreased neutrophil recruitment to the airway following antigen challenge but did not protect against the development of AHR. Instead, IL-1R-/- mice developed exacerbated AHR compared to WT mice. Lung cells from NO2-allergically inflamed mice that were treated in vitro with dexamethasone (Dex) during antigen restimulation exhibited reduced Th17 cytokine production, whereas Th17 cytokine production by lung cells from recipient mice of in vitro Th17-polarized OTII T-cells was resistant to Dex. These results demonstrate that the IL-1R/Th17 axis does not contribute to AHR development in NO2-promoted allergic airway disease, that Th17 adoptive transfer does not necessarily reflect an endogenously-generated Th17 response, and that functions of Th17 responses are contingent on the experimental conditions in which they are generated. PMID:24069338

  14. 1,25-Dihydroxyvitamin D Modulates Antibacterial and Inflammatory Response in Human Cigarette Smoke-Exposed Macrophages

    PubMed Central

    Heulens, Nele; Korf, Hannelie; Mathyssen, Carolien; Everaerts, Stephanie; De Smidt, Elien; Dooms, Christophe; Yserbyt, Jonas; Gysemans, Conny; Gayan-Ramirez, Ghislaine; Mathieu, Chantal; Janssens, Wim

    2016-01-01

    Cigarette smoking is associated with increased inflammation and defective antibacterial responses in the airways. Interestingly, vitamin D has been shown to suppress inflammation and to improve antibacterial defense. However, it is currently unknown whether vitamin D may modulate inflammation and antibacterial defects in human cigarette smoke (CS)-exposed airways. To explore these unresolved issues, alveolar macrophages obtained from non-smoking and smoking subjects as well as human cigarette smoke extract (CSE)-treated THP-1 macrophages were stimulated with 1,25-dihydroxyvitamin D (1,25(OH)2D) to address inflammatory and antibacterial responses. Although basal levels of inflammatory cytokines and chemokines did not differ between non-smoking and smoking subjects, 1,25(OH)2D did reduce levels of IL-6, TNF-α and MCP-1 in alveolar macrophages in response to LPS/IFN-γ, although not statistically significant for TNF-α and IL-6 in smokers. CSE did not significantly alter vitamin D metabolism (expression levels of CYP24A1 or CYP27B1) in THP-1 macrophages. Furthermore, stimulation with 1,25(OH)2D reduced mRNA expression levels and/or protein levels of IL-8, TNF-α and MCP-1 in CSE-treated THP-1 macrophages. 1,25(OH)2D did not improve defects in phagocytosis of E. coli bacteria or the oxidative burst response in CSE-treated THP-1 macrophages or alveolar macrophages from smokers. However, 1,25(OH)2D significantly enhanced mRNA expression and/or protein levels of the antimicrobial peptide cathelicidin in alveolar macrophages and THP-1 macrophages, independently of CS exposure. In conclusion, our results provide the first evidence that vitamin D could be a new strategy for attenuating airway inflammation and improving antibacterial defense in CS-exposed airways. PMID:27513734

  15. Resolvin D1 Attenuates Poly(I:C)-Induced Inflammatory Signaling in Human Airway Epithelial Cells via TAK1

    PubMed Central

    Hsiao, Hsi-Min; Thatcher, Thomas H.; Levy, Elizabeth P.; Fulton, Robert A.; Owens, Kristina M.; Phipps, Richard P.; Sime, Patricia J.

    2014-01-01

    The respiratory epithelium are lung sentinel cells and are the first to contact inhaled inflammatory insults including air pollutants, smoke and microorganisms. To avoid damaging exuberant or chronic inflammation, the inflammatory process must be tightly controlled and terminated once the insult is mitigated. Inflammation-resolution is now known to be an active process involving a new genus of lipid mediators called “specialized pro-resolving lipid mediators” (SPMs) that includes resolvin D1 (RvD1). We and others have reported that RvD1 counteracts pro-inflammatory signaling and promotes resolution. A knowledge gap is that the specific cellular targets and mechanisms of action for RvD1 remain largely unknown. Here, we identified the mechanism whereby RvD1 disrupts inflammatory mediator production induced by the viral mimic poly(I:C) in primary human lung epithelial cells. RvD1 strongly suppressed the viral mimic poly(I:C)-induced IL-6 and IL-8 production and pro-inflammatory signaling involving MAP kinases and NF-κB. Most importantly, we found that RvD1 inhibited the phosphorylation of TAK1, a key upstream regulatory kinase common to both the MAP kinase and NF-κB pathways, by inhibiting the formation of a poly(I:C)-induced signaling complex composed of TAK1, TAB1 and TRAF6. We confirmed that ALX/FPR2 and GPR32, two RvD1 receptors, were expressed on hSAEC. Furthermore, blocking these receptors abrogated the inhibitory action of RvD1. Herein, we present the idea that RvD1 has the potential to be used as an anti-inflammatory and pro-resolving agent, possibly in the context of exuberant host responses to damaging respirable agents such as viruses. PMID:25320283

  16. Involvement of Endoplasmic Reticulum Stress Response in Orofacial Inflammatory Pain

    PubMed Central

    Yang, Eun Sun; Bae, Jin Young; Kim, Tae Heon; Kim, Yun Sook; Suk, Kyoungho

    2014-01-01

    Endoplasmic reticulum (ER) stress is involved in many neurological diseases and inflammatory responses. Inflammatory mediators induce neuronal damage and trigger the neuropathic or inflammatory pain. But there is very little data on the role of the ER stress response in pain mechanisms. In this study, we explored whether the ER stress response is involved in orofacial inflammatory pain by using a complete Freund's adjuvant (CFA)-injected rat model. The thermal pain hypersensitivity increased significantly after CFA injection. We found that the protein and mRNA levels of ER stress response genes, GRP78/Bip and p-eIF2α, increased significantly in trigeminal ganglion (TG) of CFA-injected rats compared to control animals. In immunofluorescence analysis, a significant increase of GRP78 and p-eIF2α immunopositive neurons was observed in CFA-injected TG compared to control TG. When we administered an ER stress modulator, salubrinal, CFA-induced thermal pain hypersensitivity was temporally reduced. Thus, our study suggests that ER stress responses in TG neurons contribute to CFA-induced inflammatory pain, and may comprise an important molecular mechanism underlying the orofacial inflammatory pain pathway. PMID:25548537

  17. Innate Immune Response to LPS in Airway Epithelium Is Dependent on Chronological Age and Antecedent Exposures

    PubMed Central

    Maniar-Hew, Kinjal; Clay, Candice C.; Postlethwait, Edward M.; Evans, Michael J.; Fontaine, Justin H.

    2013-01-01

    The immune mechanisms for neonatal susceptibility to respiratory pathogens are poorly understood. Given that mucosal surfaces serve as a first line of host defense, we hypothesized that the innate immune response to infectious agents may be developmentally regulated in airway epithelium. To test this hypothesis, we determined whether the expression of IL-8 and IL-6 in airway epithelium after LPS exposure is dependent on chronological age. Tracheas from infant, juvenile, and adult rhesus monkeys were first exposed to LPS ex vivo, and then processed for air–liquid interface primary airway epithelial cell cultures and secondary LPS treatment in vitro. Compared with adult cultures, infant and juvenile cultures expressed significantly reduced concentrations of IL-8 after LPS treatment. IL-8 protein in cultures increased with animal age, whereas LPS-induced IL-6 protein was predominantly associated with juvenile cultures. Toll-like receptor (TLR) pathway RT-PCR arrays showed differential expressions of multiple mRNAs in infant cultures relative to adult cultures, including IL-1α, TLR10, and the peptidoglycan recognition protein PGLYRP2. To determine whether the age-dependent cytokine response to LPS is reflective of antecedent exposures, we assessed primary airway epithelial cell cultures established from juvenile monkeys housed in filtered air since birth. Filtered air–housed animal cultures exhibited LPS-induced IL-8 and IL-6 expression that was discordant with age-matched ambient air–housed animals. A single LPS aerosol in vivo also affected this cytokine profile. Cumulatively, our findings demonstrate that the innate immune response to LPS in airway epithelium is variable with age, and may be modulated by previous environmental exposures. PMID:23600597

  18. Signalling pathways mediating inflammatory responses in brain ischaemia.

    PubMed

    Planas, A M; Gorina, R; Chamorro, A

    2006-12-01

    Stroke causes neuronal necrosis and generates inflammation. Pro-inflammatory molecules intervene in this process by triggering glial cell activation and leucocyte infiltration to the injured tissue. Cytokines are major mediators of the inflammatory response. Pro-inflammatory and anti-inflammatory cytokines are released in the ischaemic brain. Anti-inflammatory cytokines, such as interleukin-10, promote cell survival, whereas pro-inflammatory cytokines, such as TNFalpha (tumour necrosis factor alpha), can induce cell death. However, deleterious effects of certain cytokines can turn to beneficial actions, depending on particular features such as the concentration, time point and the very intricate network of intracellular signals that become activated and interact. A key player in the intracellular response to cytokines is the JAK (Janus kinase)/STAT (signal transducer and activator of transcription) pathway that induces alterations in the pattern of gene transcription. These changes are associated either with cell death or survival depending, among other things, on the specific proteins involved. STAT1 activation is related to cell death, whereas STAT3 activation is often associated with survival. Yet, it is clear that STAT activation must be tightly controlled, and for this reason the function of JAK/STAT modulators, such as SOCS (suppressors of cytokine signalling) and PIAS (protein inhibitor of activated STAT), and phosphatases is most relevant. Besides local effects in the ischaemic brain, cytokines are released to the circulation and affect the immune system. Unbalanced pro-inflammatory and anti-inflammatory plasma cytokine concentrations favouring an 'anti-inflammatory' state can decrease the immune response. Robust evidence now supports that stroke can induce an immunodepression syndrome, increasing the risk of infection. The contribution of individual cytokines and their intracellular signalling pathways to this response needs to be further investigated

  19. Silibinin attenuates allergic airway inflammation in mice

    SciTech Connect

    Choi, Yun Ho; Jin, Guang Yu; Guo, Hui Shu; Piao, Hong Mei; Li, Liang chang; Li, Guang Zhao; Lin, Zhen Hua; Yan, Guang Hai

    2012-10-26

    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 pathogenesis 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.

  20. Transient receptor potential A1 channels: insights into cough and airway inflammatory disease.

    PubMed

    Belvisi, Maria G; Dubuis, Eric; Birrell, Mark A

    2011-10-01

    Cough is a common symptom of diseases such as asthma and COPD and also presents as a disease in its own right. Treatment options are limited; a recent meta-analysis concluded that over-the-counter remedies are ineffective, and there is increasing concern about their use in children. Transient receptor potential cation channel, subfamily A, member 1 (TRPA1) channels are nonselective cation channels that are activated by a range of natural products (eg, allyl isothiocyanate), a multitude of environmental irritants (eg, acrolein, which is present in air pollution, vehicle exhaust, and cigarette smoke), and inflammatory mediators (eg, cyclopentenone prostaglandins). TRPA1 is primarily expressed in small-diameter, nociceptive neurons where its activation probably contributes to the perception of noxious stimuli. Inhalational exposure to irritating gases, fumes, dusts, vapors, chemicals, and endogenous mediators can lead to the development of cough. The respiratory tract is innervated by primary sensory afferent nerves, which are activated by mechanical and chemical stimuli. Recent data suggest that activation of TRPA1 on these vagal sensory afferents by these irritant substances could lead to central reflexes, including dyspnea, changes in breathing pattern, and cough, which contribute to the symptoms and pathophysiology of respiratory diseases. PMID:21972382

  1. Chronic low level arsenic exposure evokes inflammatory responses and DNA damage.

    PubMed

    Dutta, Kaustav; Prasad, Priyanka; Sinha, Dona

    2015-08-01

    The cross-sectional study investigated the impact of chronic low level arsenic (As) exposure (11-50μg/L) on CD14 expression and other inflammatory responses in rural women of West Bengal enrolled from control (As level <10μg/L; N, 131) and exposed area (As level 11-50μg/L, N, 142). Atomic absorption spectroscopy revealed that As level in groundwater was higher in endemic areas (22.93±10. 1 vs. 1.61±0.15, P<0.0001) and showed a positive correlation [Pearsons r, 0.9281; 95% confidence interval, 0.8192-0.9724] with As content in nails of the exposed women. Flow cytometric analysis showed that CD 14 expression on monocytes was significantly higher (P<0.001) in exposed women and positively correlated with groundwater As [Pearsons r, 0.9191; 95% confidence interval, 0.7584-0.9745]. Leucocytes and airway cells of As exposed women exhibited up regulation of an inflammatory mediator, tumor necrosis factor-α (TNF-α) and transcription factor, nuclear factor-κB (NF-κB) (P<0.0001). Plasma pro inflammatory cytokines like - TNF-α, interleukins (ILs) - IL-6, IL-8, IL-12 were elevated whereas anti-inflammatory cytokine IL-10 was depleted in the exposed women. Sputa of the exposed women had elevated activity of inflammatory markers - MMP-2 and MMP-9 whereas sera were observed with only increased activity of MMP-9. Airway cells of the exposed women had exacerbated DNA damage than control. Level of oxidative DNA adducts like 8-hydroxy-2'-deoxyguanosine (8OHdG) were also enhanced in plasma of exposed women. Therefore it might be indicated that low level As exposure elicited a pro-inflammatory profile which might have been contributed in part by CD14 expressing monocytes and prolong persistence of pulmonary and systemic inflammation might have promoted oxidative DNA damage in the rural women. PMID:26118750

  2. Local inflammatory response in colorectal cancer.

    PubMed

    Łaskowski, P; Klim, B; Ostrowski, K; Szkudlarek, M; Litwiejko-Pietryńczak, E; Kitlas, K; Nienartowicz, S; Dzięcioł, J

    2016-06-01

    Type and intensity of tumor-infiltrating lymphocytes (TILs) in close proximity to the primary tumor are prognostically significant in postoperative patients. High intensity of TILs is considered to be a prognostically beneficial factor. The research included 66 postoperative colorectal cancer patients. The control group comprised 20 colon segments. Monoclonal antibodies LCA, CD3, CD4, CD5, CD8, CD20, CD23 and CD138 were used to differentiate between T and B lymphocytes. Types of cells in the infiltrate were defined. We found greater numbers of T and B lymphocytes located in close proximity to the cancerous tissue when compared to the control group. T lymphocyte intensity in the inflammatory infiltrations was directly correlated with the size of resected tumors, presence of regional lymphatic node metastases and histological grade of malignancy. Lymphocytic infiltrations of greater intensity located in close proximity to the primary tumor were found in subjects with less advanced colorectal cancer. The research presented here proves direct dependence between the immune system and colorectal cancer. The presence of lymphocytes in the inflammatory infiltrations located in close proximity to the cancerous tissue has been proved to be prognostically beneficial. The obtained results support the application of immunotherapy in colorectal cancer treatment. PMID:27543872

  3. Erythrocyte deformability - A partner of the inflammatory response.

    PubMed

    Silva-Herdade, Ana Santos; Andolina, Giulia; Faggio, Caterina; Calado, Ângelo; Saldanha, Carlota

    2016-09-01

    We aim to establish an in vivo animal model of acute inflammation using PAF (platelet activating factor) as inflammatory agent and to study the erythrocyte deformability changes induced by the inflammatory response. Counting the number of rolling and adherent neutrophils to endothelium after 2, 4 and 6h of intrascrotal injection of PAF we showed the induction of an inflammatory state. Blood samples are collected in order to measure the erythrocyte deformability and to quantify NO efflux from the red blood cells (RBCs). The results show an increased number of rolling and adherent neutrophils after 2h and 4h of inflammation as well as decreased values of erythrocyte deformability in the same time-points. This result is in line with the need of a low blood viscosity to the recruitment process that will improve leukocyte migration towards the endothelial wall. NO efflux from RBCs is also affected by the inflammatory response at the first hours of inflammation. This animal model demonstrates in vivo the association between an acute inflammatory response and the rheological properties of the blood, namely the RBCs deformability. For those reasons we consider this as an adequate model to study acute inflammatory responses as well as hemorheological parameters. PMID:27142964

  4. Protease inhibitor reduces airway response and underlying inflammation in cockroach allergen-induced murine model.

    PubMed

    Saw, Sanjay; Arora, Naveen

    2015-04-01

    Protease(s) enhances airway inflammation and allergic cascade. In the present study, effect of a serine protease inhibitor was evaluated in mouse model of airway disease. Mice were sensitized with cockroach extract (CE) or Per a 10 and treated with 4-(2-aminoethyl) benzenesulfonyl fluoride hydrochloride (AEBSF) 1 h before or after challenge to measure airway response. Mice were euthanized to collect bronchoalveolar lavage fluid (BALF), blood, and lung to evaluate inflammation. AEBSF treatment significantly reduced the AHR in allergen-challenged mice in dose-dependent manner (p≤ 0.01). IgE (p≤0.05) and Th2 cytokines (p≤0.05) were significantly reduced in treated mice. AEBSF treatment lowered total cell (p≤0.05), eosinophil (p≤0.05), and neutrophil (p≤0.05) in BALF and lung tissue. Oxidative stress parameters were impaired on treatment in allergen-challenged mice (p≤0.05). AEBSF had therapeutic effect in allergen-induced airway resistance and underling inflammation and had potential for combination or as add-on therapy for respiratory diseases. PMID:25052477

  5. Airway smooth muscle in airway reactivity and remodeling: what have we learned?

    PubMed Central

    2013-01-01

    It is now established that airway smooth muscle (ASM) has roles in determining airway structure and function, well beyond that as the major contractile element. Indeed, changes in ASM function are central to the manifestation of allergic, inflammatory, and fibrotic airway diseases in both children and adults, as well as to airway responses to local and environmental exposures. Emerging evidence points to novel signaling mechanisms within ASM cells of different species that serve to control diverse features, including 1) [Ca2+]i contractility and relaxation, 2) cell proliferation and apoptosis, 3) production and modulation of extracellular components, and 4) release of pro- vs. anti-inflammatory mediators and factors that regulate immunity as well as the function of other airway cell types, such as epithelium, fibroblasts, and nerves. These diverse effects of ASM “activity” result in modulation of bronchoconstriction vs. bronchodilation relevant to airway hyperresponsiveness, airway thickening, and fibrosis that influence compliance. This perspective highlights recent discoveries that reveal the central role of ASM in this regard and helps set the stage for future research toward understanding the pathways regulating ASM and, in turn, the influence of ASM on airway structure and function. Such exploration is key to development of novel therapeutic strategies that influence the pathophysiology of diseases such as asthma, chronic obstructive pulmonary disease, and pulmonary fibrosis. PMID:24142517

  6. Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin

    NASA Astrophysics Data System (ADS)

    Borovikova, Lyudmila V.; Ivanova, Svetlana; Zhang, Minghuang; Yang, Huan; Botchkina, Galina I.; Watkins, Linda R.; Wang, Haichao; Abumrad, Naji; Eaton, John W.; Tracey, Kevin J.

    2000-05-01

    Vertebrates achieve internal homeostasis during infection or injury by balancing the activities of proinflammatory and anti-inflammatory pathways. Endotoxin (lipopolysaccharide), produced by all gram-negative bacteria, activates macrophages to release cytokines that are potentially lethal. The central nervous system regulates systemic inflammatory responses to endotoxin through humoral mechanisms. Activation of afferent vagus nerve fibres by endotoxin or cytokines stimulates hypothalamic-pituitary-adrenal anti-inflammatory responses. However, comparatively little is known about the role of efferent vagus nerve signalling in modulating inflammation. Here, we describe a previously unrecognized, parasympathetic anti-inflammatory pathway by which the brain modulates systemic inflammatory responses to endotoxin. Acetylcholine, the principle vagal neurotransmitter, significantly attenuated the release of cytokines (tumour necrosis factor (TNF), interleukin (IL)-1β, IL-6 and IL-18), but not the anti-inflammatory cytokine IL-10, in lipopolysaccharide-stimulated human macrophage cultures. Direct electrical stimulation of the peripheral vagus nerve in vivo during lethal endotoxaemia in rats inhibited TNF synthesis in liver, attenuated peak serum TNF amounts, and prevented the development of shock.

  7. Airway uric acid is a sensor of inhaled protease allergens and initiates type 2 immune responses in respiratory mucosa.

    PubMed

    Hara, Kenichiro; Iijima, Koji; Elias, Martha K; Seno, Satoshi; Tojima, Ichiro; Kobayashi, Takao; Kephart, Gail M; Kurabayashi, Masahiko; Kita, Hirohito

    2014-05-01

    Although type 2 immune responses to environmental Ags are thought to play pivotal roles in asthma and allergic airway diseases, the immunological mechanisms that initiate the responses are largely unknown. Many allergens have biologic activities, including enzymatic activities and abilities to engage innate pattern-recognition receptors such as TLR4. In this article, we report that IL-33 and thymic stromal lymphopoietin were produced quickly in the lungs of naive mice exposed to cysteine proteases, such as bromelain and papain, as a model for allergens. IL-33 and thymic stromal lymphopoietin sensitized naive animals to an innocuous airway Ag OVA, which resulted in production of type 2 cytokines and IgE Ab, and eosinophilic airway inflammation when mice were challenged with the same Ag. Importantly, upon exposure to proteases, uric acid (UA) was rapidly released into the airway lumen, and removal of this endogenous UA by uricase prevented type 2 immune responses. UA promoted secretion of IL-33 by airway epithelial cells in vitro, and administration of UA into the airways of naive animals induced extracellular release of IL-33, followed by both innate and adaptive type 2 immune responses in vivo. Finally, a potent UA synthesis inhibitor, febuxostat, mitigated asthma phenotypes that were caused by repeated exposure to natural airborne allergens. These findings provide mechanistic insights into the development of type 2 immunity to airborne allergens and recognize airway UA as a key player that regulates the process in respiratory mucosa. PMID:24663677

  8. Inflammatory Pattern of the Bronchial Mucosa in Patients with Asthma with Airway Hyperresponsiveness to Hypoosmotic Stimulus.

    PubMed

    Pirogov, A B; Prikhod'ko, A G; Perelman, Yu M; Zinovyev, S V; Afanasyeva, E Yu; Kolosov, V P

    2016-08-01

    Positive reaction of the bronchi to distilled water inhalation in asthmatics is associated with significant stimulation of the respiratory epithelium desquamation against the background of increased content of eosinophilic and neutrophilic leukocytes in induced sputum, predomination of eosinophil and neutrophil cytolysis, and lower activity of myeloperoxidase in leukocyte granules (in comparison with the parameter in patients with a negative response to bronchostimulation). Enhanced cytolysis and destruction of leukocytes and high myeloperoxidase concentration in the extracellular space are essential for the development of bronchial hyperresponsiveness to hypoosmotic stimulus in asthma. PMID:27591875

  9. Tachykinin antagonists and the airways.

    PubMed

    Joos, G F; Kips, J C; Peleman, R A; Pauwels, R A

    1995-01-01

    There is now convincing evidence for the presence of substance P (SP) and neurokinin A (NKA) in human airway nerves. Studies on autopsy tissue, on bronchoalveolar lavage fluid and on sputum suggest that SP may be present in increased amounts in the asthmatic airway. Substance P and NKA are potent bronchoconstrictors of human airways, asthmatics being more sensitive than normal persons. The major enzyme responsible for the degradation of the tachykinins, the neutral endopeptidase, is present in the airways and is involved in the breakdown of exogenously administered SP and NKA, both in normal and asthmatic persons. Other, less well documented airway effects of SP and NKA include mucus secretion, vasodilation and plasma extravasation, as well as the chemoattraction and stimulation of various cells presumed to be involved in asthmatic airway inflammation. NK2 receptors and, to a lesser extent, NK1 receptors have been shown to be involved in bronchoconstriction, whereas NK1 receptors were found to be involved in mucus secretion, microvascular leakage and vasodilatation, and in most of the effects on inflammatory cells. The first clinical trial with FK224, a peptide NK1 and NK2 receptor antagonist, and CP99994, a nonpeptide NK1 receptor antagonist, are negative. However, FK224 failed to block the bronchoconstrictor effect of NKA in asthmatics and the dose of CP99994, needed to antagonize tachykinin effects in man, remains to be determined. PMID:7543746

  10. Surfactant and allergic airway inflammation.

    PubMed

    Winkler, Carla; Hohlfeld, Jens M

    2013-01-01

    Pulmonary surfactant is a complex mixture of unique proteins and lipids that covers the airway lumen. Surfactant prevents alveolar collapse and maintains airway patency by reducing surface tension at the air-liquid interface. Furthermore, it provides a defence against antigen uptake by binding foreign particles and enhancing cellular immune responses. Allergic asthma is associated with chronic airway inflammation and presents with episodes of airway narrowing. The pulmonary inflammation and bronchoconstriction can be triggered by exposure to allergens or pathogens present in the inhaled air. Pulmonary surfactant has the potential to interact with various immune cells which orchestrate allergen- or pathogen-driven episodes of airway inflammation. The complex nature of surfactant allows multiple sites of interaction, but also makes it susceptible to external alterations, which potentially impair its function. This duality of modulating airway physiology and immunology during inflammatory conditions, while at the same time being prone to alterations accompanied by restricted function, has stimulated numerous studies in recent decades, which are reviewed in this article. PMID:23896983

  11. USE OF WHOLE BODY PLETHSYMOGRAPHY TO ASSESS INFLUENCES OF RAT STRAIN AND AGE ON NONSPECIFIC AIRWAY RESPONSIVENESS

    EPA Science Inventory


    Increased airway responsiveness (AR) is a well-established characteristic of asthma that epidemiological evidence suggests may be linked to air pollutant exposure. Establishing the biologic basis between pollutant exposure and subsequent adverse public health outcome require...

  12. Lymphocyte Gene Expression Characteristic of Immediate Airway Responses (IAR) and Methacholine (MCH) Hyperresponsiveness in Mice Sensitized and Challenged with Isocyanates

    EPA Science Inventory

    Exposure to isocyanates has been associated with occupational airway diseases, including asthma. Previously we reported on respiratory and immune responses following dermal sensitization and intranasal challenge of BALB/c mice with 6 different isocyanates. The purpose of this st...

  13. Potentiation of NF-κB-dependent transcription and inflammatory mediator release by histamine in human airway epithelial cells

    PubMed Central

    Holden, N S; Gong, W; King, E M; Kaur, M; Giembycz, M A; Newton, R

    2007-01-01

    Background and purpose: In asthma, histamine contributes to bronchoconstriction, vasodilatation and oedema, and is associated with the late phase response. The current study investigates possible inflammatory effects of histamine acting on nuclear factor κB (NF-κB)-dependent transcription and cytokine release. Experimental approach: Using BEAS-2B bronchial epithelial cells, NF-κB-dependent transcription and both release and mRNA expression of IL-6 and IL-8 were examined by reporter assay, ELISA and quantitative RT-PCR. Histamine receptors were detected using qualitative RT-PCR and function examined using selective agonists and antagonists. Key results: Addition of histamine to TNFα-stimulated BEAS-2B cells maximally potentiated NF-κB-dependent transcription 1.8 fold, whereas IL-6 and IL-8 protein release were enhanced 7.3- and 2.7-fold respectively. These responses were, in part, NF-κB-dependent and were associated with 2.6- and 1.7-fold enhancements of IL-6 and IL-8 mRNA expression. The H1 receptor antagonist, mepyramine, caused a rightward shift in the concentration-response curves of TNFα-induced NF-κB-dependent transcription (pA2=9.91) and release of IL-6 (pA2=8.78) and IL-8 (pA2=8.99). Antagonists of histamine H2, H3 and H4 receptors were without effect. Similarly, H3 and H4 receptor agonists did not affect TNFα-induced NF-κB-dependent transcription, or IL-6 and IL-8 release at concentrations below 10 μM. The anti-inflammatory glucocorticoid, dexamethasone, inhibited the histamine enhanced NF-κB-dependent transcription and IL-6 and IL-8 release. Conclusions and implications: Potentiation of NF-κB-dependent transcription and inflammatory cytokine release by histamine predominantly involves receptors of the H1 receptor subtype. These data support an anti-inflammatory role for H1 receptor antagonists by preventing the transcription and release of pro-inflammatory cytokines. PMID:17891168

  14. Endothelial leukocyte adhesion molecule-1 mediates antigen-induced acute airway inflammation and late-phase airway obstruction in monkeys.

    PubMed Central

    Gundel, R H; Wegner, C D; Torcellini, C A; Clarke, C C; Haynes, N; Rothlein, R; Smith, C W; Letts, L G

    1991-01-01

    This study examines the role of endothelial leukocyte adhesion molecule-1 (ELAM-1) in the development of the acute airway inflammation (cell influx) and late-phase airway obstruction in a primate model of extrinsic asthma. In animals sensitive to antigen, a single inhalation exposure induced the rapid expression of ELAM-1 (6 h) exclusively on vascular endothelium that correlated with the influx of neutrophils into the lungs and the onset of late-phase airway obstruction. In contrast, basal levels of ICAM-1 was constitutively expressed on vascular endothelium and airway epithelium before antigen challenge. After the single antigen exposure, changes in ICAM-1 expression did not correlate with neutrophil influx or the change in airway caliber. This was confirmed by showing that pretreatment with a monoclonal antibody to ICAM-1 did not inhibit the acute influx of neutrophils associated with late-phase airway obstruction, whereas a monoclonal antibody to ELAM-1 blocked both the influx of neutrophils and the late-phase airway obstruction. This study demonstrates a functional role for ELAM-1 in the development of acute airway inflammation in vivo. We conclude that, in primates, the late-phase response is the result of an ELAM-1 dependent influx of neutrophils. Therefore, the regulation of ELAM-1 expression may provide a novel approach to controlling the acute inflammatory response, and thereby, affecting airway function associated with inflammatory disorders, including asthma. Images PMID:1717514

  15. Detonation Nanodiamond Toxicity in Human Airway Epithelial Cells Is Modulated by Air Oxidation

    EPA Science Inventory

    Detonational nanodiamonds (DND), a nanomaterial with an increasing range of industrial and biomedical applications, have previously been shown to induce a pro-inflammatory response in cultured human airway epithelial cells (HAEC). We now show that surface modifications induced by...

  16. Reduced Acute Inflammatory Responses to Microgel Conformal Coatings

    PubMed Central

    Bridges, Amanda W.; Singh, Neetu; Burns, Kellie L.; Babensee, Julia E.; Lyon, L. Andrew; García, Andrés J.

    2008-01-01

    Implantation of synthetic materials into the body elicits inflammatory host responses that limit medical device integration and biological performance. This inflammatory cascade involves protein adsorption, leukocyte recruitment and activation, cytokine release, and fibrous encapsulation of the implant. We present a coating strategy based on thin films of poly(N-isopropylacrylamide) hydrogel microparticles (i.e. microgels) cross-linked with poly(ethylene glycol) diacrylate. These particles were grafted onto a clinically relevant polymeric material to generate conformal coatings that significantly reduced in vitro fibrinogen adsorption and primary human monocytes/macrophage adhesion and spreading. These microgel coatings also reduced leukocyte adhesion and expression of pro-inflammatory cytokines (TNF-α, IL-1β, MCP-1) in response to materials implanted acutely in the murine intraperitoneal space. These microgel coatings can be applied to biomedical implants as a protective coating to attenuate biofouling, leukocyte adhesion and activation, and adverse host responses for biomedical and biotechnological applications. PMID:18804859

  17. Supression of inflammatory responses by labdane-type diterpenoids

    SciTech Connect

    Giron, Natalia; Rodriguez, Benjamin; Lopez-Fontal, Raquel; Bosca, Lisardo; Hortelano, Sonsoles Heras, Beatriz de las

    2008-04-15

    A series of 11 labdane-type diterpenoids (1-11) with various patterns of substitution were tested for potential anti-inflammatory activity. Of these compounds, 4 and 11 were selected to evaluate their influence on targets relevant to the regulation of the inflammatory response. These diterpenoids reduced the production of nitric oxide (NO), prostaglandin E2, and tumor necrosis factor-{alpha} in LPS-activated RAW 264.7 macrophages, with IC50 in the range 1-10 {mu}M. Inhibition of these inflammatory mediators was related to inhibition of the expression of nitric oxide synthase-2 (NOS-2) and cyclooxygenase-2 (COX-2) at the transcriptional level, as determined by western-blot and RT-PCR. Examination of the effects of these diterpenoids on nuclear factor {kappa}B signaling showed that both compounds inhibit the phosphorylation of I{kappa}B{alpha} and I{kappa}B{beta}, preventing their degradation and the nuclear translocation of the NF-{kappa}B p65 subunit. Inhibition of IKK activity was also observed. These derivatives displayed significant anti-inflammatory activity in vivo, suppressing mouse ear edema induced by 12-O-tetradecanoylphorbol-13-acetate (TPA) and inhibiting myeloperoxidase activity, an index of neutrophil infiltration. The anti-inflammatory effects of these labdane diterpenoids, together with their low cell toxicity, suggest potential therapeutic applications in the regulation of the inflammatory response.

  18. Saturated fatty acids trigger TLR4-mediated inflammatory response.

    PubMed

    Rocha, D M; Caldas, A P; Oliveira, L L; Bressan, J; Hermsdorff, H H

    2016-01-01

    Toll-like receptors (TLR) mediate infection-induced inflammation and sterile inflammation by endogenous molecules. Among the TLR family, TLR4 is the best understood. However, while its downstream signaling pathways have been well defined, not all ligands of TLR4 are currently known. Current evidence suggests that saturated fatty acids (SFA) act as non-microbial TLR4 agonists, and trigger its inflammatory response. Thus, our present review provides a new perspective on the potential mechanism by which SFAs could modulate TLR4-induced inflammatory responses: (1) SFAs can be recognized by CD14-TLR4-MD2 complex and trigger inflammatory pathways, similar to lipopolysaccharide (LPS). (2) SFAs lead to modification of gut microbiota with an overproduction of LPS after a high-fat intake, enhancing this natural TLR4 ligand. (3) In addition, this metabolic endotoxemia leads to an oxidative stress thereby producing atherogenic lipids - oxLDL and oxidized phospholipids - which trigger CD36-TLR4-TLR6 inflammatory response. (4) Also, the high SFA consumption increases the lipemia and the mmLDL and oxLDL formation through oxidative modifications of LDL. The mmLDL, unlike oxLDL, is involved in activation of the CD14-TLR4-MD2 inflammatory pathway. Those molecules can induce TLR4 inflammatory response by MyD88-dependent and/or MyD88-independent pathways that, in turn, promotes the expression of proinflammatory transcript factors such as factor nuclear kappa B (NF-κB), which plays a crucial role in the induction of inflammatory mediators (cytokines, chemokines, or costimulatory molecules) implicated in the development and progression of many chronic diseases. PMID:26687466

  19. Arsenic alters ATP-dependent Ca²+ signaling in human airway epithelial cell wound response.

    PubMed

    Sherwood, Cara L; Lantz, R Clark; Burgess, Jefferey L; Boitano, Scott

    2011-05-01

    Arsenic is a natural metalloid toxicant that is associated with occupational inhalation injury and contaminates drinking water worldwide. Both inhalation of arsenic and consumption of arsenic-tainted water are correlated with malignant and nonmalignant lung diseases. Despite strong links between arsenic and respiratory illness, underlying cell responses to arsenic remain unclear. We hypothesized that arsenic may elicit some of its detrimental effects on the airway through limitation of innate immune function and, specifically, through alteration of paracrine ATP (purinergic) Ca²+ signaling in the airway epithelium. We examined the effects of acute (24 h) exposure with environmentally relevant levels of arsenic (i.e., < 4 μM as Na-arsenite) on wound-induced Ca²+ signaling pathways in human bronchial epithelial cell line (16HBE14o-). We found that arsenic reduces purinergic Ca²+ signaling in a dose-dependent manner and results in a reshaping of the Ca²+ signaling response to localized wounds. We next examined arsenic effects on two purinergic receptor types: the metabotropic P2Y and ionotropic P2X receptors. Arsenic inhibited both P2Y- and P2X-mediated Ca²+ signaling responses to ATP. Both inhaled and ingested arsenic can rapidly reach the airway epithelium where purinergic signaling is essential in innate immune functions (e.g., ciliary beat, salt and water transport, bactericide production, and wound repair). Arsenic-induced compromise of such airway defense mechanisms may be an underlying contributor to chronic lung disease. PMID:21357385

  20. Characterization of the early pulmonary inflammatory response associated with PTFE fume exposure

    NASA Technical Reports Server (NTRS)

    Johnston, C. J.; Finkelstein, J. N.; Gelein, R.; Baggs, R.; Oberdorster, G.; Clarkson, T. W. (Principal Investigator)

    1996-01-01

    Heating of polytetrafluoroethylene (PTFE) has been described to release fumes containing ultrafine particles (approximately 18 nm diam). These fumes can be highly toxic in the respiratory tract inducing extensive pulmonary edema with hemorrhagic inflammation. Fischer-344 rats were exposed to PTFE fumes generated by temperatures ranging from 450 to 460 degrees C for 15 min at an exposure concentration of 5 x 10(5) particles/cm3, equivalent to approximately 50 micrograms/m3. Responses were examined 4 hr post-treatment when these rats demonstrated 60-85% neutrophils (PMNs) in their lung lavage. Increases in abundance for messages encoding the antioxidants manganese superoxide dismutase and metallothionein (MT) increased 15- and 40-fold, respectively. For messages encoding the pro- and anti-inflammatory cytokines: inducible nitric oxide synthase, interleukin 1 alpha, 1 beta, and 6 (IL-1 alpha, IL-1 beta, and IL-6), macrophage inflammatory protein-2, and tumor necrosis factor-alpha (TNF alpha) increases of 5-, 5-, 10-, 40-, 40-, and 15-fold were present. Vascular endothelial growth factor, which may play a role in the integrity of the endothelial barrier, was decreased to 20% of controls. In situ sections were hybridized with 33P cRNA probes encoding IL-6, MT, surfactant protein C, and TNF alpha. Increased mRNA abundance for MT and IL-6 was expressed around all airways and interstitial regions with MT and IL-6 demonstrating similar spatial distribution. Large numbers of activated PMNs expressed IL-6, MT, and TNF alpha. Additionally, pulmonary macrophages and epithelial cells were actively involved. These observations support the notion that PTFE fumes containing ultrafine particles initiate a severe inflammatory response at low inhaled particle mass concentrations, which is suggestive of an oxidative injury. Furthermore, PMNs may actively regulate the inflammatory process through cytokine and antioxidant expression.

  1. Sphingosine Kinases Are Not Required for Inflammatory Responses in Macrophages*

    PubMed Central

    Xiong, Yuquan; Lee, Hyeuk Jong; Mariko, Boubacar; Lu, Yi-Chien; Dannenberg, Andrew J.; Haka, Abigail S.; Maxfield, Frederick R.; Camerer, Eric; Proia, Richard L.; Hla, Timothy

    2013-01-01

    Sphingosine kinases (Sphks), which catalyze the formation of sphingosine 1-phosphate (S1P) from sphingosine, have been implicated as essential intracellular messengers in inflammatory responses. Specifically, intracellular Sphk1-derived S1P was reported to be required for NFκB induction during inflammatory cytokine action. To examine the role of intracellular S1P in the inflammatory response of innate immune cells, we derived murine macrophages that lack both Sphk1 and Sphk2 (MΦ Sphk dKO). Compared with WT counterparts, MΦ Sphk dKO cells showed marked suppression of intracellular S1P levels whereas sphingosine and ceramide levels were strongly up-regulated. Cellular proliferation and apoptosis were similar in MΦ Sphk dKO cells compared with WT counterparts. Treatment of WT and MΦ Sphk dKO with inflammatory mediators TNFα or Escherichia coli LPS resulted in similar NFκB activation and cytokine expression. Furthermore, LPS-induced inflammatory responses, mortality, and thioglycolate-induced macrophage recruitment to the peritoneum were indistinguishable between MΦ Sphk dKO and littermate control mice. Interestingly, autophagic markers were constitutively induced in bone marrow-derived macrophages from Sphk dKO mice. Treatment with exogenous sphingosine further enhanced intracellular sphingolipid levels and autophagosomes. Inhibition of autophagy resulted in caspase-dependent cell death. Together, these data suggest that attenuation of Sphk activity, particularly Sphk2, leads to increased intracellular sphingolipids and autophagy in macrophages. PMID:24081141

  2. Mechanisms of Heightened Airway Sensitivity and Responses to Inhaled SO2 in Asthmatics

    PubMed Central

    Reno, Anita L; Brooks, Edward G; Ameredes, Bill T

    2015-01-01

    Sulfur dioxide (SO2) is a problematic inhalable air pollutant in areas of widespread industrialization, not only in the United States but also in countries undergoing rapid industrialization, such as China, and it can be a potential trigger factor for asthma exacerbations. It is known that asthmatics are sensitive to the effects of SO2; however, the basis of this enhanced sensitivity remains incompletely understood. A PubMed search was performed over the course of 2014, encompassing the following terms: asthma, airway inflammation, sulfur dioxide, IL-10, mouse studies, and human studies. This search indicated that biomarkers of SO2 exposure, SO2 effects on airway epithelial cell function, and animal model data are useful in our understanding of the body’s response to SO2, as are SO2-associated amplification of allergic inflammation, and potential promotion of neurogenic inflammation due to chemical irritant properties. While definitive answers are still being sought, these areas comprise important foci of consideration regarding asthmatic responses to inhaled SO2. Furthermore, IL-10 deficiency associated with asthma may be another important factor associated with an inability to resolve inflammation and mitigate oxidative stress resulting from SO2 inhalation, supporting the idea that asthmatics are predisposed to SO2 sensitivity, leading to asthma exacerbations and airway dysfunction. PMID:25922579

  3. Mast cells mediate acute inflammatory responses to implanted biomaterials

    PubMed Central

    Tang, Liping; Jennings, Timothy A.; Eaton, John W.

    1998-01-01

    Implanted biomaterials trigger acute and chronic inflammatory responses. The mechanisms involved in such acute inflammatory responses can be arbitrarily divided into phagocyte transmigration, chemotaxis, and adhesion to implant surfaces. We earlier observed that two chemokines—macrophage inflammatory protein 1α/monocyte chemoattractant protein 1—and the phagocyte integrin Mac-1 (CD11b/CD18)/surface fibrinogen interaction are, respectively, required for phagocyte chemotaxis and adherence to biomaterial surfaces. However, it is still not clear how the initial transmigration of phagocytes through the endothelial barrier into the area of the implant is triggered. Because implanted biomaterials elicit histaminic responses in the surrounding tissue, and histamine release is known to promote rapid diapedesis of inflammatory cells, we evaluated the possible role of histamine and mast cells in the recruitment of phagocytes to biomaterial implants. Using i.p. and s.c. implantation of polyethylene terephthalate disks in mice we find: (i) Extensive degranulation of mast cells, accompanied by histamine release, occurs adjacent to short-term i.p. implants. (ii) Simultaneous administration of H1 and H2 histamine receptor antagonists (pyrilamine and famotidine, respectively) greatly diminishes recruitment and adhesion of both neutrophils (<20% of control) and monocytes/macrophages (<30% of control) to implants. (iii) Congenitally mast cell-deficient mice also exhibit markedly reduced accumulation of phagocytes on both i.p. and s.c implants. (iv) Finally, mast cell reconstitution of mast cell-deficient mice restores “normal” inflammatory responses to biomaterial implants. We conclude that mast cells and their granular products, especially histamine, are important in recruitment of inflammatory cells to biomaterial implants. Improved knowledge of such responses may permit purposeful modulation of both acute and chronic inflammation affecting implanted biomaterials. PMID

  4. Guanosine Protects Against Cortical Focal Ischemia. Involvement of Inflammatory Response.

    PubMed

    Hansel, Gisele; Tonon, André Comiran; Guella, Felipe Lhywinskh; Pettenuzzo, Letícia Ferreira; Duarte, Thiago; Duarte, Marta Maria Medeiros Frescura; Oses, Jean Pierre; Achaval, Matilde; Souza, Diogo Onofre

    2015-12-01

    Stroke is the major cause of death and the most frequent cause of disability in the adult population worldwide. Guanosine plays an important neuroprotective role in several cerebral ischemic models and is involved in the modulation of oxidative responses and glutamatergic parameters. Because the excessive reactive oxygen species produced during an ischemic event can trigger an inflammatory response, the purpose of this study was to evaluate the hypothesis that guanosine is neuroprotective against focal cerebral ischemia, inhibits microglia/macrophages activation, and mediates an inflammatory response ameliorating the neural damage. Permanent focal cerebral ischemia was induced in adult rats, and guanosine was administered immediately, 1, 3, and 6 h after surgery. Twenty-four hours after ischemia, the asymmetry scores were evaluated by the cylinder test; neuronal damage was evaluated by Fluoro-Jade C (FJC) staining and propidium iodide (PI) incorporation; microglia and immune cells were evaluated by anti-Iba-1 antibody; and inflammatory parameters such as interleukins (IL): IL-1, IL-6, IL-10; tumor necrosis factors alpha (TNF-α); and interferon-gamma (INF-γ) were evaluated in the brain tissue and cerebrospinal fluid. The ischemic event increased the levels of Iba-1-positive cells and pro-inflammatory cytokines and decreased IL-10 levels (an anti-inflammatory cytokine) in the lesion periphery. The guanosine treatment attenuated the changes in these inflammatory parameters and also reduced the infarct volume, PI incorporation, and number of FJC-positive cells, improving the functional recovery. Thus, guanosine may have been a promising therapeutic agent for the treatment of ischemic brain injury by reduction of inflammatory process triggered in an ischemic event. PMID:25394382

  5. Cessation of dexamethasone exacerbates airway responses to methacholine in asthmatic mice.

    PubMed

    Stengel, Peter W; Nickell, Laura E; Wolos, Jeffrey A; Snyder, David W

    2007-06-01

    In asthmatic mice, dexamethasone (30.0 mg/kg) was administered orally once daily on Days 24-27. One hour after dexamethasone on Day 25-27, the mice were exposed to ovalbumin aerosols. Twenty-eight days after the initial ovalbumin immunization, we found that dexamethasone reduced methacholine-induced pulmonary gas trapping and inhibited bronchoalveolar lavage eosinophils and neutrophils. However, five days after the last dose of dexamethasone and last ovalbumin aerosol exposure in other asthmatic mice, the airway obstructive response to methacholine was exacerbated in dexamethasone-treated mice compared to vehicle-treated mice on Day 32. Further, eosinophils, but not neutrophils, were still inhibited after cessation of dexamethasone. Thus, discontinuing dexamethasone worsened methacholine-induced pulmonary gas trapping of asthmatic mice in the absence of eosinophilic airway inflammation. PMID:17374534

  6. Tumor suppressor death-associated protein kinase attenuates inflammatory responses in the lung.

    PubMed

    Nakav, Sigal; Cohen, Shmuel; Feigelson, Sara W; Bialik, Shani; Shoseyov, David; Kimchi, Adi; Alon, Ronen

    2012-03-01

    Death-associated protein kinase (DAPk) is a tumor suppressor thought to inhibit cancer by promoting apoptosis and autophagy. Because cancer progression is linked to inflammation, we investigated the in vivo functions of DAPk in lung responses to various acute and chronic inflammatory stimuli. Lungs of DAPk knockout (KO) mice secreted higher concentrations of IL-6 and keratinocyte chemoattractant (or chemokine [C-X-C motif] ligand 1) in response to transient intranasal administrations of the Toll-like receptor-4 (TLR4) agonist LPS. In addition, DAPk-null macrophages and neutrophils were hyperresponsive to ex vivo stimulation with LPS. DAPk-null neutrophils were also hyperresponsive to activation via Fc receptor and Toll-like receptor-3, indicating that the suppressive functions of this kinase are not restricted to TLR4 pathways. Even after the reconstitution of DAPk-null lungs with DAPk-expressing leukocytes by transplanting wild-type (WT) bone marrow into lethally irradiated DAPk KO mice, the chimeric mice remained hypersensitive to both acute and chronic LPS challenges, as well as to tobacco smoke exposure. DAPk-null lungs reconstituted with WT leukocytes exhibited elevated neutrophil content and augmented cytokine secretion in the bronchoalveolar space, as well as enhanced epithelial cell injury in response to both acute and chronic inflammatory conditions. These results suggest that DAPk attenuates a variety of inflammatory responses, both in lung leukocytes and in lung epithelial cells. The DAPk-mediated suppression of lung inflammation and airway injury may contribute to the tumor-suppressor functions of this kinase in epithelial carcinogenesis. PMID:21997486

  7. Hypoxia Exerts Dualistic Effects on Inflammatory and Proliferative Responses of Healthy and Asthmatic Primary Human Bronchial Smooth Muscle Cells

    PubMed Central

    Keglowich, Laura; Baraket, Melissa; Tamm, Michael; Borger, Peter

    2014-01-01

    Background For oxygen supply, airway wall cells depend on diffusion though the basement membrane, as well as on delivery by micro-vessels. In the asthmatic lung, local hypoxic conditions may occur due to increased thickness and altered composition of the basement membrane, as well as due to edema of the inflamed airway wall. Objective In our study we investigated the effect of hypoxia on proliferation and pro-inflammatory and pro-angiogenic parameter production by human bronchial smooth muscle cells (BSMC). Furthermore, conditioned media of hypoxia-exposed BSMC was tested for its ability to induce sprout outgrowth from endothelial cells spheroids. Methods BSMC were cultured in RPMI1640 (5% FCS) under normoxic (21% O2) and hypoxic (1% and 5% O2) conditions. Proliferation was determined by cell count and Western blot analysis for cyclin E and Proliferating Cell Nuclear Antigen (PCNA). Secretion of IL-6, IL-8, ENA-78 and VEGF-A was analyzed by ELISA. BSMC conditioned medium was tested for its angiogenic capacity by endothelial cell (EC)-spheroid in vitro angiogenesis assay. Results Proliferation of BSMC obtained from asthmatic and non-asthmatic patients was significantly reduced in the presence of 1% O2, whereas 5% O2 reduced proliferation of asthmatic BSMC only. Hypoxia induced HIF-1α expression in asthmatic and non-asthmatic BSMC, which coincided with significantly increased release of IL-6, IL-8 and VEGF-A, but not ENA-78. Finally, endothelial sprout outgrowth from EC spheroids was increased when exposed to hypoxia conditioned BSMC medium. Conclusion Hypoxia had dualistic effects on proliferative and inflammatory responses of asthmatic and non-asthmatic BSMC. First, hypoxia reduced BSMC proliferation. Second, hypoxia induced a pro-inflammatory, pro-angiogenic response. BSMC and EC may thus be promising new targets to counteract and/or alleviate airway wall remodeling. PMID:24587090

  8. Differential Gene Expression Profiles and Selected Cytokine Protein Analysis of Mediastinal Lymph Nodes of Horses with Chronic Recurrent Airway Obstruction (RAO) Support an Interleukin-17 Immune Response

    PubMed Central

    2015-01-01

    Recurrent airway obstruction (RAO) is a pulmonary inflammatory condition that afflicts certain mature horses exposed to organic dust particulates in hay. Its clinical and pathological features, manifested by reversible bronchoconstriction, excessive mucus production and airway neutrophilia, resemble the pulmonary alterations that occur in agricultural workers with occupational asthma. The immunological basis of RAO remains uncertain although its chronicity, its localization to a mucosal surface and its domination by a neutrophilic, non-septic inflammatory response, suggest involvement of Interleukin-17 (IL-17). We examined global gene expression profiles in mediastinal (pulmonary-draining) lymph nodes isolated from RAO-affected and control horses. Differential expression of > 200 genes, coupled with network analysis, supports an IL-17 response centered about NF-κB. Immunohistochemical analysis of mediastinal lymph node sections demonstrated increased IL-17 staining intensity in diseased horses. This result, along with the finding of increased IL-17 concentrations in lymph node homogenates from RAO-affected horses (P = 0.1) and a down-regulation of IL-4 gene and protein expression, provides additional evidence of the involvement of IL-17 in the chronic stages of RAO. Additional investigations are needed to ascertain the cellular source of IL-17 in this equine model of occupational asthma. Understanding the immunopathogenesis of this disorder likely will enhance the development of therapeutic interventions beneficial to human and animal pulmonary health. PMID:26561853

  9. Alterations of the Lung Methylome in Allergic Airway Hyper-Responsiveness

    PubMed Central

    Cheng, Robert YS; Shang, Yan; Limjunyawong, Nathachit; Dao, Tyna; Das, Sandhya; Rabold, Richard; Sham, James SK; Mitzner, Wayne; Tang, Wan-Yee

    2014-01-01

    Asthma is a chronic airway disorder characterized by recurrent attacks of breathlessness and wheezing, affecting 300 million people around the world (available at: www.who.int). To date, genetic factors associated with asthma susceptibility have been unable to explain the full etiology of asthma. Recent studies have demonstrated that the epigenetic disruption of gene expression plays an equally important role in the development of asthma through interaction with our environment. We sensitized 6-week-old C57BL/6J mice with house-dust-mite (HDM) extracts intraperitoneally followed by 5 weeks of exposure to HDM challenges (three times a week) intratracheally. HDM-exposed mice showed an increase in airway hyper-responsiveness (AHR) and inflammation together with structural remodeling of the airways. We applied methylated DNA immunoprecipitation-next generation sequencing (MeDIP-seq) for profiling of DNA methylation changes in the lungs in response to HDM. We observed about 20 million reads by a single-run of massive parallel sequencing. We performed bioinformatics and pathway analysis on the raw sequencing data to identify differentially methylated candidate genes in HDM-exposed mice. Specifically, we have revealed that the transforming growth factor beta signaling pathway is epigenetically modulated by chronic exposure to HDM. Here, we demonstrated that a specific allergen may play a role in AHR through an epigenetic mechanism by disrupting the expression of genes in lungs that might be involved in airway inflammation and remodeling. Our findings provide new insights into the potential mechanisms by which environmental allergens induce allergic asthma and such insights may assist in the development of novel preventive and therapeutic options for this debilitative disease. PMID:24446183

  10. Persistence of serotonergic enhancement of airway response in a model of childhood asthma.

    PubMed

    Moore, Brian D; Hyde, Dallas M; Miller, Lisa A; Wong, Emily M; Schelegle, Edward S

    2014-07-01

    The persistence of airway hyperresponsiveness (AHR) and serotonergic enhancement of airway smooth muscle (ASM) contraction induced by ozone (O3) plus allergen has not been evaluated. If this mechanism persists after a prolonged recovery, it would indicate that early-life exposure to O3 plus allergen induces functional changes predisposing allergic individuals to asthma-related symptoms throughout life, even in the absence of environmental insult. A persistent serotonergic mechanism in asthma exacerbations may offer a novel therapeutic target, widening treatment options for patients with asthma. The objective of this study was to determine if previously documented AHR and serotonin-enhanced ASM contraction in allergic monkeys exposed to O3 plus house dust mite allergen (HDMA) persist after prolonged recovery. Infant rhesus monkeys sensitized to HDMA were exposed to filtered air (FA) (n = 6) or HDMA plus O3 (n = 6) for 5 months. Monkeys were then housed in a FA environment for 30 months. At 3 years, airway responsiveness was assessed. Airway rings were then harvested, and ASM contraction was evaluated using electrical field stimulation with and without exogenous serotonin and serotonin-subtype receptor antagonists. Animals exposed to O3 plus HDMA exhibited persistent AHR. Serotonin exacerbated the ASM contraction in the exposure group but not in the FA group. Serotonin subtype receptors 2, 3, and 4 appear to drive the response. Our study shows that AHR and serotonin-dependent exacerbation of cholinergic-mediated ASM contraction induced by early-life exposure to O3 plus allergen persist for at least 2.5 years and may contribute to a persistent asthma phenotype. PMID:24484440

  11. Alterations of the lung methylome in allergic airway hyper-responsiveness.

    PubMed

    Cheng, Robert Ys; Shang, Yan; Limjunyawong, Nathachit; Dao, Tyna; Das, Sandhya; Rabold, Richard; Sham, James Sk; Mitzner, Wayne; Tang, Wan-Yee

    2014-04-01

    Asthma is a chronic airway disorder characterized by recurrent attacks of breathlessness and wheezing, affecting 300 million people around the world (available at: www.who.int). To date, genetic factors associated with asthma susceptibility have been unable to explain the full etiology of asthma. Recent studies have demonstrated that the epigenetic disruption of gene expression plays an equally important role in the development of asthma through interaction with our environment. We sensitized 6-week-old C57BL/6J mice with house-dust-mite (HDM) extracts intraperitoneally followed by 5 weeks of exposure to HDM challenges (three times a week) intratracheally. HDM-exposed mice showed an increase in airway hyper-responsiveness (AHR) and inflammation together with structural remodeling of the airways. We applied methylated DNA immunoprecipitation-next generation sequencing (MeDIP-seq) for profiling of DNA methylation changes in the lungs in response to HDM. We observed about 20 million reads by a single-run of massive parallel sequencing. We performed bioinformatics and pathway analysis on the raw sequencing data to identify differentially methylated candidate genes in HDM-exposed mice. Specifically, we have revealed that the transforming growth factor beta signaling pathway is epigenetically modulated by chronic exposure to HDM. Here, we demonstrated that a specific allergen may play a role in AHR through an epigenetic mechanism by disrupting the expression of genes in lungs that might be involved in airway inflammation and remodeling. Our findings provide new insights into the potential mechanisms by which environmental allergens induce allergic asthma and such insights may assist in the development of novel preventive and therapeutic options for this debilitative disease. PMID:24446183

  12. SERCA2 Regulates Non-CF and CF Airway Epithelial Cell Response to Ozone

    PubMed Central

    Ahmad, Shama; Nichols, David P.; Strand, Matthew; Rancourt, Raymond C.; Randell, Scott H.; White, Carl W.; Ahmad, Aftab

    2011-01-01

    Calcium mobilization can regulate a wide range of essential functions of respiratory epithelium, including ion transport, ciliary beat frequency, and secretion of mucus, all of which are modified in cystic fibrosis (CF). SERCA2, an important controller of calcium signaling, is deficient in CF epithelium. We conducted this study to determine whether SERCA2 deficiency can modulate airway epithelial responses to environmental oxidants such as ozone. This could contribute to the pathogenesis of pulmonary exacerbations, which are important and frequent clinical events in CF. To address this, we used air-liquid interface (ALI) cultures of non-CF and CF cell lines, as well as differentiated cultures of cells derived from non-CF and CF patients. We found that ozone exposure caused enhanced membrane damage, mitochondrial dysfunction and apoptotic cell death in CF airway epithelial cell lines relative to non-CF. Ozone exposure caused increased proinflammatory cytokine production in CF airway epithelial cell lines. Elevated proinflammatory cytokine production also was observed in shRNA-mediated SERCA2 knockdown cells. Overexpression of SERCA2 reversed ozone-induced proinflammatory cytokine production. Ozone-induced proinflammatory cytokine production was NF-κB- dependent. In a stable NF-κB reporter cell line, SERCA2 inhibition and knockdown both upregulated cytomix-induced NF-κB activity, indicating importance of SERCA2 in modulating NF-κB activity. In this system, increased NF-κB activity was also accompanied by increased IL-8 production. Ozone also induced NF-κB activity and IL-8 release, an effect that was greater in SERCA2-silenced NF-κB-reporter cells. SERCA2 overexpression reversed cytomix-induced increased IL-8 release and total nuclear p65 in CFTR-deficient (16HBE-AS) cells. These studies suggest that SERCA2 is an important regulator of the proinflammatory response of airway epithelial cells and could be a potential therapeutic target. PMID:22096575

  13. Association of Lung Inflammatory Cells with Small Airways Function and Exhaled Breath Markers in Smokers – Is There a Specific Role for Mast Cells?

    PubMed Central

    Nussbaumer-Ochsner, Yvonne; Stolk, Jan; Ferraz da Silva, Luiz F.; van Schadewijk, Annemarie; de Jeu, Ronald C.; Prins, Frans A.; Mauad, Thais; Rabe, Klaus F.; Hiemstra, Pieter S.

    2015-01-01

    Background Smoking is associated with a mixed inflammatory infiltrate in the airways. We evaluated whether airway inflammation in smokers is related to lung function parameters and inflammatory markers in exhaled breath. Methods Thirty-seven smokers undergoing lung resection for primary lung cancer were assessed pre-operatively by lung function testing including single-breath-nitrogen washout test (sb-N2-test), measurement of fractional exhaled nitric oxide (FeNO) and pH/8-isoprostane in exhaled breath condensate (EBC). Lung tissue sections containing cancer-free large (LA) and small airways (SA) were stained for inflammatory cells. Mucosal (MCT) respectively connective tissue mast cells (MCTC) and interleukin-17A (IL-17A) expression by mast cells was analysed using a double-staining protocol. Results The median number of neutrophils, macrophages and mast cells infiltrating the lamina propria and adventitia of SA was higher than in LA. Both MCTC and MCT were higher in the lamina propria of SA compared to LA (MCTC: 49 vs. 27.4 cells/mm2; MCT: 162.5 vs. 35.4 cells/mm2; P<0.005 for both instances). IL-17A expression was predominantly detected in MCTC of LA. Significant correlations were found for the slope of phase III % pred. of the sb-N2-test (rs= -0.39), for the FEV1% pred. (rs= 0.37) and for FEV1/FVC ratio (rs=0.38) with MCT in SA (P<0.05 for all instances). 8-isoprostane concentration correlated with the mast cells in the SA (rs=0.44), there was no correlation for pH or FeNO with cellular distribution in SA. Conclusions Neutrophils, macrophages and mast cells are more prominent in the SA indicating that these cells are involved in the development of small airway dysfunction in smokers. Among these cell types, the best correlation was found for mast cells with lung function parameters and inflammatory markers in exhaled breath. Furthermore, the observed predominant expression of IL-17A in mast cells warrants further investigation to elucidate their role in smoking

  14. Genomic responses in mouse models poorly mimic human inflammatory diseases

    PubMed Central

    Seok, Junhee; Warren, H. Shaw; Cuenca, Alex G.; Mindrinos, Michael N.; Baker, Henry V.; Xu, Weihong; Richards, Daniel R.; McDonald-Smith, Grace P.; Gao, Hong; Hennessy, Laura; Finnerty, Celeste C.; López, Cecilia M.; Honari, Shari; Moore, Ernest E.; Minei, Joseph P.; Cuschieri, Joseph; Bankey, Paul E.; Johnson, Jeffrey L.; Sperry, Jason; Nathens, Avery B.; Billiar, Timothy R.; West, Michael A.; Jeschke, Marc G.; Klein, Matthew B.; Gamelli, Richard L.; Gibran, Nicole S.; Brownstein, Bernard H.; Miller-Graziano, Carol; Calvano, Steve E.; Mason, Philip H.; Cobb, J. Perren; Rahme, Laurence G.; Lowry, Stephen F.; Maier, Ronald V.; Moldawer, Lyle L.; Herndon, David N.; Davis, Ronald W.; Xiao, Wenzhong; Tompkins, Ronald G.; Abouhamze, Amer; Balis, Ulysses G. J.; Camp, David G.; De, Asit K.; Harbrecht, Brian G.; Hayden, Douglas L.; Kaushal, Amit; O’Keefe, Grant E.; Kotz, Kenneth T.; Qian, Weijun; Schoenfeld, David A.; Shapiro, Michael B.; Silver, Geoffrey M.; Smith, Richard D.; Storey, John D.; Tibshirani, Robert; Toner, Mehmet; Wilhelmy, Julie; Wispelwey, Bram; Wong, Wing H

    2013-01-01

    A cornerstone of modern biomedical research is the use of mouse models to explore basic pathophysiological mechanisms, evaluate new therapeutic approaches, and make go or no-go decisions to carry new drug candidates forward into clinical trials. Systematic studies evaluating how well murine models mimic human inflammatory diseases are nonexistent. Here, we show that, although acute inflammatory stresses from different etiologies result in highly similar genomic responses in humans, the responses in corresponding mouse models correlate poorly with the human conditions and also, one another. Among genes changed significantly in humans, the murine orthologs are close to random in matching their human counterparts (e.g., R2 between 0.0 and 0.1). In addition to improvements in the current animal model systems, our study supports higher priority for translational medical research to focus on the more complex human conditions rather than relying on mouse models to study human inflammatory diseases. PMID:23401516

  15. Schistosoma mansoni antigens modulate the allergic response in a murine model of ovalbumin-induced airway inflammation.

    PubMed

    Cardoso, L S; Oliveira, S C; Góes, A M; Oliveira, R R; Pacífico, L G; Marinho, F V; Fonseca, C T; Cardoso, F C; Carvalho, E M; Araujo, M I

    2010-05-01

    Schistosoma mansoni infection has been associated with protection against allergies. The mechanisms underlying this association may involve regulatory cells and cytokines. We evaluated the immune response induced by the S. mansoni antigens Sm22.6, PIII and Sm29 in a murine model of ovalbumin (OVA)-induced airway inflammation. BALB/c mice were sensitized with subcutaneously injected OVA-alum and challenged with aerolized OVA. Mice were given three doses of the different S. mansoni antigens. Lung histopathology, cellularity of bronchoalveolar lavage (BAL) and eosinophil peroxidase activity in lung were evaluated. Immunoglobulin (Ig)E levels in serum and cytokines in BAL were also measured. Additionally, we evaluated the frequency of CD4+forkhead box P3 (FoxP3)+ T cells in cultures stimulated with OVA and the expression of interleukin (IL)-10 by these cells. The number of total cells and eosinophils in BAL and the levels of OVA-specific IgE were reduced in the immunized mice. Also, the levels of IL-4 and IL-5 in the BAL of mice immunized with PIII and Sm22.6 were decreased, while the levels of IL-10 were higher in mice immunized with Sm22.6 compared to the non-immunized mice. The frequency of CD4+FoxP3+ T cells was higher in the groups of mice who received Sm22.6, Sm29 and PIII, being the expression of IL-10 by these cells only higher in mice immunized with Sm22.6. We concluded that the S. mansoni antigens used in this study are able to down-modulate allergic inflammatory mediators in a murine model of airway inflammation and that the CD4+FoxP3+ T cells, even in the absence of IL-10 expression, might play an important role in this process. PMID:20132231

  16. Schistosoma mansoni antigens modulate the allergic response in a murine model of ovalbumin-induced airway inflammation

    PubMed Central

    Cardoso, L S; Oliveira, S C; Góes, A M; Oliveira, R R; Pacífico, L G; Marinho, F V; Fonseca, C T; Cardoso, F C; Carvalho, E M; Araujo, M I

    2010-01-01

    Schistosoma mansoni infection has been associated with protection against allergies. The mechanisms underlying this association may involve regulatory cells and cytokines. We evaluated the immune response induced by the S. mansoni antigens Sm22·6, PIII and Sm29 in a murine model of ovalbumin (OVA)-induced airway inflammation. BALB/c mice were sensitized with subcutaneously injected OVA-alum and challenged with aerolized OVA. Mice were given three doses of the different S. mansoni antigens. Lung histopathology, cellularity of bronchoalveolar lavage (BAL) and eosinophil peroxidase activity in lung were evaluated. Immunoglobulin (Ig)E levels in serum and cytokines in BAL were also measured. Additionally, we evaluated the frequency of CD4+forkhead box P3 (FoxP3)+ T cells in cultures stimulated with OVA and the expression of interleukin (IL)-10 by these cells. The number of total cells and eosinophils in BAL and the levels of OVA-specific IgE were reduced in the immunized mice. Also, the levels of IL-4 and IL-5 in the BAL of mice immunized with PIII and Sm22·6 were decreased, while the levels of IL-10 were higher in mice immunized with Sm22·6 compared to the non-immunized mice. The frequency of CD4+FoxP3+ T cells was higher in the groups of mice who received Sm22·6, Sm29 and PIII, being the expression of IL-10 by these cells only higher in mice immunized with Sm22·6. We concluded that the S. mansoni antigens used in this study are able to down-modulate allergic inflammatory mediators in a murine model of airway inflammation and that the CD4+FoxP3+ T cells, even in the absence of IL-10 expression, might play an important role in this process. PMID:20132231

  17. Interleukin-1 Receptor and Caspase-1 Are Required for the Th17 Response in Nitrogen Dioxide–Promoted Allergic Airway Disease

    PubMed Central

    Martin, Rebecca A.; Ather, Jennifer L.; Lundblad, Lennart K. A.; Suratt, Benjamin T.; Boyson, Jonathan E.; Budd, Ralph C.; Alcorn, John F.; Flavell, Richard A.; Eisenbarth, Stephanie C.

    2013-01-01

    Nitrogen dioxide (NO2) is an environmental pollutant and endogenously generated oxidant associated with the development, severity, and exacerbation of asthma. NO2 exposure is capable of allergically sensitizing mice to the innocuous inhaled antigen ovalbumin (OVA), promoting neutrophil and eosinophil recruitment, and a mixed Th2/Th17 response upon antigen challenge that is reminiscent of severe asthma. However, the identity of IL-17A–producing cells and the mechanisms governing their ontogeny in NO2-promoted allergic airway disease remain unstudied. We measured the kinetics of lung inflammation after antigen challenge in NO2-promoted allergic airway disease, including inflammatory cells in bronchoalveolar lavage and antigen-specific IL-17A production from the lung. We determined that IL-17A+ cells were predominately CD4+T cell receptor (TCR)β+ Th17 cells, and that a functional IL-1 receptor was required for Th17, but not Th2, cytokine production after in vitro antigen restimulation of lung cells. The absence of natural killer T cells, γδ T cells, or the inflammasome scaffold nucleotide-binding oligomerization domain, leucine rich repeat and pyrin domain (Nlrp)3 did not affect the development of NO2-promoted allergic inflammation or IL-17A production. Similarly, neutrophil depletion or the neutralization of IL-1α during sensitization exerted no effect on these parameters. However, the absence of caspase-1 significantly reduced IL-17A production from lung cells without affecting Th2 cytokines or lung inflammation. Finally, the intranasal administration of IL-1β and the inhalation of antigen promoted allergic sensitization that was reflected by neutrophilic airway inflammation and IL-17A production from CD4+TCRβ+ Th17 cells subsequent to antigen challenge. These data implicate a role for caspase-1 and IL-1β in the IL-1 receptor–dependent Th17 response manifest in NO2-promoted allergic airway disease. PMID:23371061

  18. CORRELATES BETWEEN HUMAN LUNG INJURY AFTER PARTICLE EXPOSURE AND RECURRENT AIRWAY OBSTRUCTION IN THE HORSE

    EPA Science Inventory

    Characteristics of the clinical presentation, physiologic changes, and pathology of the human response to particulate matter (PM) are comparable to inflammatory airway disease (lAD) and recurrent airway obstruction (RAO)lheaves in the horse. Both present with symptoms of cough,...

  19. The Pathogenesis of ACLF: The Inflammatory Response and Immune Function.

    PubMed

    Moreau, Richard

    2016-05-01

    Although systemic inflammation is a hallmark of acute-on-chronic liver failure (ACLF), its role in the development of this syndrome is poorly understood. Here the author first summarizes the general principles of the inflammatory response. Inflammation can be triggered by exogenous or endogenous inducers. Important exogenous inducers include bacterial products such as pathogen-associated molecular patterns (PAMPs) and virulence factors. Pathogen-associated molecular patterns elicit inflammation through structural feature recognition (using innate pattern-recognition receptors [PRRs]), whereas virulence factors generally trigger inflammation via functional feature recognition. Endogenous inducers are called danger-associated molecular patterns (DAMPs) and include molecules released by necrotic cells and products of extracellular matrix breakdown. Danger-associated molecular patterns use different PRRs. The purpose of the inflammatory response may differ according to the type of stimulus: The aim of infection-induced inflammation is to decrease pathogen burden, whereas the DAMP-induced inflammation aims to promote tissue repair. An excessive inflammatory response can induce collateral tissue damage (a process called immunopathology). However immunopathology may not be the only mechanism of tissue damage; for example, organ failure can develop because of failed disease tolerance. In this review, the author also discusses how general principles of the inflammatory response can help us to understand the development of ACLF in different contexts: bacterial infection, severe alcoholic hepatitis, and cases in which there is no identifiable trigger. PMID:27172355

  20. Effects of nanoporous alumina on inflammatory cell response.

    PubMed

    Pujari, Shiuli; Hoess, Andreas; Shen, Jinhui; Thormann, Annika; Heilmann, Andreas; Tang, Liping; Karlsson-Ott, Marjam

    2014-11-01

    The present study focuses on the effects of nanoscale porosity on inflammatory response in vitro and in vivo. Nanoporous alumina membranes with different pore sizes, 20 and 200 nm in diameter, were used. We first evaluated cell/alumina interactions in vitro by observing adhesion, proliferation, and activation of a murine fibroblast and a macrophage cell line. To investigate the chronic inflammatory response, the membranes were implanted subcutaneously in mice for 2 weeks. Cell recruitment to the site of implantation was determined by histology and the production of cytokines was measured by protein array analysis. Both in vitro and in vivo studies showed that 200 nm pores induced a stronger inflammatory response as compared to the alumina with 20 nm pores. This was observed by an increase in macrophage activation in vitro as well as higher cell recruitment and generation of proinflammatory cytokines around the alumina with 200 nm pores, in vivo. Our results suggest that nanofeatures can be modulated in order to control the inflammatory response to implants. PMID:24288233

  1. Extracellular Cyclophilins Contribute to the Regulation of Inflammatory Responses1

    PubMed Central

    Arora, Kamalpreet; Gwinn, William M.; Bower, Molly A.; Watson, Alan; Okwumabua, Ifeanyi; MacDonald, H. Robson; Bukrinsky, Michael I.; Constant, Stephanie L.

    2010-01-01

    The main regulators of leukocyte trafficking during inflammatory responses are chemokines. However, another class of recently identified chemotactic agents is extracellular cyclophilins, the proteins mostly known as receptors for the immunosuppressive drug, cyclosporine A. Cyclophilins can induce leukocyte chemotaxis in vitro and have been detected at elevated levels in inflamed tissues, suggesting that they might contribute to inflammatory responses. We recently identified CD147 as the main signaling receptor for cyclophilin A. In the current study we examined the contribution of cyclophilin-CD147 interactions to inflammatory responses in vivo using a mouse model of acute lung injury. Blocking cyclophilin-CD147 interactions by targeting CD147 (using anti-CD147 Ab) or cyclophilin (using nonimmunosuppressive cyclosporine A analog) reduced tissue neutrophilia by up to 50%, with a concurrent decrease in tissue pathology. These findings are the first to demonstrate the significant contribution of cyclophilins to inflammatory responses and provide a potentially novel approach for reducing inflammation-mediated diseases. PMID:15972687

  2. COMPARTMENTALIZATION OF THE INFLAMMATORY RESPONSE TO INHALED GRAIN DUST

    EPA Science Inventory


    Interleukin (IL)-1beta, IL-6, IL-8, tumor necrosis factor (TNF)-alpha, and the secreted form of the IL-1 receptor antagonist (sIL-1RA) are involved in the inflammatory response to inhaled grain dust. Previously, we found considerable production of these cytokines in the lower...

  3. Bronchodilator and anti-inflammatory activities of glaucine: In vitro studies in human airway smooth muscle and polymorphonuclear leukocytes.

    PubMed

    Cortijo, J; Villagrasa, V; Pons, R; Berto, L; Martí-Cabrera, M; Martinez-Losa, M; Domenech, T; Beleta, J; Morcillo, E J

    1999-08-01

    1. Selective phosphodiesterase 4 (PDE4) inhibitors are of potential interest in the treatment of asthma. We examined the effects of the alkaloid S-(+)-glaucine, a PDE4 inhibitor, on human isolated bronchus and granulocyte function. 2. Glaucine selectively inhibited PDE4 from human bronchus and polymorphonuclear leukocytes (PMN) in a non-competitive manner (Ki=3.4 microM). Glaucine displaced [3H]-rolipram from its high-affinity binding sites in rat brain cortex membranes (IC50 approximately 100 microM). 3. Glaucine inhibited the spontaneous and histamine-induced tone in human isolated bronchus (pD2 approximately 4.5). Glaucine (10 microM) did not potentiate the isoprenaline-induced relaxation but augmented cyclic AMP accumulation by isoprenaline. The glaucine-induced relaxation was resistant to H-89, a protein kinase A inhibitor. Glaucine depressed the contractile responses to Ca2+ (pD'2 approximately 3.62) and reduced the sustained rise of [Ca2+]i produced by histamine in cultured human airway smooth muscle cells (-log IC50 approximately 4.3). 4. Glaucine augmented cyclic AMP levels in human polymorphonuclear leukocytes challenged with N-formyl-Met-Leu-Phe (FMLP) or isoprenaline, and inhibited FMLP-induced superoxide generation, elastase release, leukotriene B4 production, [Ca2+]i signal and platelet aggregation as well as opsonized zymosan-, phorbol myristate acetate-, and A23187-induced superoxide release. The inhibitory effect of glaucine on superoxide generation by FMLP was reduced by H-89. 5. In conclusion, Ca2+ channel antagonism by glaucine appears mainly responsible for the relaxant effect of glaucine in human isolated bronchus while PDE4 inhibition contributes to the inhibitory effects of glaucine in human granulocytes. The very low PDE4/binding site ratio found for glaucine makes this compound attractive for further structure-activity studies. PMID:10455321

  4. Bronchodilator and anti-inflammatory activities of glaucine: In vitro studies in human airway smooth muscle and polymorphonuclear leukocytes

    PubMed Central

    Cortijo, J; Villagrasa, V; Pons, R; Berto, L; Martí-Cabrera, M; Martinez-Losa, M; Domenech, T; Beleta, J; Morcillo, E J

    1999-01-01

    Selective phosphodiesterase 4 (PDE4) inhibitors are of potential interest in the treatment of asthma. We examined the effects of the alkaloid S-(+)-glaucine, a PDE4 inhibitor, on human isolated bronchus and granulocyte function.Glaucine selectively inhibited PDE4 from human bronchus and polymorphonuclear leukocytes (PMN) in a non-competitive manner (Ki=3.4 μM). Glaucine displaced [3H]-rolipram from its high-affinity binding sites in rat brain cortex membranes (IC50∼100 μM).Glaucine inhibited the spontaneous and histamine-induced tone in human isolated bronchus (pD2∼4.5). Glaucine (10 μM) did not potentiate the isoprenaline-induced relaxation but augmented cyclic AMP accumulation by isoprenaline. The glaucine-induced relaxation was resistant to H-89, a protein kinase A inhibitor. Glaucine depressed the contractile responses to Ca2+ (pD'2∼3.62) and reduced the sustained rise of [Ca2+]i produced by histamine in cultured human airway smooth muscle cells (−log IC50∼4.3).Glaucine augmented cyclic AMP levels in human polymorphonuclear leukocytes challenged with N-formyl-Met-Leu-Phe (FMLP) or isoprenaline, and inhibited FMLP-induced superoxide generation, elastase release, leukotriene B4 production, [Ca2+]i signal and platelet aggregation as well as opsonized zymosan-, phorbol myristate acetate-, and A23187-induced superoxide release. The inhibitory effect of glaucine on superoxide generation by FMLP was reduced by H-89.In conclusion, Ca2+ channel antagonism by glaucine appears mainly responsible for the relaxant effect of glaucine in human isolated bronchus while PDE4 inhibition contributes to the inhibitory effects of glaucine in human granulocytes. The very low PDE4/binding site ratio found for glaucine makes this compound attractive for further structure-activity studies. PMID:10455321

  5. Oxidative effects on lung inflammatory response in rats exposed to different concentrations of formaldehyde.

    PubMed

    Murta, Giselle Luciane; Campos, Keila Karine Duarte; Bandeira, Ana Carla Balthar; Diniz, Mirla Fiuza; Costa, Guilherme de Paula; Costa, Daniela Caldeira; Talvani, André; Lima, Wanderson Geraldo; Bezerra, Frank Silva

    2016-04-01

    The formaldehyde (FA) is a crosslinking agent that reacts with cellular macromolecules such as proteins, nucleic acids and molecules with low molecular weight such as amino acids, and it has been linked to inflammatory processes and oxidative stress. This study aimed to analyze the oxidative effects on pulmonary inflammatory response in Fischer rats exposed to different concentrations of FA. Twenty-eight Fischer rats were divided into 4 groups (N = 7). The control group (CG) was exposed to ambient air and three groups were exposed to different concentrations of FA: 1% (FA1%), 5% (FA5%) and 10% (FA10%). In the Bronchoalveolar Lavage Fluid (BALF), the exposure to a concentration of 10% promoted the increase of inflammatory cells compared to CG. There was also an increase of macrophages and lymphocytes in FA10% and lymphocytes in FA5% compared to CG. The activity of NADPH oxidase in the blood had been higher in FA5% and FA10% compared to CG. The activity of superoxide dismutase enzyme (SOD) had an increase in FA5% and the activity of the catalase enzyme (CAT) showed an increase in FA1% compared to CG. As for the glutathione system, there was an increase in total glutathione (tGSH), reduced glutathione (GSH) and oxidized glutathione (GSSG) in FA5% compared to CG. The reduced/oxidized glutathione ratio (GSH/GSSG) had a decrease in FA5% compared to CG. There was an increase in lipid peroxidation compared to all groups and the protein carbonyl formation in FA10% compared to CG. We also observed an increase in CCL2 and CCL5 chemokines in the treatment groups compared to CG and in serum there was an increase in CCL2, CCL3 and CCL5 compared to CG. Our results point out to the potential of formaldehyde in promoting airway injury by increasing the inflammatory process as well as by the redox imbalance. PMID:26774767

  6. INSTILLATION OF COARSE ASH PARTICULATE MATTER AND LIPOPOLYSACCHARIDE PRODUCES A SYSTEMIC INFLAMMATORY RESPONSE IN MICE

    EPA Science Inventory

    Coronary ischemic events increase significantly floowing a “bad air” day. Ambient particulate matter (PM10) is the pollutant most strongly associated with these events. PM10 causes inflammatory injury to the lower airways. It is not clear, however, if pulmonary inflation transl...

  7. The choroid plexus response to a repeated peripheral inflammatory stimulus

    PubMed Central

    2009-01-01

    Background Chronic systemic inflammation triggers alterations in the central nervous system that may relate to the underlying inflammatory component reported in neurodegenerative disorders such as multiple sclerosis and Alzheimer's disease. However, it is far from being understood whether and how peripheral inflammation contributes to induce brain inflammatory response in such illnesses. As part of the barriers that separate the blood from the brain, the choroid plexus conveys inflammatory immune signals into the brain, largely through alterations in the composition of the cerebrospinal fluid. Results In the present study we investigated the mouse choroid plexus gene expression profile, using microarray analyses, in response to a repeated inflammatory stimulus induced by the intraperitoneal administration of lipopolysaccharide every two weeks for a period of three months; mice were sacrificed 3 and 15 days after the last lipopolysaccharide injection. The data show that the choroid plexus displays a sustained response to the repeated inflammatory stimuli by altering the expression profile of several genes. From a total of 24,000 probes, 369 are up-regulated and 167 are down-regulated 3 days after the last lipopolysaccharide injection, while at 15 days the number decreases to 98 and 128, respectively. The pathways displaying the most significant changes include those facilitating entry of cells into the cerebrospinal fluid, and those participating in the innate immune response to infection. Conclusion These observations contribute to a better understanding of the brain response to peripheral inflammation and pave the way to study their impact on the progression of several disorders of the central nervous system in which inflammation is known to be implicated. PMID:19922669

  8. Titanium surface hydrophilicity modulates the human macrophage inflammatory cytokine response.

    PubMed

    Alfarsi, Mohammed A; Hamlet, Stephen M; Ivanovski, Saso

    2014-01-01

    Increased titanium surface hydrophilicity has been shown to accelerate dental implant osseointegration. Macrophages are important in the early inflammatory response to surgical implant placement and influence the subsequent healing response. This study investigated the modulatory effect of a hydrophilic titanium surface on the inflammatory cytokine expression profile in a human macrophage cell line (THP-1). Genes for 84 cytokines, chemokines, and their receptors were analyzed following exposure to (1) polished (SMO), (2) micro-rough sand blasted, acid etched (SLA), and (3) hydrophilic-modified SLA (modSLA) titanium surfaces for 1 and 3 days. By day 3, the SLA surface elicited a pro-inflammatory response compared to the SMO surface with statistically significant up-regulation of 16 genes [Tumor necrosis factor (TNF) Interleukin (IL)-1β, Chemokine (C-C motif) ligand (CCL)-1, 2, 3, 4, 18, 19, and 20, Chemokine (C-X-C motif) ligand (CXCL)-1, 5, 8 and 12, Chemokine (C-C motif) receptor (CCR)-7, Lymphotoxin-beta (LTB), and Leukotriene B4 receptor (LTB4R)]. This effect was countered by the modSLA surface, which down-regulated the expression of 10 genes (TNF, IL-1α and β, CCL-1, 3, 19 and 20, CXCL-1 and 8, and IL-1 receptor type 1), while two were up-regulated (osteopontin and CCR5) compared to the SLA surface. These cytokine gene expression changes were confirmed by decreased levels of corresponding protein secretion in response to modSLA compared to SLA. These results show that a hydrophilic titanium surface can modulate human macrophage pro-inflammatory cytokine gene expression and protein secretion. An attenuated pro-inflammatory response may be an important molecular mechanism for faster and/or improved wound healing. PMID:23595995

  9. Age specific responses to acute inhalation of diffusion flame soot particles: Cellular injury and the airway antioxidant response

    PubMed Central

    Van Winkle, Laura S.; Chan, Jackie K.W.; Anderson, Donald S.; Kumfer, Benjamin M.; Kennedy, Ian M.; Wexler, Anthony S; Wallis, Christopher; Abid, Aamir D.; Sutherland, Katherine M.; Fanucchi, Michelle V.

    2011-01-01

    Current studies of particulate matter (PM) are confounded by the fact that PM is a complex mixture of primary (crustal material, soot, metals) and secondary (nitrates, sulfates and organics formed in the atmosphere) compounds with considerable variance in composition by sources and location. We have developed a laboratory-based PM that is replicable, does not contain dust or metals and that can be used to study specific health effects of PM composition in animal models. We exposed both neonatal (7 days of age) and adult rats to a single 6-hr exposure of laboratory generated fine diffusion flame soot (DFP; 170 ug/m3), or filtered air. Pulmonary gene and protein expression as well as indicators of cytotoxicity were evaluated 24 hours after exposure. Although DFP exposure did not alter airway epithelial cell composition in either neonates or adults, increased LDH activity was found in the bronchoalveolar lavage fluid of neonates indicating an age-specific increase in susceptibility. In adults, 16 genes were differentially expressed as a result of DFP exposure while only 6 genes were altered in the airways of neonates. Glutamate cytsteine ligase protein was increased in abundance in both DFP exposed neonates and adults indicating an initiation of antioxidant responses involving the synthesis of glutathione. DFP significantly decreased catalase gene expression in adult airways, although catalase protein expression was increased by DFP in both neonates and adults. We conclude that key airway antioxidant enzymes undergo changes in expression in response to a moderate PM exposure that does not cause frank epithelial injury and that neonates have a different response pattern than adults. PMID:20961279

  10. A20-Deficient Mast Cells Exacerbate Inflammatory Responses In Vivo

    PubMed Central

    Vahl, J. Christoph; Aszodi, Attila; Peschke, Katrin; Schenten, Dominik; Hammad, Hamida; Beyaert, Rudi; Saur, Dieter; van Loo, Geert; Roers, Axel; Lambrecht, Bart N.; Kool, Mirjam; Schmidt-Supprian, Marc

    2014-01-01

    Mast cells are implicated in the pathogenesis of inflammatory and autoimmune diseases. However, this notion based on studies in mast cell-deficient mice is controversial. We therefore established an in vivo model for hyperactive mast cells by specifically ablating the NF-κB negative feedback regulator A20. While A20 deficiency did not affect mast cell degranulation, it resulted in amplified pro-inflammatory responses downstream of IgE/FcεRI, TLRs, IL-1R, and IL-33R. As a consequence house dust mite- and IL-33-driven lung inflammation, late phase cutaneous anaphylaxis, and collagen-induced arthritis were aggravated, in contrast to experimental autoimmune encephalomyelitis and immediate anaphylaxis. Our results provide in vivo evidence that hyperactive mast cells can exacerbate inflammatory disorders and define diseases that might benefit from therapeutic intervention with mast cell function. PMID:24453940

  11. Lung epithelial cells modulate the inflammatory response of alveolar macrophages.

    PubMed

    Rubovitch, Vardit; Gershnabel, Shoham; Kalina, Moshe

    2007-12-01

    The goal of this study was to examine the effect of alveolar epithelial cells on inflammatory responses in macrophages. Lung epithelial cells (either rat RLE-6TN or human A549 cells) reduced LPS-induced NO production in alveolar macrophages (AM) in a contact-independent mechanism. The inhibitory effect of the epithelial cells was present already at the transcriptional level: LPS-induced inducible NO synthase (iNOS) expression was significantly smaller. Surfactant protein A (SP-A)-induced NO production by alveolar macrophages was also reduced in the presence of A549 cells, though, by a different kinetics. LPS-induced interleukin-6 (IL-6) production (another inflammatory pathway) by alveolar macrophages was also reduced in the presence of RLE-6TN cells. These data suggest a role for lung epithelial cells in the complicated modulation of inflammatory processes, and provide an insight into the mechanism underlying. PMID:17851743

  12. Regulation of airway neurogenic inflammation by neutral endopeptidase.

    PubMed

    Di Maria, G U; Bellofiore, S; Geppetti, P

    1998-12-01

    Airway neurogenic inflammation is caused by tachykinins released from peripheral nerve endings of sensory neurons within the airways, and is characterized by plasma protein extravasation, airway smooth muscle contraction and increased secretion of mucus. Tachykinins are degraded and inactivated by neutral endopeptidase (NEP), a membrane-bound metallopeptidase, which is located mainly at the surface of airway epithelial cells, but is also present in airway smooth muscle cells, submucosal gland cells and fibroblasts. The key role of NEP in limiting and regulating the neurogenic inflammation provoked by different stimuli has been demonstrated in a large series of studies published in recent years. It has also been shown that a variety of factors, which are relevant for airway diseases, including viral infections, allergen exposure, inhalation of cigarette smoke and other respiratory irritants, is able to reduce NEP activity, thus enhancing the effects of tachykinins within the airways. On the basis of these observations, the reduction of neutral endopeptidase activity may be regarded as a factor that switches neurogenic airway responses from their physiological and protective functions to a detrimental role that increases and perpetuates airway inflammation. However, further studies are needed to assess the role of neutral endopeptidase down regulation in the pathogenesis of asthma and other inflammatory airway diseases. PMID:9877509

  13. Ibuprofen modifies the inflammatory response of the murine lung to Pseudomonas aeruginosa.

    PubMed

    Sordelli, D O; Cerquetti, M C; el-Tawil, G; Ramwell, P W; Hooke, A M; Bellanti, J A

    1985-08-01

    In chronic P. aeruginosa infection, lung tissue damage is induced by either the microorganism or the inflammatory response. We investigated, in an animal model, whether a non-steroidal anti-inflammatory drug, ibuprofen, reduced lung inflammation produced by P. aeruginosa. Lung lavages, pulmonary clearance of P. aeruginosa and lung pathology were studied in CD-1 mice injected with sodium ibuprofenate. A single dose of the drug, injected immediately after 30 min exposure to the P. aeruginosa aerosol, decreased the recruitment of granulocytes into airways in a dose-dependent manner. Pretreatment with 2 doses of the drug 18 and 6 h before the P. aeruginosa challenge was even more effective. The kinetics of changes in prostaglandin E2, 6-keto-prostaglandin F1 alpha and thromboxane B2 concentrations in lung lavage fluids after P. aeruginosa aerosol were also modified by ibuprofen. Moreover, ibuprofen treatment did not impair lung clearance of the challenge microorganisms, and the animals had less inflammation of the lungs. PMID:3863757

  14. Modulation of Hemostatic and Inflammatory Responses by Leptospira Spp.

    PubMed Central

    Vieira, Mônica L.; Naudin, Clément; Mörgelin, Matthias; Romero, Eliete C.; Nascimento, Ana Lucia T. O.; Herwald, Heiko

    2016-01-01

    Leptospirosis is a worldwide spread zoonotic and neglected infectious disease of human and veterinary concern that is caused by pathogenic Leptospira species. In severe infections, hemostatic impairments such as coagulation/fibrinolysis dysfunction are frequently observed. These complications often occur when the host response is controlled and/or modulated by the bacterial pathogen. In the present investigation, we aimed to analyze the modulation of the hemostatic and inflammatory host responses by the bacterial pathogen Leptospira. The effects of leptospires and their secreted products on stimulation of human intrinsic and extrinsic pathways of coagulation were investigated by means of altered clotting times, assembly and activation of contact system and induction of tissue factor. We show that both extrinsic and intrinsic coagulation cascades are modulated in response to Leptospira or leptospiral secreted proteins. We further find that the pro-inflammatory mediator bradykinin is released following contact activation at the bacterial surface and that pro-coagulant microvesicles are shed from monocytes in response to infection. Also, we show that human leptospirosis patients present higher levels of circulating pro-coagulant microvesicles than healthy individuals. Here we show that both pathways of the coagulation system are modulated by leptospires, possibly leading to altered hemostatic and inflammatory responses during the disease. Our results contribute to the understanding of the leptospirosis pathophysiological mechanisms and may open new routes for the discovery of novel treatments for the severe manifestations of the disease. PMID:27167223

  15. Modulation of Hemostatic and Inflammatory Responses by Leptospira Spp.

    PubMed

    Vieira, Mônica L; Naudin, Clément; Mörgelin, Matthias; Romero, Eliete C; Nascimento, Ana Lucia T O; Herwald, Heiko

    2016-05-01

    Leptospirosis is a worldwide spread zoonotic and neglected infectious disease of human and veterinary concern that is caused by pathogenic Leptospira species. In severe infections, hemostatic impairments such as coagulation/fibrinolysis dysfunction are frequently observed. These complications often occur when the host response is controlled and/or modulated by the bacterial pathogen. In the present investigation, we aimed to analyze the modulation of the hemostatic and inflammatory host responses by the bacterial pathogen Leptospira. The effects of leptospires and their secreted products on stimulation of human intrinsic and extrinsic pathways of coagulation were investigated by means of altered clotting times, assembly and activation of contact system and induction of tissue factor. We show that both extrinsic and intrinsic coagulation cascades are modulated in response to Leptospira or leptospiral secreted proteins. We further find that the pro-inflammatory mediator bradykinin is released following contact activation at the bacterial surface and that pro-coagulant microvesicles are shed from monocytes in response to infection. Also, we show that human leptospirosis patients present higher levels of circulating pro-coagulant microvesicles than healthy individuals. Here we show that both pathways of the coagulation system are modulated by leptospires, possibly leading to altered hemostatic and inflammatory responses during the disease. Our results contribute to the understanding of the leptospirosis pathophysiological mechanisms and may open new routes for the discovery of novel treatments for the severe manifestations of the disease. PMID:27167223

  16. Arousal and breathing responses to airway occlusion in healthy sleeping adults.

    PubMed

    Issa, F G; Sullivan, C E

    1983-10-01

    The arousal and breathing responses to total airway occlusion during sleep were measured in 12 normal subjects (7 males and 5 females) aged 25-36 yr. Subjects slept while breathing through a specially designed nosemask, which was glued to the nose with medical-grade silicon rubber. The lips were sealed together with a thin layer of Silastic. The nosemask was attached to a wide-bore (20 mm ID) rigid tube to allow a constant-bias flow of room air from a blower. Total airway occlusion was achieved by simultaneously inflating two rubber balloons fixed in the inspiratory and expiratory pipes. A total of 39 tests were done in stage III/IV nonrapid-eye movement (NREM) sleep in 11 subjects and 10 tests in rapid-eye-movement (REM) sleep in 5 subjects. The duration of total occlusion tolerated before arousal from NREM sleep varied widely (range 0.9-67.0 s) with a mean duration of 20.4 +/- 2.3 (SE) s. The breathing response to occlusion in NREM sleep was characterised by a breath-by-breath progressive increase in suction pressure achieved by an increase in the rate of inspiratory pressure generation during inspiration. In contrast, during REM sleep, arousal invariably occurred after a short duration of airway occlusion (mean duration 6.2 +/- 1.2 s, maximum duration 11.8 s), and the occlusion induced a rapid shallow breathing pattern. Our results indicate that total nasal occlusion during sleep causes arousal with the response during REM sleep being more predictable and with a generally shorter latency than that in NREM sleep. PMID:6629941

  17. Acid-sensing by airway afferent nerves

    PubMed Central

    Lee, Lu-Yuan; Gu, Qihai; Xu, Fadi; Hong, Ju-Lun

    2013-01-01

    Inhalation of acid aerosol or aspiration of acid solution evokes a stimulatory effect on airway C-fiber and Aδ afferents, which in turn causes airway irritation and triggers an array of defense reflex responses (e.g., cough, reflex bronchoconstriction, etc.). Tissue acidosis can also occur locally in the respiratory tract as a result of ischemia or inflammation, such as in the airways of asthmatic patients during exacerbation. The action of proton on the airway sensory neurons is generated by activation of two different current species: a transient (rapidly activating and inactivating) current mediated through the acid-sensing ion channels, and a slowly activating and sustained current mediated through the transient receptor potential vanilloid type 1 (TRPV1) receptor. In view of the recent findings that the expression and/or sensitivity of TRPV1 are up-regulated in the airway sensory nerves during chronic inflammatory reaction, the proton-evoked irritant effects on these nerves may play an important part in the manifestation of various symptoms associated with airway inflammatory diseases. PMID:23524016

  18. Primary Paediatric Bronchial Airway Epithelial Cell in Vitro Responses to Environmental Exposures

    PubMed Central

    McInnes, Neil; Davidson, Matthew; Scaife, Alison; Miller, David; Spiteri, Daniella; Engelhardt, Tom; Semple, Sean; Devereux, Graham; Walsh, Garry; Turner, Steve

    2016-01-01

    The bronchial airway epithelial cell (BAEC) is the site for initial encounters between inhaled environmental factors and the lower respiratory system. Our hypothesis was that release of pro inflammatory interleukins (IL)-6 and IL-8 from primary BAEC cultured from children will be increased after in vitro exposure to common environmental factors. Primary BAEC were obtained from children undergoing clinically indicated routine general anaesthetic procedures. Cells were exposed to three different concentrations of lipopolysaccharide (LPS) or house dust mite allergen (HDM) or particulates extracted from side stream cigarette smoke (SSCS). BAEC were obtained from 24 children (mean age 7.0 years) and exposed to stimuli. Compared with the negative control, there was an increase in IL-6 and IL-8 release after exposure to HDM (p ≤ 0.001 for both comparisons). There was reduced IL-6 after higher compared to lower SSCS exposure (p = 0.023). There was no change in BAEC release of IL-6 or IL-8 after LPS exposure. BAEC from children are able to recognise and respond in vitro with enhanced pro inflammatory mediator secretion to some inhaled exposures. PMID:27023576

  19. Primary Paediatric Bronchial Airway Epithelial Cell in Vitro Responses to Environmental Exposures.

    PubMed

    McInnes, Neil; Davidson, Matthew; Scaife, Alison; Miller, David; Spiteri, Daniella; Engelhardt, Tom; Semple, Sean; Devereux, Graham; Walsh, Garry; Turner, Steve

    2016-01-01

    The bronchial airway epithelial cell (BAEC) is the site for initial encounters between inhaled environmental factors and the lower respiratory system. Our hypothesis was that release of pro inflammatory interleukins (IL)-6 and IL-8 from primary BAEC cultured from children will be increased after in vitro exposure to common environmental factors. Primary BAEC were obtained from children undergoing clinically indicated routine general anaesthetic procedures. Cells were exposed to three different concentrations of lipopolysaccharide (LPS) or house dust mite allergen (HDM) or particulates extracted from side stream cigarette smoke (SSCS). BAEC were obtained from 24 children (mean age 7.0 years) and exposed to stimuli. Compared with the negative control, there was an increase in IL-6 and IL-8 release after exposure to HDM (p ≤ 0.001 for both comparisons). There was reduced IL-6 after higher compared to lower SSCS exposure (p = 0.023). There was no change in BAEC release of IL-6 or IL-8 after LPS exposure. BAEC from children are able to recognise and respond in vitro with enhanced pro inflammatory mediator secretion to some inhaled exposures. PMID:27023576

  20. The Systemic Inflammatory Response to Clostridium difficile Infection

    PubMed Central

    Rao, Krishna; Erb-Downward, John R.; Walk, Seth T.; Micic, Dejan; Falkowski, Nicole; Santhosh, Kavitha; Mogle, Jill A.; Ring, Cathrin; Young, Vincent B.; Huffnagle, Gary B.; Aronoff, David M.

    2014-01-01

    Background The systemic inflammatory response to Clostridium difficile infection (CDI) is incompletely defined, particularly for patients with severe disease. Methods Analysis of 315 blood samples from 78 inpatients with CDI (cases), 100 inpatients with diarrhea without CDI (inpatient controls), and 137 asymptomatic outpatient controls without CDI was performed. Serum or plasma was obtained from subjects at the time of CDI testing or shortly thereafter. Severe cases had intensive care unit admission, colectomy, or death due to CDI within 30 days after diagnosis. Thirty different circulating inflammatory mediators were quantified using an antibody-linked bead array. Principal component analysis (PCA), multivariate analysis of variance (MANOVA), and logistic regression were used for analysis. Results Based on MANOVA, cases had a significantly different inflammatory profile from outpatient controls but not from inpatient controls. In logistic regression, only chemokine (C-C motif) ligand 5 (CCL5) levels were associated with cases vs. inpatient controls. Several mediators were associated with cases vs. outpatient controls, especially hepatocyte growth factor, CCL5, and epithelial growth factor (inversely associated). Eight cases were severe and associated with elevations in IL-8, IL-6, and eotaxin. Conclusions A broad systemic inflammatory response occurs during CDI and severe cases appear to differ from non-severe infections. PMID:24643077

  1. Acute and chronic responses of the upper airway to inspiratory loading in healthy awake humans: an MRI study.

    PubMed

    How, Stephen C; McConnell, Alison K; Taylor, Bryan J; Romer, Lee M

    2007-08-01

    We assessed upper airway responses to acute and chronic inspiratory loading. In Experiment I, 11 healthy subjects underwent T(2)-weighted magnetic resonance imaging (MRI) of upper airway dilator muscles (genioglossus and geniohyoid) before and up to 10 min after a single bout of pressure threshold inspiratory muscle training (IMT) at 60% maximal inspiratory mouth pressure (MIP). T(2) values for genioglossus and geniohyoid were increased versus control (p<0.001), suggesting that these airway dilator muscles are activated in response to acute IMT. In Experiment II, nine subjects underwent 2D-Flash sequence MRI of the upper airway during quiet breathing and while performing single inspirations against resistive loads (10%, 30% and 50% MIP); this procedure was repeated after 6 weeks of IMT. Lateral narrowing of the upper airway occurred at all loads, whilst anteroposterior narrowing occurred at the level of the laryngopharynx at loads > or =30% MIP. Changes in upper airway morphology and narrowing after IMT were undetectable using MRI. PMID:17341450

  2. Influenza A infection enhances antigen-induced airway inflammation and hyper-responsiveness in young but not aged mice

    PubMed Central

    Birmingham, Janette M.; Gillespie, Virginia L.; Srivastava, Kamal; Li, Xiu-Min; Busse, Paula J.

    2015-01-01

    Background Although morbidity and mortality rates from asthma are highest in patients > 65 years of age, the effect of older age on airway inflammation in asthma is not well established. Objective To investigate age-related differences in the promotion of allergic inflammation after influenza A viral respiratory infection on antigen specific IgE production, antigen-induced airway inflammation and airway hyper-responsiveness in mice. Methods To accomplish this objective, the following model system was used. Young (six-week) and aged (18-month) BALB/c mice were first infected with a non-lethal dose of influenza virus A (H/HK×31). Mice were then ovalbumin (OVA) sensitized during the acute-infection (3-days post inoculation) and then chronically underwent challenge to the airways with OVA. Forty-eight hours after the final OVA-challenge, airway hyperresponsiveness (AHR), bronchoalveolar fluid (BALF) cellular and cytokine profile, antigen-specific IgE and IgG1, and lung tissue inflammation were measured. Results Age-specific differences were noted on the effect of a viral infection, allergic sensitization, airway inflammation and airway hyperresponsiveness. Serum OVA-specific IgE was significantly increased in only the aged mice infected with influenza virus. Despite greater morbidity (e.g. weight loss and sickness scores) during the acute infection in the 18-month old mice that were OVA-sensitized there was little effect on the AHR and BALF cellular differential. In contrast, BALF neutrophils and AHR increased, but eosinophils decreased in 6-week mice that were OVA-sensitized during an acute influenza infection. Conclusion With increased age in a mouse model, viral infection prior to antigen sensitization affects the airway and systemic allergic response differently. These differences may reflect distinct phenotypic features of allergic inflammation in older patients with asthma PMID:25039815

  3. Filoviruses and the balance of innate, adaptive, and inflammatory responses.

    PubMed

    Mohamadzadeh, Mansour; Chen, Lieping; Olinger, Gene G; Pratt, William D; Schmaljohn, Alan L

    2006-01-01

    The Filoviruses Marburg virus and Ebola virus are among the deadliest of human pathogens, causing fulminant hemorrhagic fevers typified by overmatched specific immune responses and profuse inflammatory responses. Keys to both vaccination and treatment may reside, first, in the understanding of immune dysfunctions that parallel Filoviral disease and, second, in devising ways to redirect and restore normal immune function as well as to mitigate inflammation. Here, we describe how Filoviral infections may subvert innate immune responses through perturbances of dendritic cells and neutrophils, with particular emphasis on the downstream effects on adaptive immunity and inflammation. We suggest that pivotal events may be subject to therapeutic intervention as Filoviruses encounter immune processes. PMID:17201655

  4. Invasive versus noninvasive measurement of allergic and cholinergic airway responsiveness in mice

    PubMed Central

    Glaab, Thomas; Ziegert, Michaela; Baelder, Ralf; Korolewitz, Regina; Braun, Armin; Hohlfeld, Jens M; Mitzner, Wayne; Krug, Norbert; Hoymann, Heinz G

    2005-01-01

    Background This study seeks to compare the ability of repeatable invasive and noninvasive lung function methods to assess allergen-specific and cholinergic airway responsiveness (AR) in intact, spontaneously breathing BALB/c mice. Methods Using noninvasive head-out body plethysmography and the decrease in tidal midexpiratory flow (EF50), we determined early AR (EAR) to inhaled Aspergillus fumigatus antigens in conscious mice. These measurements were paralleled by invasive determination of pulmonary conductance (GL), dynamic compliance (Cdyn) and EF50 in another group of anesthetized, orotracheally intubated mice. Results With both methods, allergic mice, sensitized and boosted with A. fumigatus, elicited allergen-specific EAR to A. fumigatus (p < 0.05 versus controls). Dose-response studies to aerosolized methacholine (MCh) were performed in the same animals 48 h later, showing that allergic mice relative to controls were distinctly more responsive (p < 0.05) and revealed acute airway inflammation as evidenced from increased eosinophils and lymphocytes in bronchoalveolar lavage. Conclusion We conclude that invasive and noninvasive pulmonary function tests are capable of detecting both allergen-specific and cholinergic AR in intact, allergic mice. The invasive determination of GL and Cdyn is superior in sensitivity, whereas the noninvasive EF50 method is particularly appropriate for quick and repeatable screening of respiratory function in large numbers of conscious mice. PMID:16309547

  5. Markers of airway inflammation and airway hyperresponsiveness in patients with well-controlled asthma.

    PubMed

    Leuppi, J D; Salome, C M; Jenkins, C R; Koskela, H; Brannan, J D; Anderson, S D; Andersson, M; Chan, H K; Woolcock, A J

    2001-09-01

    In steroid-naive asthmatics, airway hyperresponsiveness correlates with noninvasive markers of airway inflammation. Whether this is also true in steroid-treated asthmatics, is unknown. In 31 stable asthmatics (mean age 45.4 yrs, range 22-69; 17 females) taking a median dose of 1,000 microg inhaled corticosteroids (ICS) per day (range 100-3,600 microg x day(-1)), airway responsiveness to the "direct" agent histamine and to the "indirect" agent mannitol, lung function (forced expiratory volume in one second (FEV1), forced vital capacity (FVC), peak expiratory flow (PEF)), exhaled nitric oxide (eNO), and number of inflammatory cells in induced sputum as a percentage of total cell count were measured. Of the 31 subjects, 16 were hyperresponsive to mannitol and 11 to histamine. The dose-response ratio (DRR: % fall in FEV1/cumulative dose) to both challenge tests was correlated (r=0.59, p=0.0004). However, DRR for histamine and DRR for mannitol were not related to basic lung function, eNO, per cent sputum eosinophils and ICS dose. In addition, NO was not related to basic lung function and per cent sputum eosinophils. In clinically well-controlled asthmatics taking inhaled corticosteroids, there is no relationship between markers of airway inflammation (such as exhaled nitric oxide and sputum eosinophils) and airway responsiveness to either direct (histamine) or indirect (mannitol) challenge. Airway hyperresponsiveness in clinically well-controlled asthmatics appears to be independent of eosinophilic airway inflammation. PMID:11589340

  6. CD38 and Airway hyperresponsiveness: Studies on human airway smooth muscle cells and mouse models

    PubMed Central

    Guedes, Alonso GP; Deshpande, Deepak A; Dileepan, Mythili; Walseth, Timothy F; Panettieri, Reynold A; Subramanian, Subbaya; Kannan, Mathur S

    2015-01-01

    Asthma is an inflammatory disease in which altered calcium regulation, contractility and airway smooth muscle (ASM) proliferation contribute to airway hyperresponsiveness and airway wall remodeling. The enzymatic activity of CD38, a cell-surface protein expressed in human ASM cells, generates calcium mobilizing second messenger molecules such as cyclic ADP-ribose. CD38 expression in human ASM cells is augmented by cytokines (e.g. TNF-α) that requires activation of MAP kinases and the transcription factors, NF-ƙB and AP-1 and post-transcriptionally regulated by miR-140-3p and miR-708 by binding to 3’ Untranslated Region of CD38 as well as by modulating the activation of signaling mechanisms involved in its regulation. Mice deficient in CD38 exhibit reduced airway responsiveness to inhaled methacholine relative to response in wild-type mice. Intranasal challenge of CD38 deficient mice with TNF-α or IL-13, or the environmental fungus Alternaria alternata, causes significantly attenuated methacholine responsiveness compared to wild-type mice, with comparable airway inflammation. Reciprocal bone marrow transfer studies revealed partial restoration of airway hyperresponsiveness to inhaled methacholine in the Cd38 deficient mice. These studies provide evidence for CD38 involvement in the development of airway hyperresponsiveness, a hallmark feature of asthma. Future studies aimed at drug discovery and delivery targeting CD38 expression and/or activity are warranted. PMID:25594684

  7. The effects of inhaled corticosteroids on intrinsic responsiveness and histology of airways from infant monkeys exposed to house dust mite allergen and ozone

    SciTech Connect

    Joad, Jesse P. Kott, Kayleen S.; Bric, John M.; Schelegle, Edward S.; Gershwin, Laurel J.; Plopper, Charles G.; Peake, Janice L.; Pinkerton, Kent E.

    2008-01-15

    Inhaled corticosteroids (ICS) are recommended to treat infants with asthma, some with intermittent asthma. We previously showed that exposing infant monkeys to allergen/ozone resulted in asthma-like characteristics of their airways. We evaluated the effects of ICS on histology and intrinsic responsiveness of allergen/ozone-exposed and normal infant primate airways. Infant monkeys were exposed by inhalation to (1) filtered air and saline, (2) house dust mite allergen (HDMA) + ozone and saline, (3) filtered air and ICS (budesonide) or (4) HDMA + ozone and ICS. Allergen/ozone exposures started at 1 month and ICS at 3 months of age. At 6 months of age, methacholine-induced changes in luminal area of airways in proximal and distal lung slices were determined using videomicrometry, followed by histology of the same slices. Proximal airway responsiveness was increased by allergen/ozone and by ICS. Eosinophil profiles were increased by allergen/ozone in both proximal and distal airways, an effect that was decreased by ICS in distal airways. In both allergen/ozone- and air-exposed monkeys, ICS increased the number of alveolar attachments in distal airways, decreased mucin in proximal airways and decreased epithelial volume in both airways. ICS increased smooth muscle in air-exposed animals while decreasing it in allergen/ozone-exposed animals in both airways. In proximal airways, there was a small but significant positive correlation between smooth muscle and airway responsiveness, as well as between alveolar attachments and responsiveness. ICS change morphology and function in normal airways as well as allergen/ozone-exposed airways, suggesting that they should be reserved for infants with active symptoms.

  8. Benfotiamine Attenuates Inflammatory Response in LPS Stimulated BV-2 Microglia

    PubMed Central

    Bozic, Iva; Savic, Danijela; Laketa, Danijela; Bjelobaba, Ivana; Milenkovic, Ivan; Pekovic, Sanja; Nedeljkovic, Nadezda; Lavrnja, Irena

    2015-01-01

    Microglial cells are resident immune cells of the central nervous system (CNS), recognized as key elements in the regulation of neural homeostasis and the response to injury and repair. As excessive activation of microglia may lead to neurodegeneration, therapeutic strategies targeting its inhibition were shown to improve treatment of most neurodegenerative diseases. Benfotiamine is a synthetic vitamin B1 (thiamine) derivate exerting potentially anti-inflammatory effects. Despite the encouraging results regarding benfotiamine potential to alleviate diabetic microangiopathy, neuropathy and other oxidative stress-induced pathological conditions, its activities and cellular mechanisms during microglial activation have yet to be elucidated. In the present study, the anti-inflammatory effects of benfotiamine were investigated in lipopolysaccharide (LPS)-stimulated murine BV-2 microglia. We determined that benfotiamine remodels activated microglia to acquire the shape that is characteristic of non-stimulated BV-2 cells. In addition, benfotiamine significantly decreased production of pro-inflammatory mediators such as inducible form of nitric oxide synthase (iNOS) and NO; cyclooxygenase-2 (COX-2), heat-shock protein 70 (Hsp70), tumor necrosis factor alpha α (TNF-α), interleukin-6 (IL-6), whereas it increased anti-inflammatory interleukin-10 (IL-10) production in LPS stimulated BV-2 microglia. Moreover, benfotiamine suppressed the phosphorylation of extracellular signal-regulated kinases 1/2 (ERK1/2), c-Jun N-terminal kinases (JNK) and protein kinase B Akt/PKB. Treatment with specific inhibitors revealed that benfotiamine-mediated suppression of NO production was via JNK1/2 and Akt pathway, while the cytokine suppression includes ERK1/2, JNK1/2 and Akt pathways. Finally, the potentially protective effect is mediated by the suppression of translocation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) in the nucleus. Therefore, benfotiamine may

  9. Small airway dysfunction and flow and volume bronchodilator responsiveness in patients with chronic obstructive pulmonary disease

    PubMed Central

    Pisi, Roberta; Aiello, Marina; Zanini, Andrea; Tzani, Panagiota; Paleari, Davide; Marangio, Emilio; Spanevello, Antonio; Nicolini, Gabriele; Chetta, Alfredo

    2015-01-01

    Background We investigated whether a relationship between small airways dysfunction and bronchodilator responsiveness exists in patients with chronic obstructive pulmonary disease (COPD). Methods We studied 100 (20 female; mean age: 68±10 years) patients with COPD (forced expiratory volume in 1 second [FEV1]: 55% pred ±21%; FEV1/forced vital capacity [FVC]: 53%±10%) by impulse oscillometry system. Resistance at 5 Hz and 20 Hz (R5 and R20, in kPa·s·L−1) and the fall in resistance from 5 Hz to 20 Hz (R5 – R20) were used as indices of total, proximal, and peripheral airway resistance; reactance at 5 Hz (X5, in kPa·s·L−1) was also measured. Significant response to bronchodilator (salbutamol 400 μg) was expressed as absolute (≥0.2 L) and percentage (≥12%) change relative to the prebronchodilator value of FEV1 (flow responders, FRs) and FVC (volume responders, VRs). Results Eighty out of 100 participants had R5 – R20 >0.03 kPa·s·L−1 (> upper normal limit) and, compared to patients with R5 – R20 ≤0.030 kPa·s·L−1, showed a poorer health status, lower values of FEV1, FVC, FEV1/FVC, and X5, along with higher values of residual volume/total lung capacity and R5 (P<0.05 for all comparisons). Compared to the 69 nonresponders and the 8 FRs, the 16 VRs had significantly higher R5 and R5 – R20 values (P<0.05), lower X5 values (P<0.05), and greater airflow obstruction and lung hyperinflation. Conclusion This study shows that peripheral airway resistance is increased in the vast majority of patients with COPD, who showed worse respiratory reactance, worse spirometry results, more severe lung hyperinflation, and poorer health status. Small airway dysfunction was also associated with the bronchodilator responsiveness in terms of FVC, but not in terms of FEV1. PMID:26150710

  10. Sensory Neural Responses to Ozone Exposure during Early Postnatal Development in Rat Airways

    PubMed Central

    Hunter, Dawn D.; Wu, Zhongxin; Dey, Richard D.

    2010-01-01

    Airway infections or irritant exposures during early postnatal periods may contribute to the onset of childhood asthma. The purpose of this study was to examine critical periods of postnatal airway development during which ozone (O3) exposure leads to heightened neural responses. Rats were exposed to O3 (2 ppm) or filtered air for 1 hour on specific postnatal days (PDs) between PD1 and PD29, and killed 24 hours after exposure. In a second experiment, rats were exposed to O3 on PD2–PD6, inside a proposed critical period of development, or on PD19–PD23, outside the critical period. Both groups were re-exposed to O3 on PD28, and killed 24 hours later. Airways were removed, fixed, and prepared for substance P (SP) immunocytochemistry. SP nerve fiber density (NFD) in control extrapulmonary (EXP) epithelium/lamina propria (EPLP) increased threefold, from 1% to 3.3% from PD1–PD3 through PD13–PD15, and maintained through PD29. Upon O3 exposure, SP-NFD in EXP–smooth muscle (SM) and intrapulmonary (INT)-SM increased at least twofold at PD1–PD3 through PD13–PD15 in comparison to air exposure. No change was observed at PD21–PD22 or PD28–PD29. In critical period studies, SP-NFD in the INT-SM and EXP-SM of the PD2–PD6 O3 group re-exposed to O3 on PD28 was significantly higher than that of the group exposed at PD19–PD23 and re-exposed at PD28. These findings suggest that O3-mediated changes in sensory innervation of SM are more responsive during earlier postnatal development. Enhanced responsiveness of airway sensory nerves may be a contributing mechanism of increased susceptibility to environmental exposures observed in human infants and children. PMID:20118220

  11. Virulence Factors of Pseudomonas aeruginosa Induce Both the Unfolded Protein and Integrated Stress Responses in Airway Epithelial Cells.

    PubMed

    van 't Wout, Emily F A; van Schadewijk, Annemarie; van Boxtel, Ria; Dalton, Lucy E; Clarke, Hanna J; Tommassen, Jan; Marciniak, Stefan J; Hiemstra, Pieter S

    2015-06-01

    Pseudomonas aeruginosa infection can be disastrous in chronic lung diseases such as cystic fibrosis and chronic obstructive pulmonary disease. Its toxic effects are largely mediated by secreted virulence factors including pyocyanin, elastase and alkaline protease (AprA). Efficient functioning of the endoplasmic reticulum (ER) is crucial for cell survival and appropriate immune responses, while an excess of unfolded proteins within the ER leads to "ER stress" and activation of the "unfolded protein response" (UPR). Bacterial infection and Toll-like receptor activation trigger the UPR most likely due to the increased demand for protein folding of inflammatory mediators. In this study, we show that cell-free conditioned medium of the PAO1 strain of P. aeruginosa, containing secreted virulence factors, induces ER stress in primary bronchial epithelial cells as evidenced by splicing of XBP1 mRNA and induction of CHOP, GRP78 and GADD34 expression. Most aspects of the ER stress response were dependent on TAK1 and p38 MAPK, except for the induction of GADD34 mRNA. Using various mutant strains and purified virulence factors, we identified pyocyanin and AprA as inducers of ER stress. However, the induction of GADD34 was mediated by an ER stress-independent integrated stress response (ISR) which was at least partly dependent on the iron-sensing eIF2α kinase HRI. Our data strongly suggest that this increased GADD34 expression served to protect against Pseudomonas-induced, iron-sensitive cell cytotoxicity. In summary, virulence factors from P. aeruginosa induce ER stress in airway epithelial cells and also trigger the ISR to improve cell survival of the host. PMID:26083346

  12. Inflammatory Responses to Salmonella Infections Are Serotype-Specific

    PubMed Central

    Ktsoyan, Zhanna; Ghazaryan, Karine; Manukyan, Gayane; Martirosyan, Anush; Mnatsakanyan, Armine; Arakelova, Karine; Gevorgyan, Zaruhi; Sedrakyan, Anahit; Asoyan, Ara; Boyajyan, Anna; Aminov, Rustam

    2013-01-01

    The main purpose of this study was to investigate the profile of inflammatory response in patients with acute salmonellosis caused by two serotypes of Salmonella enterica, S. Enteritidis and S. Typhimurium, as well as in convalescent patients with previous acute disease caused by S. Enteritidis. Patients with acute disease showed significantly elevated levels of IL-1β, IL-17, IL-10, and calprotectin compared to healthy control subjects. In convalescent patients, these markers were also significantly elevated, with the exception of IL-1β. Multivariate statistical analyses with the use of these variables produced models with a good predictive accuracy resulting in excellent separation of the diseased and healthy cohorts studied. Overall, the results suggest that the profile of inflammatory response in this disease is determined, to a significant degree, by the serotype of Salmonella, and the profile of certain cytokines and calprotectin remains abnormal for a number of months following the acute disease stage. PMID:26904722

  13. Inflammatory Responses to Salmonella Infections Are Serotype-Specific.

    PubMed

    Ktsoyan, Zhanna; Ghazaryan, Karine; Manukyan, Gayane; Martirosyan, Anush; Mnatsakanyan, Armine; Arakelova, Karine; Gevorgyan, Zaruhi; Sedrakyan, Anahit; Asoyan, Ara; Boyajyan, Anna; Aminov, Rustam

    2013-01-01

    The main purpose of this study was to investigate the profile of inflammatory response in patients with acute salmonellosis caused by two serotypes of Salmonella enterica, S. Enteritidis and S. Typhimurium, as well as in convalescent patients with previous acute disease caused by S. Enteritidis. Patients with acute disease showed significantly elevated levels of IL-1β, IL-17, IL-10, and calprotectin compared to healthy control subjects. In convalescent patients, these markers were also significantly elevated, with the exception of IL-1β. Multivariate statistical analyses with the use of these variables produced models with a good predictive accuracy resulting in excellent separation of the diseased and healthy cohorts studied. Overall, the results suggest that the profile of inflammatory response in this disease is determined, to a significant degree, by the serotype of Salmonella, and the profile of certain cytokines and calprotectin remains abnormal for a number of months following the acute disease stage. PMID:26904722

  14. Th2 and eosinophil responses suppress inflammatory arthritis

    PubMed Central

    Chen, Zhu; Andreev, Darja; Oeser, Katharina; Krljanac, Branislav; Hueber, Axel; Kleyer, Arnd; Voehringer, David; Schett, Georg; Bozec, Aline

    2016-01-01

    Th2–eosinophil immune responses are well known for mediating host defence against helminths. Herein we describe a function of Th2–eosinophil responses in counteracting the development of arthritis. In two independent models of arthritis, Nippostrongylus brasiliensis infection leads to Th2 and eosinophil accumulation in the joints associated with robust inhibition of arthritis and protection from bone loss. Mechanistically, this protective effect is dependent on IL-4/IL-13-induced STAT6 pathway. Furthermore, we show that eosinophils play a central role in the modulation of arthritis probably through the increase of anti-inflammatory macrophages into arthritic joints. The presence of these pathways in human disease is confirmed by detection of GATA3-positive cells and eosinophils in the joints of rheumatoid arthritis patients. Taken together, these results demonstrate that eosinophils and helminth-induced activation of the Th2 pathway axis effectively mitigate the course of inflammatory arthritis. PMID:27273006

  15. Th2 and eosinophil responses suppress inflammatory arthritis.

    PubMed

    Chen, Zhu; Andreev, Darja; Oeser, Katharina; Krljanac, Branislav; Hueber, Axel; Kleyer, Arnd; Voehringer, David; Schett, Georg; Bozec, Aline

    2016-01-01

    Th2-eosinophil immune responses are well known for mediating host defence against helminths. Herein we describe a function of Th2-eosinophil responses in counteracting the development of arthritis. In two independent models of arthritis, Nippostrongylus brasiliensis infection leads to Th2 and eosinophil accumulation in the joints associated with robust inhibition of arthritis and protection from bone loss. Mechanistically, this protective effect is dependent on IL-4/IL-13-induced STAT6 pathway. Furthermore, we show that eosinophils play a central role in the modulation of arthritis probably through the increase of anti-inflammatory macrophages into arthritic joints. The presence of these pathways in human disease is confirmed by detection of GATA3-positive cells and eosinophils in the joints of rheumatoid arthritis patients. Taken together, these results demonstrate that eosinophils and helminth-induced activation of the Th2 pathway axis effectively mitigate the course of inflammatory arthritis. PMID:27273006

  16. The role of peroxiredoxin 4 in inflammatory response and aging.

    PubMed

    Klichko, Vladimir I; Orr, William C; Radyuk, Svetlana N

    2016-02-01

    In prior studies, we determined that the moderate overexpression of the Drosophila endoplasmic reticulum (ER)-localized peroxiredoxin (Prx), dPrx4, reduced oxidative damage and conferred beneficial effects on life span, while a high-level expression increased the incidence of tissue-specific apoptosis and dramatically shortened longevity. The detrimental pro-apoptotic and life-shortening effects were attributed to aberrant localization of dPrx4 and the apparent ER stress elicited by dPrx4 overexpression. In addition, the activation of both the NF-κB- and the JAK/STAT-mediated stress responses was detected, although it was not clear whether these served as functional alarm signals. Here we extend these findings to show that the activation of the NF-κB-dependent immunity-related/inflammatory genes, associated with life span shortening effects, is dependent on the activity of a Drosophila NF-κB ortholog, Relish. In the absence of Relish, the pro-inflammatory effects typically elicited by dPrx4 overexpression were not detected. The absence of Relish not only prevented the hyperactivation of the immunity-related genes but also significantly rescued the severe shortening of life span normally observed in dPrx4 overexpressors. The overactivation of the immune/inflammatory responses was also lessened by JAK/STAT signaling. In addition, we found that cellular immune/pro-inflammatory responses provoked by the oxidant paraquat but not bacteria are mediated via dPrx4 activity in the ER, as the upregulation of the immune-related genes was eliminated in flies underexpressing dPrx4, whereas immune responses triggered by bacteria were unaffected. Finally, efforts to reveal critical tissues where dPrx4 modulates longevity showed that broad targeting of dPrx4 to neuronal tissue had strong beneficial effects, while targeting expression to the fat body had deleterious effects. PMID:26689888

  17. Engineering macrophages to control the inflammatory response and angiogenesis.

    PubMed

    Eaton, K V; Yang, H L; Giachelli, C M; Scatena, M

    2015-12-10

    Macrophage (MΦ) dysregulation is increasingly becoming recognized as a risk factor for a number of inflammatory complications including atherosclerosis, cancer, and the host response elicited by biomedical devices. It is still unclear what roles the pro-inflammatory (M1) MΦ and pro-healing (M2) MΦ phenotypes play during the healing process. However, it has been shown that a local overabundance of M1 MΦs can potentially lead to a chronically inflamed state of the tissue; while a local over-exuberant M2 MΦ response can lead to tissue fibrosis and even promote tumorigenesis. These notions strengthen the argument that the tight temporal regulation of this phenotype balance is necessary to promote inflammatory resolution that leads to tissue homeostasis. In this study, we have engineered pro-inflammatory MΦs, MΦ-cTLR4 cells, which can be activated to a M1-like MΦ phenotype with a small molecule, the chemical inducer of dimerization (CID) drug. The MΦ-cTLR4 cells when activated with the CID drug, express increased levels of TNFα, IL-6, and iNOS. Activated MΦ-cTLR4 cells stay stimulated for at least 48h; once the CID drug is withdrawn, the MΦ-cTLR4 cells return to baseline state within 18h. Further, in vitro CID-activated MΦ-cTLR4 cells induce upregulation of VCAM-1 and ICAM-1 on endothelial cells (EC) in a TNFα-dependent manner. With the ability to specifically modulate the MФ-cTLR4 cells with the presence or absence of a small molecule, we now have the tool necessary to observe a primarily M1 MФ response during inflammation. By isolating this phase of the wound healing response, it may be possible to determine conditions for ideal healing. PMID:26610863

  18. Post-mating inflammatory responses of the uterus.

    PubMed

    Katila, T

    2012-08-01

    This review attempts to summarize the current knowledge on uterine inflammatory response after mating in horses, pigs and cattle. Post-mating endometritis has been extensively studied in horses as it has been considered to cause infertility. The inflammation is known to occur also in cattle, but it has not been investigated to a similar extent. There are a number of publications about mechanisms of post-mating uterine inflammation in pigs, which seem to resemble those in horses. The major focus of this review is the horse, but relevant literature is presented also on swine and cattle. Spermatozoa, seminal plasma and semen extenders play roles in the induction of inflammation. In addition, sperm numbers, concentration and viability, as well as the site of semen deposition may modulate the inflammatory response. Cytokines, polymorphonuclear leucocytes (PMN) and mononuclear cells represent the uterine inflammatory response to mating. Inflammation is the first line of defence against invasion and eliminates excess spermatozoa and bacteria. Semen deposition elicits a massive PMN invasion, followed by phagocytosis of sperm aided by the formation of neutrophil extracellular traps. Exposure of the female genital tract to semen is important also for endometrial receptivity and pre-implantation embryo development. Seminal plasma (SP) and inflammation elicit transient immune tolerance to antigens present in semen. SP contains immune-regulatory molecules that activate and control immune responses to antigens by stimulating expression of cytokines and growth factors and by initiating tissue remodelling. SP also regulates ovarian function. Effective elimination of excess sperm and inflammatory by-products and subsequent rapid return of the endometrium to the normal state is a prerequisite for pregnancy. Uterine backflow, driven by myometrial contractions and requiring a patent cervix, is an important physical tool in uterine drainage. PMID:22913558

  19. Cutaneous antigen priming via gene gun leads to skin-selective Th2 immune-inflammatory responses.

    PubMed

    Alvarez, David; Harder, Greg; Fattouh, Ramzi; Sun, Jiangfeng; Goncharova, Susanna; Stämpfli, Martin R; Coyle, Anthony J; Bramson, Jonathan L; Jordana, Manel

    2005-02-01

    It is becoming increasingly evident that the compartmentalization of immune responses is governed, in part, by tissue-selective homing instructions imprinted during T cell differentiation. In the context of allergic diseases, the fact that "disease" primarily manifests in particular tissue sites, despite pervasive allergen exposure, supports this notion. However, whether the original site of Ag exposure distinctly privileges memory Th2 immune-inflammatory responses to the same site, while sparing remote tissue compartments, remains to be fully investigated. We examined whether skin-targeted delivery of plasmid DNA encoding OVA via gene-gun technology in mice could generate allergic sensitization and give rise to Th2 effector responses in the skin as well as in the lung upon subsequent Ag encounter. Our data show that cutaneous Ag priming induced OVA-specific serum IgE and IgG1, robust Th2-cytokine production, and late-phase cutaneous responses and systemic anaphylactic shock upon skin and systemic Ag recall, respectively. However, repeated respiratory exposure to aerosolized OVA failed to instigate airway inflammatory responses in cutaneous Ag-primed mice, but not in mice initially sensitized to OVA via the respiratory mucosa. Importantly, these contrasting airway memory responses correlated with the occurrence of Th2 differentiation events at anatomically separate sites: indeed cutaneous Ag priming resulted in Ag-specific proliferative responses and Th2 differentiation in skin-, but not thoracic-, draining lymph nodes. These data indicate that Ag exposure to the skin leads to Th2 differentiation within skin-draining lymph nodes and subsequent Th2 immunity that is selectively manifested in the skin. PMID:15661930

  20. Putting the Squeeze on Airway Epithelia.

    PubMed

    Park, Jin-Ah; Fredberg, Jeffrey J; Drazen, Jeffrey M

    2015-07-01

    Asthma is characterized by chronic inflammation, airway hyperresponsiveness, and progressive airway remodeling. The airway epithelium is known to play a critical role in the initiation and perpetuation of these processes. Here, we review how excessive epithelial stress generated by bronchoconstriction is sufficient to induce airway remodeling, even in the absence of inflammatory cells. PMID:26136543

  1. Putting the Squeeze on Airway Epithelia

    PubMed Central

    Park, Jin-Ah; Fredberg, Jeffrey J.

    2015-01-01

    Asthma is characterized by chronic inflammation, airway hyperresponsiveness, and progressive airway remodeling. The airway epithelium is known to play a critical role in the initiation and perpetuation of these processes. Here, we review how excessive epithelial stress generated by bronchoconstriction is sufficient to induce airway remodeling, even in the absence of inflammatory cells. PMID:26136543

  2. Innate immune inflammatory response in the acutely ischemic myocardium.

    PubMed

    Deftereos, Spyridon; Angelidis, Christos; Bouras, Georgios; Raisakis, Konstantinos; Gerckens, Ulrich; Cleman, Michael W; Giannopoulos, Georgios

    2014-01-01

    The "holy grail" of modern interventional cardiology is the salvage of viable myocardial tissue in the distribution of an acutely occluded coronary artery. Thrombolysis and percutaneous coronary interventions, provided they can be delivered on time, can interrupt the occlusion and save tissue. At the same time restoring the patency of the coronary vessels and providing the ischemic myocardium with blood can cause additional tissue damage. A key element of ischemic and reperfusion injury and major determinant of the evolution of damage in the injured myocardium is the inflammatory response. The innate immune system initiates and directs this response which is a prerequisite for subsequent healing. The complement cascade is set in motion following the release of subcellular membrane constituents. Endogenous 'danger' signals known as danger-associated molecular patterns (DAMPs) released from ischemic and dying cells alert the innate immune system and activate several signal transduction pathways through interactions with the highly conserved Toll like receptors (TLRs). Reactive oxygen species (ROS) generation directly induces pro-inflammatory cascades and triggers formation of the inflammasome. The challenge lies into designing strategies that specifically block the inflammatory cascades responsible for tissue damage without affecting those concerned with tissue healing. PMID:25102201

  3. Attenuation of human nasal airway responses to bradykinin and histamine by inhibitors of nitric oxide synthase.

    PubMed Central

    Dear, J. W.; Ghali, S.; Foreman, J. C.

    1996-01-01

    1. The effects of inhibitors of nitric oxide synthase and local anaesthetics were studied on changes in human nasal airway patency and albumin extravasation in response to bradykinin and histamine, in vivo. 2. Compared with the action of the vasoconstrictor, ephedrine, 2.5 mumol, NG-nitro-L-arginine methyl ester (L-NAME), 1 mumol alone, did not change the resting value of the minimal cross-sectional area (A min) of the human nasal airway. L-NAME, 0.1 to 10 mumol, produced a dose-related inhibition of the reduction in A min caused by bradykinin, 300 micrograms. NG-monomethyl-L-arginine (L-NMMA), 1 mumol, similarly reduced the effect of bradykinin, 300 micrograms, on A min, but NG-nitro-D-arginine methyl ester (D-NAME), had no effect. L-NAME, 0.1 to 10 mumol, or L-NMMA, 10 mumol, failed to inhibit the effect of histamine, 300 micrograms on A min. 3. The inhibition by L-NAME, 1 mumol of the action of bradykinin, 300 micrograms on A min was maximal between 15 and 30 min after pretreatment with L-NAME. 4. L-NAME, 1 and 10 mumol, inhibited the extravasation of albumin into the nasal cavity induced by bradykinin, 300 micrograms, and also by histamine, 300 micrograms. D-NAME, 1 and 10 mumol had no effect on the extravasation of albumin in response to bradykinin or histamine. 5. L-Arginine, 30 mumol, reversed the effect of L-NAME, 1 mumol, on the bradykinin- and histamine-induced albumin extravasation into the nasal airway. 6. Local anaesthesia of the nasal airway with lignocaine, 10 mg, or benzocaine, 10 mg, failed to inhibit the reduction in A min or the albumin extravasation induced by either bradykinin, 300 micrograms, and histamine, 300 micrograms. 7. We conclude that the extravasation of plasma albumin caused by bradykinin and by histamine involves the generation of nitric oxide. The nasal blockage induced by bradykinin involves nitric oxide generation but the nasal blockage induced by histamine does not. PMID:8818341

  4. Pulmonary vascular and airway responses to systemic vasoconstrictors in anesthetized BALB/c mice.

    PubMed

    Wang, Mofei; Shibamoto, Toshishige; Shinomiya, Shohei; Yamamoto, Yuki; Kurata, Yasutaka; Kuda, Yuhichi; Tanida, Mamoru; Toga, Hirohisa

    2015-04-01

    There is no systematic study in which the effects of vasoactive substances were investigated on pulmonary vascular resistance (PVR) in in vivo mouse by directly measuring cardiac output and the inflow and outflow pressures in the pulmonary circulation. We determined the responses of PVR, total peripheral resistance (TPR), and airway pressure (AWP) to angiotensin II, endothelin-1, vasopressin, phenylephrine, and thromboxane A2 analog U46619 in anesthetized BALB/c mice. Pulmonary arterial pressure, left atrial pressure (LAP), and aortic blood flow were measured. TPR increased dose-dependently in response to consecutive administration of all vasoconstrictors except vasopressin which reduced TPR at the highest dose of 100 nmol/kg. At high doses of vasoconstrictors, pulmonary arterial pressure and AWP increased due to increased LAP, as demonstrated by the separate LAP elevation experiments. When LAP transiently increased at high doses, PVR did not increase but decreased. Nonetheless, enodothelin-1, angiotensin II, and U46619 increased PVR. Vasopressin at 100 nmol/kg increased AWP without LAP elevation. In conclusion, the high doses of the vasoconstrictors studied here exert indirectly a transient pulmonary vasodilatory and AWP increasing actions due to pulmonary congestion evoked by strong systemic vasoconstriction. Nevertheless, enodothelin-1, angiotensin II, and U46619 cause pulmonary vasoconstriction, and vasopressin constricts airway in anesthetized BALB/c mice. PMID:25853950

  5. Effect of reproterol either alone or combined with disodium cromoglycate on airway responsiveness to methacholine.

    PubMed

    Kanniess, Frank; Jörres, Rudolf A; Magnussen, Helgo

    2005-01-01

    Regular use of inhaled beta2-agonists might lead to tolerance as reflected in a loss of bronchoprotection. In vitro-data suggest that this might be prevented by disodium cromoglycate (DSCG). Therefore, we studied the effect of the beta2-agonist reproterol in combination with DSCG. In a cross-over design, 19 subjects with airway hyperresponsiveness inhaled either placebo, 1mg reproterol, 2 mg DSCG, or 1mg reproterol plus 2 mg DSCG 4x daily over 2 weeks. Treatment periods were separated by > or = 7 days. Before and at the end of periods, lung function and methacholine responsiveness were determined in the morning, and 6h later the bronchodilator effect and the protection against methacholine-induced bronchoconstriction. Reproterol or DSCG or their combination did not exert detrimental effects on lung function, airway responsiveness, or bronchodilator capacity. However, bronchoprotection was significantly reduced (p < 0.05) after treatment with placebo, reproterol or reproterol plus DSCG, the respective changes being 0.59, 0.96 and 1.37 doubling concentrations. All changes were small as compared to intraindividual variability. In this model all treatments except with DSCG caused a significant but small loss of protection against methacholine-induced bronchoconstriction. Thus, tolerance was not prevented by 2 weeks of additional treatment with DSCG, in contrast to in vitro findings. PMID:15939309

  6. Inflammatory responses in Ebola virus-infected patients

    PubMed Central

    BAIZE, S; LEROY, E M; GEORGES, A J; GEORGES-COURBOT, M-C; CAPRON, M; BEDJABAGA, I; LANSOUD-SOUKATE, J; MAVOUNGOU, E

    2002-01-01

    Ebola virus subtype Zaire (Ebo-Z) induces acute haemorrhagic fever and a 60–80% mortality rate in humans. Inflammatory responses were monitored in victims and survivors of Ebo-Z haemorrhagic fever during two recent outbreaks in Gabon. Survivors were characterized by a transient release in plasma of interleukin-1β (IL-1β), IL-6, tumour necrosis factor-α (TNFα), macrophage inflammatory protein-1α (MIP-1α) and MIP-1β early in the disease, followed by circulation of IL-1 receptor antagonist (IL-1RA) and soluble receptors for TNFα (sTNF-R) and IL-6 (sIL-6R) towards the end of the symptomatic phase and after recovery. Fatal infection was associated with moderate levels of TNFα and IL-6, and high levels of IL-10, IL-1RA and sTNF-R, in the days before death, while IL-1β was not detected and MIP-1α and MIP-1β concentrations were similar to those of endemic controls. Simultaneous massive activation of monocytes/macrophages, the main target of Ebo-Z, was suggested in fatal infection by elevated neopterin levels. Thus, presence of IL-1β and of elevated concentrations of IL-6 in plasma during the symptomatic phase can be used as markers of non-fatal infection, while release of IL-10 and of high levels of neopterin and IL-1RA in plasma as soon as a few days after the disease onset is indicative of a fatal outcome. In conclusion, recovery from Ebo-Z infection is associated with early and well-regulated inflammatory responses, which may be crucial in controlling viral replication and inducing specific immunity. In contrast, defective inflammatory responses and massive monocyte/macrophage activation were associated with fatal outcome. PMID:11982604

  7. On the inflammatory response in metal-on-metal implants

    PubMed Central

    2014-01-01

    Background Metal-on-metal implants are a special form of hip endoprostheses that despite many advantages can entail serious complications due to release of wear particles from the implanted material. Metal wear particles presumably activate local host defence mechanisms, which causes a persistent inflammatory response with destruction of bone followed by a loosening of the implant. To better characterize this inflammatory response and to link inflammation to bone degradation, the local generation of proinflammatory and osteoclast-inducing cytokines was analysed, as was systemic T cell activation. Methods By quantitative RT-PCR, gene expression of cytokines and markers for T lymphocytes, monocytes/macrophages and osteoclasts, respectively, was analysed in tissue samples obtained intraoperatively during exchange surgery of the loosened implant. Peripheral T cells were characterized by cytofluorometry before surgery and 7 to 10 days thereafter. Results At sites of osteolysis, gene expression of cathepsin K, CD14 and CD3 was seen, indicating the generation of osteoclasts, and the presence of monocytes and of T cells, respectively. Also cytokines were highly expressed, including CXCL8, IL-1ß, CXCL2, MRP-14 and CXCL-10. The latter suggest T cell activation, a notion that could be confirmed by detecting a small, though conspicuous population of activated CD4+ cells in the peripheral blood T cells prior to surgery. Conclusion Our data support the concept that metallosis is the result of a local inflammatory response, which according to histomorphology and the composition of the cellular infiltrate classifies as an acute phase of a chronic inflammatory disease. The proinflammatory environment, particularly the generation of the osteoclast-inducing cytokines CXCL8 and IL1-ß, promotes bone resorption. Loss of bone results in implant loosening, which then causes the major symptoms of metallosis, pain and reduced range of motion. PMID:24650243

  8. Inflammatory biomarkers as differential predictors of antidepressant response.

    PubMed

    Hashimoto, Kenji

    2015-01-01

    Although antidepressants are generally effective in the treatment of major depressive disorder (MDD), it can still take weeks before patients feel the full antidepressant effects. Despite the efficacy of standard treatments, approximately two-thirds of patients with MDD fail to respond to pharmacotherapy. Therefore, the identification of blood biomarkers that can predict the treatment response to antidepressants would be highly useful in order to improve this situation. This article discusses inflammatory molecules as predictive biomarkers for antidepressant responses to several classes of antidepressants, including the N-methyl-d-aspartate (NMDA) receptor antagonist ketamine. PMID:25856677

  9. Defining the Systemic Inflammatory Response Syndrome in Equine Neonates.

    PubMed

    Wong, David M; Wilkins, Pamela A

    2015-12-01

    Defining and describing the systemic inflammatory response syndrome (SIRS) and sepsis facilitated recognition and investigation of the complex disease processes involving the host response to infection and trauma. Over the years a variety of definitions of SIRS have been examined and applied to numerous research studies to improve critical care in both human and veterinary clinical practice. This article summarizes the history of the development of the SIRS definition, outlines the pathophysiologic processes that are involved in SIRS, and provides a specific definition for use in foal medicine. PMID:26612743

  10. Pathophysiological role of the acute inflammatory response during acetaminophen hepatotoxicity

    SciTech Connect

    Cover, Cathleen; Liu Jie; Farhood, Anwar; Malle, Ernst; Waalkes, Michael P.; Bajt, Mary Lynn; Jaeschke, Hartmut . E-mail: jaeschke@email.arizona.edu

    2006-10-01

    Neutrophils are recruited into the liver after acetaminophen (AAP) overdose but the pathophysiological relevance of this acute inflammatory response remains unclear. To address this question, we compared the time course of liver injury, hepatic neutrophil accumulation and inflammatory gene mRNA expression for up to 24 h after treatment with 300 mg/kg AAP in C3Heb/FeJ and C57BL/6 mice. Although there was no relevant difference in liver injury (assessed by the increase of plasma alanine aminotransferase activities and the areas of necrosis), the number of neutrophils and the expression of several pro-inflammatory genes (e.g., tumor necrosis factor-{alpha}, interleukin-1{beta} and macrophage inflammatory protein-2) was higher in C3Heb/FeJ than in C57BL/6 mice. In contrast, the expression of the anti-inflammatory genes interleukin-10 and heme oxygenase-1 was higher in C57BL/6 mice. Despite substantial hepatic neutrophil accumulation, none of the liver sections from both strains stained positive for hypochlorite-modified proteins, a specific marker for a neutrophil-induced oxidant stress. In addition, treatment with the NADPH oxidase inhibitors diphenyleneiodonium chloride or apocynin or the anti-neutrophil antibody Gr-1 did not protect against AAP hepatotoxicity. Furthermore, although intercellular adhesion molecule-1 (ICAM-1) was previously shown to be important for neutrophil extravasation and tissue injury in several models, ICAM-1-deficient mice were not protected against AAP-mediated liver injury. Together, these data do not support the hypothesis that neutrophils aggravate liver injury induced by AAP overdose.

  11. Pathophysiological role of the acute inflammatory response during acetaminophen hepatotoxicity.

    PubMed

    Cover, Cathleen; Liu, Jie; Farhood, Anwar; Malle, Ernst; Waalkes, Michael P; Bajt, Mary Lynn; Jaeschke, Hartmut

    2006-10-01

    Neutrophils are recruited into the liver after acetaminophen (AAP) overdose but the pathophysiological relevance of this acute inflammatory response remains unclear. To address this question, we compared the time course of liver injury, hepatic neutrophil accumulation and inflammatory gene mRNA expression for up to 24 h after treatment with 300 mg/kg AAP in C3Heb/FeJ and C57BL/6 mice. Although there was no relevant difference in liver injury (assessed by the increase of plasma alanine aminotransferase activities and the areas of necrosis), the number of neutrophils and the expression of several pro-inflammatory genes (e.g., tumor necrosis factor-alpha, interleukin-1beta and macrophage inflammatory protein-2) was higher in C3Heb/FeJ than in C57BL/6 mice. In contrast, the expression of the anti-inflammatory genes interleukin-10 and heme oxygenase-1 was higher in C57BL/6 mice. Despite substantial hepatic neutrophil accumulation, none of the liver sections from both strains stained positive for hypochlorite-modified proteins, a specific marker for a neutrophil-induced oxidant stress. In addition, treatment with the NADPH oxidase inhibitors diphenyleneiodonium chloride or apocynin or the anti-neutrophil antibody Gr-1 did not protect against AAP hepatotoxicity. Furthermore, although intercellular adhesion molecule-1 (ICAM-1) was previously shown to be important for neutrophil extravasation and tissue injury in several models, ICAM-1-deficient mice were not protected against AAP-mediated liver injury. Together, these data do not support the hypothesis that neutrophils aggravate liver injury induced by AAP overdose. PMID:16781746

  12. The Inflammatory Response in Psoriasis: a Comprehensive Review.

    PubMed

    Deng, Yaxiong; Chang, Christopher; Lu, Qianjin

    2016-06-01

    Psoriasis is a chronic inflammatory autoimmune disease characterized by an excessively aberrant hyperproliferation of keratinocytes. The pathogenesis of psoriasis is complex and the exact mechanism remains elusive. However, psoriasis is thought to result from a combination of genetic, epigenetic, and environmental influences. Recent studies have identified that epigenetic factors including dysregulated DNA methylation levels, abnormal histone modification and microRNAs expressions are involved in the development of psoriasis. The interplay of immune cells and cytokines is another critical factor in the pathogenesis of psoriasis. These factors or pathways include Th1/Th2 homeostasis, the Th17/Treg balance and the IL-23/Th17 axis. Th17 is believed particularly important in psoriasis due to its pro-inflammatory effects and its involvement in an integrated inflammatory loop with dendritic cells and keratinocytes, contributing to an overproduction of antimicrobial peptides, inflammatory cytokines, and chemokines that leads to amplification of the immune response. In addition, other pathways and signaling molecules have been found to be involved, including Th9, Th22, regulatory T cells, γδ T cells, CD8(+) T cells, and their related cytokines. Understanding the pathogenesis of psoriasis will allow us to develop increasingly efficient targeted treatment by blocking relevant inflammatory signaling pathways and molecules. There is no cure for psoriasis at the present time, and much of the treatment involves managing the symptoms. The biologics, while lacking the adverse effects associated with some of the traditional medications such as corticosteroids and methotrexate, have their own set of side effects, which may include reactivation of latent infections. Significant challenges remain in developing safe and efficacious novel targeted therapies that depend on a better understanding of the immunological dysfunction in psoriasis. PMID:27025861

  13. Role of moesin in HMGB1-stimulated severe inflammatory responses.

    PubMed

    Lee, W; Kwon, O K; Han, M-S; Lee, Y-M; Kim, S-W; Kim, K-M; Lee, T; Lee, S; Bae, J-S

    2015-08-01

    Sepsis is a life-threatening condition that arises when the body's response to infection causes systemic inflammation. High-mobility group box 1 (HMGB1), as a late mediator of sepsis, enhances hyperpermeability, and it is therefore a therapeutic target. Despite extensive research into the underlying mechanisms of sepsis, the target molecules controlling vascular leakage remain largely unknown. Moesin is a cytoskeletal protein involved in cytoskeletal changes and paracellular gap formation. The objectives of this study were to determine the roles of moesin in HMGB1-mediated vascular hyperpermeability and inflammatory responses and to investigate the mechanisms of action underlying these responses. Using siRNA knockdown of moesin expression in primary human umbilical vein endothelial cells (HUVECs), moesin was found to be required in HMGB1-induced F-actin rearrangement, hyperpermeability, and inflammatory responses. The mechanisms involved in moesin phosphorylation were analysed by blocking the binding of the HMGB1 receptor (RAGE) and inhibiting the Rho and MAPK pathways. HMGB1-treated HUVECs exhibited an increase in Thr558 phosphorylation of moesin. Circulating levels of moesin were measured in patients admitted to the intensive care unit with sepsis, severe sepsis, and septic shock; these patients showed significantly higher levels of moesin than healthy controls, which was strongly correlated with disease severity. High blood moesin levels were also observed in cecal ligation and puncture (CLP)-induced sepsis in mice. Administration of blocking moesin antibodies attenuated CLP-induced septic death. Collectively, our findings demonstrate that the HMGB1-RAGE-moesin axis can elicit severe inflammatory responses, suggesting it to be a potential target for the development of diagnostics and therapeutics for sepsis. PMID:25947626

  14. Airway Dysfunction in Obesity: Response to Voluntary Restoration of End Expiratory Lung Volume

    PubMed Central

    Oppenheimer, Beno W.; Berger, Kenneth I.; Segal, Leopoldo N.; Stabile, Alexandra; Coles, Katherine D.; Parikh, Manish; Goldring, Roberta M.

    2014-01-01

    Introduction Abnormality in distal lung function may occur in obesity due to reduction in resting lung volume; however, airway inflammation, vascular congestion and/or concomitant intrinsic airway disease may also be present. The goal of this study is to 1) describe the phenotype of lung function in obese subjects utilizing spirometry, plethysmography and oscillometry; and 2) evaluate residual abnormality when the effect of mass loading is removed by voluntary elevation of end expiratory lung volume (EELV) to predicted FRC. Methods 100 non-smoking obese subjects without cardio-pulmonary disease and with normal airflow on spirometry underwent impulse oscillometry (IOS) at baseline and at the elevated EELV. Results FRC and ERV were reduced (44±22, 62±14% predicted) with normal RV/TLC (29±9%). IOS demonstrated elevated resistance at 20 Hz (R20, 4.65±1.07 cmH2O/L/s); however, specific conductance was normal (0.14±0.04). Resistance at 5–20 Hz (R5−20, 1.86±1.11 cmH2O/L/s) and reactance at 5 Hz (X5, −2.70±1.44 cmH2O/L/s) were abnormal. During elevation of EELV, IOS abnormalities reversed to or towards normal. Residual abnormality in R5−20 was observed in some subjects despite elevation of EELV (1.16±0.8 cmH2O/L/s). R5−20 responded to bronchodilator at baseline but not during elevation of EELV. Conclusions This study describes the phenotype of lung dysfunction in obesity as reduction in FRC with airway narrowing, distal respiratory dysfunction and bronchodilator responsiveness. When R5−20 normalized during voluntary inflation, mass loading was considered the predominant mechanism. In contrast, when residual abnormality in R5−20 was demonstrable despite return of EELV to predicted FRC, mechanisms for airway dysfunction in addition to mass loading could be invoked. PMID:24505355

  15. [Cardiovascular responses during laryngeal mask airway insertion in normotensive, hypertensive and chronic renal failure patients].

    PubMed

    Yamauchi, M; Igarashi, M; Tsunoda, K; Edanaga, M; Suzuki, H; Tohdoh, Y; Namiki, A

    1999-08-01

    The hemodynamic response to the insertion of the laryngeal mask airway (LM) following induction with propofol 2 mg.kg-1 was assessed and compared in normotensive (Normal), hypertensive (HT) and chronic renal failure (CRF) patients (n = 23 in each group). Before induction, in HT and CRF groups blood pressure and rate pressure products (RPP) were higher than in Normal group (P < 0.05). Although blood pressure and RPP were decreased in every patient by induction with propofol, no patients needed vasopressor drugs. The decreases of blood pressure and RPP were larger in HT and CRF groups than in Normal group (P < 0.05). There were no differences between groups in heart rate and rate of successful LM insertion. We concluded that LM insertion with propofol 2 mg.kg-1 was an effective induction method preventing the adverse circulatory responses in normotensive, hypertensive and chronic renal failure patients. PMID:10481421

  16. Inhibition of CD23-mediated IgE transcytosis suppresses the initiation and development of airway allergic inflammation

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The epithelium lining the airway tract and allergen-specific IgE are considered essential controllers of inflammatory responses to allergens. The human IgE receptor, CD23 (Fc'RII), is capable of transporting IgE or IgE-allergen complexes across the polarized human airway epithelial cell (AEC) monola...

  17. Early onset airway obstruction in response to organic dust in the horse.

    PubMed

    Deaton, Christopher M; Deaton, Laura; Jose-Cunilleras, Eduard; Vincent, Thea L; Baird, Alan W; Dacre, K; Marlin, David J

    2007-03-01

    Equine recurrent airway obstruction (RAO) has been used as a naturally occurring model of human asthma. However, it is unknown whether there is an early-phase response in RAO. The aim of this study was to determine whether exposure to organic dust induces immediate changes in lung function in RAO-affected horses, which could be mediated by airway mast cells. Six RAO-affected horses in remission and six control horses were challenged with hay-straw dust suspension by nebulization. Total respiratory resistance at 1 Hz, measured by forced oscillation, was increased from 0.62 +/- 0.09 cmH(2)O.l(-1).s (mean +/- SE) to 1.23 +/- 0.20 cmH(2)O.l(-1).s 15 min after nebulization in control horses (P = 0.023) but did not change significantly in the RAO group. Total respiratory reactance at 1 Hz (P = 0.005) was significantly lower in the control horses (-0.77 +/- 0.07 cmH(2)O.l(-1).s) than in the RAO group (-0.49 +/- 0.04 cmH(2)O.l(-1).s) 15 min after nebulization. Bronchoalveolar lavage fluid (BALF) histamine concentration was significantly elevated 10 and 20 min postnebulization in control horses but not in RAO horses. Minimum reactance at 1 Hz in the early postnebulization period significantly correlated with both prechallenge BALF mast cell numbers (r = -0.65, P = 0.02) and peak BALF histamine concentration postnebulization (r = -0.61, P = 0.04). In conclusion, RAO horses, unlike human asthmatic patients, do not exhibit an early-phase response. However, healthy control horses do demonstrate a mild but significant early (<20 min) phase response to inhaled organic dust. This response may serve to decrease the subsequent dose of dust inhaled and as such provide a protective mechanism, which may be compromised in RAO horses. PMID:17158251

  18. Immunological and Inflammatory Responses to Organic Dust in Agriculture

    PubMed Central

    Poole, Jill A.; Romberger, Debra J.

    2012-01-01

    Purpose of review Agriculture represents a major industry worldwide, and despite protection against the development of IgE-mediated diseases, chronic exposure to agriculture-related organic dusts is associated with an increased risk of developing respiratory disease. This article will review the literature regarding new knowledge of important etiologic agents in the dusts and focus on the immunologic responses following acute and repetitive organic dust exposures. Recent findings Although endotoxin remains important, there is an emerging role for non-endotoxin components such as peptidoglycans from Gram-positive bacteria. Pattern recognition receptors including Toll-like receptor 4 (TLR4), TLR2 and intracellular nucleotide oligomerization domain-like receptors are partially responsible for mediating the inflammatory consequences. Repeated organic dust exposures modulate innate and adaptive immune function with a resultant adaptation-like response. However, repetitive exposures cause lung parenchymal inflammation, chronic disease, and lung function decline over time. Summary The immunological consequences of organic dust exposure in the farming industry are likely explained by the diversity of microbial motifs in dust that can elicit differing innate immune receptor signaling pathways. Whereas initial activation results in a robust inflammatory response, repetitive dust exposures modulate immunity. This can result in low-grade, chronic inflammation and/or protection against allergic disease. PMID:22306554

  19. Selective response of human airway epithelia to luminal but not serosal solution hypertonicity. Possible role for proximal airway epithelia as an osmolality transducer.

    PubMed Central

    Willumsen, N J; Davis, C W; Boucher, R C

    1994-01-01

    The response of cultured human nasal epithelia to hypertonic bathing solutions was tested using ion-selective microelectrode and quantitative microscopy. Raised luminal, but not serosal, osmolality (+/- 150 mM mannitol) decreased Na+ absorption but did not induce Cl- secretion. Raised luminal osmolality increased cell Cl- activity, Na+ activity, and transepithelial resistance and decreased both apical and basolateral membrane potentials and the fractional resistance of the apical membrane; equivalent circuit analysis revealed increases in apical, basolateral, and shunt resistances. Prolonged exposure (10 min) to 430 mosM luminal solution elicited no regulation of any parameter. Optical measurements revealed a reduction in the thickness of preparations only in response to luminal hypertonic solutions. We conclude that (a) airway epithelial cells exhibit asymmetric water transport properties, with the apical membrane water permeability exceeding that of the basolateral membrane; (b) the cellular response to volume loss is a deactivation of the basolateral membrane K+ conductance and the apical membrane Cl- conductance; (c) luminal hypertonicity slows the rate of Na+ absorption but does not induce Cl- secretion; and (d) cell volume loss increases the resistance of the paracellular path. We speculate that these properties configure human nasal epithelium to behave as an osmotic sensor, transducing information about luminal solutions to the airway wall. Images PMID:8040333

  20. Recruited alveolar macrophages, in response to airway epithelial-derived monocyte chemoattractant protein 1/CCl2, regulate airway inflammation and remodeling in allergic asthma.

    PubMed

    Lee, Yong Gyu; Jeong, Jong Jin; Nyenhuis, Sharmilee; Berdyshev, Evgeny; Chung, Sangwoon; Ranjan, Ravi; Karpurapu, Manjula; Deng, Jing; Qian, Feng; Kelly, Elizabeth A B; Jarjour, Nizar N; Ackerman, Steven J; Natarajan, Viswanathan; Christman, John W; Park, Gye Young

    2015-06-01

    Although alveolar macrophages (AMs) from patients with asthma are known to be functionally different from those of healthy individuals, the mechanism by which this transformation occurs has not been fully elucidated in asthma. The goal of this study was to define the mechanisms that control AM phenotypic and functional transformation in response to acute allergic airway inflammation. The phenotype and functional characteristics of AMs obtained from human subjects with asthma after subsegmental bronchoprovocation with allergen was studied. Using macrophage-depleted mice, the role and trafficking of AM populations was determined using an acute allergic lung inflammation model. We observed that depletion of AMs in a mouse allergic asthma model attenuates Th2-type allergic lung inflammation and its consequent airway remodeling. In both human and mouse, endobronchial challenge with allergen induced a marked increase in monocyte chemotactic proteins (MCPs) in bronchoalveolar fluid, concomitant with the rapid appearance of a monocyte-derived population of AMs. Furthermore, airway allergen challenge of allergic subjects with mild asthma skewed the pattern of AM gene expression toward high levels of the receptor for MCP1 (CCR2/MCP1R) and expression of M2 phenotypic proteins, whereas most proinflammatory genes were highly suppressed. CCL2/MCP-1 gene expression was prominent in bronchial epithelial cells in a mouse allergic asthma model, and in vitro studies indicate that bronchial epithelial cells produced abundant MCP-1 in response to house dust mite allergen. Thus, our study indicates that bronchial allergen challenge induces the recruitment of blood monocytes along a chemotactic gradient generated by allergen-exposed bronchial epithelial cells. PMID:25360868

  1. Zerumbone enhances the Th1 response and ameliorates ovalbumin-induced Th2 responses and airway inflammation in mice.

    PubMed

    Shieh, Ying-Hua; Huang, Huei-Mei; Wang, Ching-Chiung; Lee, Chen-Chen; Fan, Chia-Kwung; Lee, Yueh-Lun

    2015-02-01

    Zerumbone is a sesquiterpene compound isolated from the rhizome of wild ginger, Zingiber zerumbet Smith. The rhizomes of the plant are used as a spice and traditional medicine. Zerumbone was shown to possess anticarcinogenic, anti-inflammatory, and antioxidant properties. However, the antiallergic activity and the underlying mechanism of zerumbone have not been reported. Herein, we investigated the immunomodulatory effects of zerumbone on antigen-presenting dendritic cells (DCs) in vitro and its potential therapeutic effects against ovalbumin (OVA)-induced T helper 2 (Th2)-mediated asthma in mice. In the presence of zerumbone, lipopolysaccharide-activated bone marrow-derived DCs enhanced T cell proliferation and Th1 cell polarization in an allogeneic mixed lymphocyte reaction. In animal experiments, mice were sensitized and challenged with OVA, and were orally treated with different doses of zerumbone after sensitization. Circulating titers of OVA-specific antibodies, airway hyperresponsiveness to methacholine, histological changes in lung tissues, the cell composition and cytokine levels in bronchoalveolar lavage fluid, and cytokine profiles of spleen cells were assessed. Compared to OVA-induced hallmarks of asthma, oral administration of zerumbone induced lower OVA-specific immunoglobulin E (IgE) and higher IgG2a antibody production, attenuated airway hyperresponsiveness, prevented eosinophilic pulmonary infiltration, and ameliorated mucus hypersecretion. Zerumbone treatment also reduced the production of eotaxin, keratinocyte-derived chemokine (KC), interleukin (IL)-4, IL-5, IL-10, and IL-13, and promoted Th1 cytokine interferon (IFN)-γ production in asthmatic mice. Taken together, these results suggest that zerumbone exhibits an antiallergic effect via modulation of Th1/Th2 cytokines in an asthmatic mouse model. PMID:25573403

  2. Inflammatory Signals Regulate IL-15 in Response to Lymphodepletion.

    PubMed

    Anthony, Scott M; Rivas, Sarai C; Colpitts, Sara L; Howard, Megan E; Stonier, Spencer W; Schluns, Kimberly S

    2016-06-01

    Induction of lymphopenia has been exploited therapeutically to improve immune responses to cancer therapies and vaccinations. Whereas IL-15 has well-established roles in stimulating lymphocyte responses after lymphodepletion, the mechanisms regulating these IL-15 responses are unclear. We report that cell surface IL-15 expression is upregulated during lymphopenia induced by total body irradiation (TBI), cyclophosphamide, or Thy1 Ab-mediated T cell depletion, as well as in RAG(-/-) mice; interestingly, the cellular profile of surface IL-15 expression is distinct in each model. In contrast, soluble IL-15 (sIL-15) complexes are upregulated only after TBI or αThy1 Ab. Analysis of cell-specific IL-15Rα conditional knockout mice revealed that macrophages and dendritic cells are important sources of sIL-15 complexes after TBI but provide minimal contribution in response to Thy1 Ab treatment. Unlike with TBI, induction of sIL-15 complexes by αThy1 Ab is sustained and only partially dependent on type I IFNs. The stimulator of IFN genes pathway was discovered to be a potent inducer of sIL-15 complexes and was required for optimal production of sIL-15 complexes in response to Ab-mediated T cell depletion and TBI, suggesting products of cell death drive production of sIL-15 complexes after lymphodepletion. Lastly, we provide evidence that IL-15 induced by inflammatory signals in response to lymphodepletion drives lymphocyte responses, as memory CD8 T cells proliferated in an IL-15-dependent manner. Overall, these studies demonstrate that the form in which IL-15 is expressed, its kinetics and cellular sources, and the inflammatory signals involved are differentially dictated by the manner in which lymphopenia is induced. PMID:27183627

  3. Chronic exposure to a beta 2-adrenoceptor agonist increases the airway response to methacholine.

    PubMed

    Witt-Enderby, P A; Yamamura, H I; Halonen, M; Palmer, J D; Bloom, J W

    1993-09-01

    Scheduled chronic administration of beta 2-adrenoceptor agonist bronchodilators in patients with asthma recently has been reported to be associated with a worsening of symptoms and an increase in bronchial responsiveness. We wanted to determine whether a 28-day in vivo exposure to albuterol (beta 2-adrenoceptor agonist) altered the response of rabbit airways to the cholinergic agonist methacholine. We found, using in vitro tissue bath techniques, that in mainstem bronchi from rabbits given a 28-day exposure to albuterol, maximum contraction to methacholine was increased in the albuterol-treated group (control group = 1.10 +/- 0.11 g vs. treated group = 1.50 +/- 0.13 g, P < 0.05). The potency (EC75) was also increased in the albuterol-treated group. The potency for the control group was 5.6 microM (95% confidence limit: 2.3-13 microM) and was 1.7 microM (95% confidence limit: 1.1-2.8 microM, P < 0.05) for the albuterol-treated group. In a subgroup of animals, maximum contraction to KCl, a receptor-independent contractile stimulus, was not significantly different between the groups (control group = 0.79 +/- 0.23 g vs. treated group = 0.82 +/- 0.20 g). The potency (EC50) for KCl-induced contractions was also not significantly different between the groups: control = 12 mM (95% confidence limit: 3.3-44 mM) vs. treated 19 mM (95% confidence limit: 18-20 mM). These data demonstrate that chronic in vivo exposure to a beta 2-adrenoceptor agonist can alter the in vitro tissue bath response of airway smooth muscle to methacholine.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7901034

  4. Systemic inflammatory responses in African tick-bite fever.

    PubMed

    Jensenius, Mogens; Ueland, Thor; Fournier, Pierre-Edouard; Brosstad, Frank; Stylianou, Eva; Vene, Sirkka; Myrvang, Bjørn; Raoult, Didier; Aukrust, Pål

    2003-04-15

    Information regarding the inflammatory response in African tick-bite fever (ATBF), an emerging spotted-fever-group rickettsiosis, in international travelers to sub-Saharan Africa, is scarce. Plasma/serum levels of von Willebrand factor (vWF), soluble (s) E-selectin, tumor necrosis factor-alpha, interleukin (IL)-6, interferon-gamma, IL-10, IL-13, IL-8, RANTES, macrophage inflammatory protein-1alpha, and C-reactive protein were studied, at both first presentation and follow-up, in 15 patients with travel-associated ATBF and in 14 healthy travelers who served as control subjects. Our main and novel findings are the following: (1) patients with ATBF had increased levels of vWF and sE-selectin, with a subsequent decrease at follow-up; (2) with the exception of IFN-gamma, levels of cytokines and chemokines were also increased in these patients at the first presentation; and (3) IL-10 and IL-13 tended to increase during follow-up, whereas most of the inflammatory cytokines decreased. The induction of these mediators and the balance between them may be critical both for the regulation of inflammation and for protective immunity in ATBF. PMID:12696016

  5. Platelets in Pulmonary Immune Responses and Inflammatory Lung Diseases.

    PubMed

    Middleton, Elizabeth A; Weyrich, Andrew S; Zimmerman, Guy A

    2016-10-01

    Platelets are essential for physiological hemostasis and are central in pathological thrombosis. These are their traditional and best known activities in health and disease. In addition, however, platelets have specializations that broaden their functional repertoire considerably. These functional capabilities, some of which are recently discovered, include the ability to sense and respond to infectious and immune signals and to act as inflammatory effector cells. Human platelets and platelets from mice and other experimental animals can link the innate and adaptive limbs of the immune system and act across the immune continuum, often also linking immune and hemostatic functions. Traditional and newly recognized facets of the biology of platelets are relevant to defensive, physiological immune responses of the lungs and to inflammatory lung diseases. The emerging view of platelets as blood cells that are much more diverse and versatile than previously thought further predicts that additional features of the biology of platelets and of megakaryocytes, the precursors of platelets, will be discovered and that some of these will also influence pulmonary immune defenses and inflammatory injury. PMID:27489307

  6. Airway Epithelial Orchestration of Innate Immune Function in Response to Virus Infection. A Focus on Asthma.

    PubMed

    Ritchie, Andrew I; Jackson, David J; Edwards, Michael R; Johnston, Sebastian L

    2016-03-01

    Asthma is a very common respiratory condition with a worldwide prevalence predicted to increase. There are significant differences in airway epithelial responses in asthma that are of particular interest during exacerbations. Preventing exacerbations is a primary aim when treating asthma because they often necessitate unscheduled healthcare visits and hospitalizations and are a significant cause of morbidity and mortality. The most common cause of asthma exacerbations is a respiratory virus infection, of which the most likely type is rhinovirus infection. This article focuses on the role played by the epithelium in orchestrating the innate immune responses to respiratory virus infection. Recent studies show impaired bronchial epithelial cell innate antiviral immune responses, as well as augmentation of a pro-Th2 response characterized by the epithelial-derived cytokines IL-25 and IL-33, crucial in maintaining the Th2 cytokine response to virus infection in asthma. A better understanding of the mechanisms of these abnormal immune responses has the potential to lead to the development of novel therapeutic targets for virus-induced exacerbations. The aim of this article is to highlight current knowledge regarding the role of viruses and immune modulation in the asthmatic epithelium and to discuss exciting areas for future research and novel treatments. PMID:27027954

  7. The hepatic inflammatory response after acetaminophen overdose: role of neutrophils.

    PubMed

    Lawson, J A; Farhood, A; Hopper, R D; Bajt, M L; Jaeschke, H

    2000-04-01

    Acetaminophen overdose induces severe liver injury and hepatic failure. There is evidence that inflammatory cells may be involved in the pathophysiology. Thus, the aim of this investigation was to characterize the neutrophilic inflammatory response after treatment of C3Heb/FeJ mice with 300 mg/kg acetaminophen. A time course study showed that neutrophils accumulate in the liver parallel to or slightly after the development of liver injury. The number of neutrophils in the liver was substantial (209 +/- 64 PMN/50 high-power fields at 12 h) compared to baseline levels (7 +/- 1). Serum levels of TNF-alpha and the C-X-C chemokines KC and MIP-2 increased by 28-, 14-, and 295-fold, respectively, over levels found in controls during the injury process. In addition, mRNA expression of MIP-2 and KC were upregulated in livers of acetaminophen-treated animals as determined by ribonuclease protection assay. However, none of these mediators were generated in large enough quantities to account for neutrophil sequestration in the liver. There was no upregulation of Mac-1 (CD11b/ CD18) or shedding of L-selectin on circulating neutrophils. Moreover, an anti-CD18 antibody had no protective effect against acetaminophen overdose during the first 24 h. These results indicate that there is a local inflammatory response after acetaminophen overdose, including a substantial accumulation of neutrophils in the liver. Because of the critical importance of beta2 integrins for neutrophil cytotoxicity, these results suggest that neutrophils do not contribute to the initiation or progression of AAP-induced liver. The inflammation observed after acetaminophen overdose may be characteristic for a response sufficient to recruit neutrophils for the purpose of removing necrotic cells but is not severe enough to cause additional damage. PMID:10774834

  8. Scutellarein Reduces Inflammatory Responses by Inhibiting Src Kinase Activity

    PubMed Central

    Sung, Nak Yoon

    2015-01-01

    Flavonoids are plant pigments that have been demonstrated to exert various pharmacological effects including anti-cancer, anti-diabetic, anti-atherosclerotic, anti-bacterial, and anti-inflammatory activities. However, the molecular mechanisms in terms of exact target proteins of flavonoids are not fully elucidated yet. In this study, we aimed to evaluate the anti-inflammatory mechanism of scutellarein (SCT), a flavonoid isolated from Erigeron breviscapus, Clerodendrum phlomidis and Oroxylum indicum Vent that have been traditionally used to treat various inflammatory diseases in China and Brazil. For this purpose, a nitric oxide (NO) assay, polymerase chain reaction (PCR), nuclear fractionation, immunoblot analysis, a kinase assay, and an overexpression strategy were employed. Scutellarein significantly inhibited NO production in a dose-dependent manner and reduced the mRNA expression levels of inducible NO synthase (iNOS) and tumor necrosis factor (TNF)-α in lipopolysaccharide (LPS)-activated RAW264.7 cells. In addition, SCT also dampened nuclear factor (NF)-κB-driven expression of a luciferase reporter gene upon transfection of a TIR-domain-containing adapter-inducing interferon-β (TRIF) construct into Human embryonic kidney 293 (HEK 293) cells; similarly, NF-κ B nuclear translocation was inhibited by SCT. Moreover, the phosphorylation levels of various upstream signaling enzymes involved in NF-κB activation were decreased by SCT treatment in LPS-treated RAW264.7 cells. Finally, SCT strongly inhibited Src kinase activity and also inhibited the autophosphorylation of overexpressed Src. Therefore, our data suggest that SCT can block the inflammatory response by directly inhibiting Src kinase activity linked to NF-κB activation. PMID:26330757

  9. Systemic inflammatory response and neuromuscular involvement in amyotrophic lateral sclerosis

    PubMed Central

    Lu, Ching-Hua; Allen, Kezia; Oei, Felicia; Leoni, Emanuela; Kuhle, Jens; Tree, Timothy; Fratta, Pietro; Sharma, Nikhil; Sidle, Katie; Howard, Robin; Orrell, Richard; Fish, Mark; Greensmith, Linda; Pearce, Neil; Gallo, Valentina

    2016-01-01

    Objective: To evaluate the combined blood expression of neuromuscular and inflammatory biomarkers as predictors of disease progression and prognosis in amyotrophic lateral sclerosis (ALS). Methods: Logistic regression adjusted for markers of the systemic inflammatory state and principal component analysis were carried out on plasma levels of creatine kinase (CK), ferritin, and 11 cytokines measured in 95 patients with ALS and 88 healthy controls. Levels of circulating biomarkers were used to study survival by Cox regression analysis and correlated with disease progression and neurofilament light chain (NfL) levels available from a previous study. Cytokines expression was also tested in blood samples longitudinally collected for up to 4 years from 59 patients with ALS. Results: Significantly higher levels of CK, ferritin, tumor necrosis factor (TNF)–α, and interleukin (IL)–1β, IL-2, IL-8, IL-12p70, IL-4, IL-5, IL-10, and IL-13 and lower levels of interferon (IFN)–γ were found in plasma samples from patients with ALS compared to controls. IL-6, TNF-α, and IFN-γ were the most highly regulated markers when all explanatory variables were jointly analyzed. High ferritin and IL-2 levels were predictors of poor survival. IL-5 levels were positively correlated with CK, as was TNF-α with NfL. IL-6 was strongly associated with CRP levels and was the only marker showing increasing expression towards end-stage disease in the longitudinal analysis. Conclusions: Neuromuscular pathology in ALS involves the systemic regulation of inflammatory markers mostly active on T-cell immune responses. Disease stratification based on the prognostic value of circulating inflammatory markers could improve clinical trials design in ALS. PMID:27308305

  10. Attachment avoidance predicts inflammatory responses to marital conflict.

    PubMed

    Gouin, Jean-Philippe; Glaser, Ronald; Loving, Timothy J; Malarkey, William B; Stowell, Jeffrey; Houts, Carrie; Kiecolt-Glaser, Janice K

    2009-10-01

    Marital stress has been associated with immune dysregulation, including increased production of interleukin-6 (IL-6). Attachment style, one's expectations about the availability and responsiveness of others in intimate relationships, appears to influence physiological stress reactivity and thus could influence inflammatory responses to marital conflict. Thirty-five couples were invited for two 24-h admissions to a hospital research unit. The first visit included a structured social support interaction, while the second visit comprised the discussion of a marital disagreement. A mixed effect within-subject repeated measure model indicated that attachment avoidance significantly influenced IL-6 production during the conflict visit but not during the social support visit. Individuals with higher attachment avoidance had on average an 11% increase in total IL-6 production during the conflict visit as compared to the social support visit, while individuals with lower attachment avoidance had, on average, a 6% decrease in IL-6 production during the conflict visit as compared to the social support visit. Furthermore, greater attachment avoidance was associated with a higher frequency of negative behaviors and a lower frequency of positive behaviors during the marital interaction, providing a mechanism by which attachment avoidance may influence inflammatory responses to marital conflict. In sum, these results suggest that attachment avoidance modulates marital behavior and stress-induced immune dysregulation. PMID:18952163

  11. Oxidative Stress Regulates CFTR Gene Expression in Human Airway Epithelial Cells through a Distal Antioxidant Response Element

    PubMed Central

    Zhang, Zhaolin; Leir, Shih-Hsing

    2015-01-01

    Cystic fibrosis transmembrane conductance regulator gene (CFTR) expression in human airway epithelial cells involves the recruitment of distal cis-regulatory elements, which are associated with airway-selective DNase hypersensitive sites at −44 kb and −35 kb from the gene. The −35-kb site encompasses an enhancer that is regulated by the immune mediators interferon regulatory factor 1 and 2 and by nuclear factor Y. Here we investigate the −44-kb element, which also has enhancer activity in vitro in airway epithelial cells but is inactive in intestinal epithelial cells. This site contains an antioxidant response element (ARE) that plays a critical role in its function in airway cell lines and primary human bronchial epithelial cells. The natural antioxidant sulforaphane (SFN) induces nuclear translocation of nuclear factor, erythroid 2-like 2 (Nrf2), a transcription factor that regulates genes with AREs in their promoters, many of which are involved in response to injury. Under normal conditions, the −44-kb ARE is occupied by the repressor BTB and CNC homology 1, basic leucine zipper transcription factor (Bach1), and v-Maf avian musculoaponeurotic fibrosarcoma oncogene homolog K (MafK) heterodimers. After 2 hours of SFN treatment, Nrf2 displaces these repressive factors and activates CFTR expression. Site-directed mutagenesis shows that both the ARE and an adjacent NF-κB binding site are required for activation of the –44-kb element in airway epithelial cells. Moreover, this element is functionally linked to the −35-kb enhancer in modulating CFTR expression in response to environmental stresses in the airway. PMID:25259561

  12. Evaluation of cytotoxic, genotoxic and inflammatory responses of nanoparticles from photocopiers in three human cell lines

    PubMed Central

    2013-01-01

    Background Photocopiers emit nanoparticles with complex chemical composition. Short-term exposures to modest nanoparticle concentrations triggered upper airway inflammation and oxidative stress in healthy human volunteers in a recent study. To further understand the toxicological properties of copier-emitted nanoparticles, we studied in-vitro their ability to induce cytotoxicity, pro-inflammatory cytokine release, DNA damage, and apoptosis in relevant human cell lines. Methods Three cell types were used: THP-1, primary human nasal- and small airway epithelial cells. Following collection in a large volume photocopy center, nanoparticles were extracted, dispersed and characterized in the cell culture medium. Cells were doped at 30, 100 and 300 μg/mL administered doses for up to 24 hrs. Estimated dose delivered to cells, was ~10% and 22% of the administered dose at 6 and 24 hrs, respectively. Gene expression analysis of key biomarkers was performed using real time quantitative PCR (RT-qPCR) in THP-1 cells at 5 μg nanoparticles/mL for 6-hr exposure for confirmation purposes. Results Multiple cytokines, GM-CSF, IL-1β, IL-6, IL-8, IFNγ, MCP-1, TNF-α and VEGF, were significantly elevated in THP-1 cells in a dose-dependent manner. Gene expression analysis confirmed up-regulation of the TNF-α gene in THP-1 cells, consistent with cytokine findings. In both primary epithelial cells, cytokines IL-8, VEGF, EGF, IL-1α, TNF-α, IL-6 and GM-CSF were significantly elevated. Apoptosis was induced in all cell lines in a dose-dependent manner, consistent with the significant up-regulation of key apoptosis-regulating genes P53 and Casp8 in THP-1 cells. No significant DNA damage was found at any concentration with the comet assay. Up-regulation of key DNA damage and repair genes, Ku70 and Rad51, were also observed in THP-1 cells, albeit not statistically significant. Significant up-regulation of the key gene HO1 for oxidative stress, implicates oxidative stress induced by

  13. Pulmonary neuroendocrine cells function as airway sensors to control lung immune response.

    PubMed

    Branchfield, Kelsey; Nantie, Leah; Verheyden, Jamie M; Sui, Pengfei; Wienhold, Mark D; Sun, Xin

    2016-02-12

    The lung is constantly exposed to environmental atmospheric cues. How it senses and responds to these cues is poorly defined. Here, we show that Roundabout receptor (Robo) genes are expressed in pulmonary neuroendocrine cells (PNECs), a rare, innervated epithelial population. Robo inactivation in mouse lung results in an inability of PNECs to cluster into sensory organoids and triggers increased neuropeptide production upon exposure to air. Excess neuropeptides lead to an increase in immune infiltrates, which in turn remodel the matrix and irreversibly simplify the alveoli. We demonstrate in vivo that PNECs act as precise airway sensors that elicit immune responses via neuropeptides. These findings suggest that the PNEC and neuropeptide abnormalities documented in a wide array of pulmonary diseases may profoundly affect symptoms and progression. PMID:26743624

  14. Hyperosmolar solution effects in guinea pig airways. IV. Lipopolysaccharide-induced alterations in airway reactivity and epithelial bioelectric responses to methacholine and hyperosmolarity.

    PubMed

    Johnston, Richard A; Van Scott, Michael R; Kommineni, Choudari; Millecchia, Lyndell L; Dortch-Carnes, Juanita; Fedan, Jeffrey S

    2004-01-01

    We investigated the in vivo and in vitro effects of lipopolysaccharide (LPS) treatment (4 mg/kg i.p.) on guinea pig airway smooth muscle reactivity and epithelial bioelectric responses to methacholine (MCh) and hyperosmolarity. Hyperosmolar challenge of the epithelium releases epithelium-derived relaxing factor (EpDRF). Using a two-chamber, whole body plethysmograph 18 h post-treatment, animals treated with LPS were hyporeactive to inhaled MCh aerosol. This could involve an increase in the release and/or actions of EpDRF, because LPS treatment enhanced EpDRF-induced smooth muscle relaxation in vitro in the isolated perfused trachea apparatus. In isolated perfused tracheas the basal transepithelial potential difference (Vt) was increased after LPS treatment. The increase in Vt was inhibited by amiloride and indomethacin. Concentration-response curves for changes in Vt in response to serosally and mucosally applied MCh were biphasic (hyperpolarization, <3 x 10(-7)M; depolarization, >3 x 10(-7)M); MCh was more potent when applied serosally. The hyperpolarization response to MCh, but not the depolarization response, was potentiated after LPS treatment. In both treatment groups, mucosally applied hyperosmolar solution (using added NaCl) depolarized the epithelium; this response was greater in tracheas from LPS-treated animals. The results of this study indicate that airway hyporeactivity in vivo after LPS treatment is accompanied by an increase in the release and/or actions of EpDRF in vitro. These changes may involve LPS-induced bioelectric alterations in the epithelium. PMID:14566002

  15. REAL-TIME MEASUREMENT OF AIRWAY RESPONSES TO SULOFUR DIOXIDE (SO2) IN AN INTACT, AWAKE GUINEA PIG MODEL

    EPA Science Inventory

    Real-time measurment of airway responses to Sulfur Dioxide (SO2) in an intact, awake guinea pig model. J Stanek1,2, Q Krantz2, J Nolan2, D Winsett2, W Watkinson2, and D Costa2. 1College of Veterinary Medicine, NCSU, Raleigh, NC, USA; 2Pulmonary Toxicology Branch, ETD, NHEERL, US...

  16. Paradoxical responses to positive end-expiratory pressure in patients with airway obstruction during controlled ventilation*

    PubMed Central

    Caramez, Maria Paula; Borges, Joao B.; Tucci, Mauro R.; Okamoto, Valdelis N.; Carvalho, Carlos R. R.; Kacmarek, Robert M.; Malhotra, Atul; Velasco, Irineu Tadeu; Amato, Marcelo B. P.

    2008-01-01

    Objective To reevaluate the clinical impact of external positive end-expiratory pressure (external-PEEP) application in patients with severe airway obstruction during controlled mechanical ventilation. The controversial occurrence of a paradoxic lung deflation promoted by PEEP was scrutinized. Design External-PEEP was applied stepwise (2 cm H2O, 5-min steps) from zero-PEEP to 150% of intrinsic-PEEP in patients already submitted to ventilatory settings minimizing overinflation. Two commonly used frequencies during permissive hypercapnia (6 and 9/min), combined with two different tidal volumes (VT: 6 and 9 mL/kg), were tested. Setting A hospital intensive care unit. Patients Eight patients were enrolled after confirmation of an obstructive lung disease (inspiratory resistance, >20 cm H2O/L per sec) and the presence of intrinsic-PEEP (≥5 cm H2O) despite the use of very low minute ventilation. Interventions All patients were continuously monitored for intra-arterial blood gas values, cardiac output, lung mechanics, and lung volume with plethysmography. Measurements and Main Results Three different responses to external-PEEP were observed, which were independent of ventilatory settings. In the biphasic response, isovolume-expiratory flows and lung volumes remained constant during progressive PEEP steps until a threshold, beyond which overinflation ensued. In the classic overinflation response, any increment of external-PEEP caused a decrease in isovolume-expiratory flows, with evident overinflation. In the paradoxic response, a drop in functional residual capacity during external-PEEP application (when compared to zero-external-PEEP) was commonly accompanied by decreased plateau pressures and total-PEEP, with increased isovolume-expiratory flows. The paradoxic response was observed in five of the eight patients (three with asthma and two with chronic obstructive pulmonary disease) during at least one ventilator pattern. Conclusions External-PEEP application may

  17. Non-Invasive Optical Imaging of Eosinophilia during the Course of an Experimental Allergic Airways Disease Model and in Response to Therapy

    PubMed Central

    Markus, M. Andrea; Dullin, Christian; Mitkovski, Miso; Prieschl-Grassauer, Eva; Epstein, Michelle M.; Alves, Frauke

    2014-01-01

    Background Molecular imaging of lung diseases, including asthma, is limited and either invasive or non-specific. Central to the inflammatory process in asthma is the recruitment of eosinophils to the airways, which release proteases and proinflammatory factors and contribute to airway remodeling. The aim of this study was to establish a new approach to non-invasively assess lung eosinophilia during the course of experimental asthma by combining non-invasive near-infrared fluorescence (NIRF) imaging with the specific detection of Siglec-F, a lectin found predominantly on eosinophils. Methodology/Principal Findings An ovalbumin (OVA)-based model was used to induce asthma-like experimental allergic airway disease (EAAD) in BALB/c mice. By means of a NIRF imager, we demonstrate that 48 h–72 h after intravenous (i.v.) application of a NIRF-labeled anti-Siglec-F antibody, mice with EAAD exhibited up to 2 times higher fluorescence intensities compared to lungs of control mice. Furthermore, average lung intensities of dexamethasone-treated as well as beta-escin-treated mice were 1.8 and 2 times lower than those of untreated, EAAD mice, respectively and correlated with the reduction of cell infiltration in the lung. Average fluorescence intensities measured in explanted lungs confirmed the in vivo findings of significantly higher values in inflamed lungs as compared to controls. Fluorescence microscopy of lung cryosections localized the i.v. applied NIRF-labeled anti-Siglec-F antibody predominantly to eosinophils in the peribronchial areas of EAAD lungs as opposed to control lungs. Conclusion/Significance We show that monitoring the occurrence of eosinophils, a prominent feature of allergic asthma, by means of a NIRF-labeled antibody directed against Siglec-F is a novel and powerful non-invasive optical imaging approach to assess EAAD and therapeutic response in mice over time. PMID:24587190

  18. Exposure of humans to a volatile organic mixture. 3. Inflammatory response

    SciTech Connect

    Koren, H.S.; Graham, D.E.; Devlin, R.B.

    1992-01-01

    A set of symptoms has been described during the past two decades that has been called the sick building syndrome. These symptoms include eye, nose, and throat irritation; headache; mental fatigue; and respiratory distress. It is likely that the volatile organic compounds (VOCs) present in synthetic materials used in homes and office buildings contribute to these symptoms. However, there have been very few studies in which humans have been exposed to known amounts of VOCs under carefully controlled conditions. In the study, 14 subjects were exposed to a mixture of VOCs (25 mg/sq meter total hydrocarbon) that is representative of what is found in new homes and office buildings. Because irritations of the nose and throat are symptoms often associated with the upper respiratory tract and may result from an inflammatory response in the upper airways, the authors used nasal lavage to monitor neutrophil (PMN) influx into the nasal passages following exposure to VOCs. There were statistically significant increases in PMNs, both immediately after a 4-h exposure to VOCs and 18 h later.

  19. LIGHT is a crucial mediator of airway remodeling.

    PubMed

    Hung, Jen-Yu; Chiang, Shyh-Ren; Tsai, Ming-Ju; Tsai, Ying-Ming; Chong, Inn-Wen; Shieh, Jiunn-Min; Hsu, Ya-Ling

    2015-05-01

    Chronic inflammatory airway diseases like asthma and chronic obstructive pulmonary disease are major health problems globally. Airway epithelial cells play important role in airway remodeling, which is a critical process in the pathogenesis of diseases. This study aimed to demonstrate that LIGHT, an inflammatory factor secreted by T cells after allergen exposure, is responsible for promoting airway remodeling. LIGHT increased primary human bronchial epithelial cells (HBECs) undergoing epithelial-mesenchymal transition (EMT) and expressing MMP-9. The induction of EMT was associated with increased NF-κB activation and p300/NF-κB association. The interaction of NF-κB with p300 facilitated NF-κB acetylation, which in turn, was bound to the promoter of ZEB1, resulting in E-cadherin downregulation. LIGHT also stimulated HBECs to produce numerous cytokines/chemokines that could worsen airway inflammation. Furthermore, LIGHT enhanced HBECs to secrete activin A, which increased bronchial smooth muscle cell (BSMC) migration. In contrast, depletion of activin A decreased such migration. The findings suggest a new molecular determinant of LIGHT-mediated pathogenic changes in HBECs and that the LIGHT-related vicious cycle involving HBECs and BSMCs may be a potential target for the treatment of chronic inflammation airway diseases with airway remodeling. PMID:25251281

  20. Effects of tityustoxin on cerebral inflammatory response in young rats.

    PubMed

    Van Fraga, Iva Tereza; Limborço-Filho, Marcelo; Lima, Onésia Cristina Oliveira; Lacerda-Queiroz, Norinne; Guidine, Patrícia Alves Maia; Moraes, Márcio Flávio Dutra; Nascimento Araújo, Ricardo; Moraes-Santos, Tasso; Massensini, André Ricardo; Arantes, Rosa Maria Esteves; Carvalho-Tavares, Juliana

    2015-02-19

    Accidents caused by scorpion stings, mainly affecting children, are considered an important cause of morbidity and mortality in tropical countries. Clinical studies demonstrate the relevant role of systemic inflammatory events in scorpion envenoming. However, remains poorly understood whether the major lethal component in Tityus serrulatus venom, tityustoxin (TsTX), is able to induce inflammatory responses in the cerebral microcirculation. In this study, we systematically examined leukocyte recruitment into the CNS in response to TsTX injection. Accordingly, developing rats were subjected to a subcutaneous (s.c.) injection of TsTX (0.75mg/kg), and leukocyte recruitment (i.e., 4, 8 and 12h after injection) and TNF-α levels were evaluated. Rats injected with TsTX presented a significant increase in leukocyte rolling and adhesion and higher levels of TNF-α at all time points studied, compared to the control group. Altogether, this work demonstrates the triggering of neuroimmunological mechanisms induced by TsTX injection in young rats. PMID:25545555

  1. Inflammatory Response in Preterm and Very Preterm Newborns with Sepsis

    PubMed Central

    Segura-Cervantes, Enrique; Mancilla-Ramírez, Javier; González-Canudas, Jorge; Alba, Erika; Santillán-Ballesteros, René; Morales-Barquet, Deneb; Sandoval-Plata, Gabriela

    2016-01-01

    The response of the adaptive immune system is usually less intense in premature neonates than term neonates. The primary objective of this study was to determine whether immunological parameters vary between preterm (PT) neonates (≥32 weeks of gestational age) and very preterm (VPT) neonates (<32 weeks of gestational age). A cross-sectional study was designed to prospectively follow PT and VPT neonates at risk of developing sepsis. Plasma concentrations of IFN-γ, TNF-α, IL-6, IL-4, and IL-10 were detected using flow cytometry. C-reactive protein (C-RP) and the complex SC5b-9 were detected in the plasma using commercial kits. A total of 83 patients were included. The laboratory results and clinical histories showed that 26 patients had sepsis; 14 were VPT, and 12 were PT. The levels of C-RP, SC5b-9 (innate immune response mediators), and IL-10 or IL-4 (anti-inflammatory cytokines) were elevated during sepsis in both groups. IFN-γ, TNF-α, and IL-6 (proinflammatory cytokines) were differentially elevated only in PT neonates. The VPT neonates with sepsis presented increases in C-RP, SC5b-9, and anti-inflammatory cytokines but not in proinflammatory cytokines, whereas PT neonates showed increases in all studied mediators of inflammation. PMID:27293317

  2. Inflammatory Response in Preterm and Very Preterm Newborns with Sepsis.

    PubMed

    Segura-Cervantes, Enrique; Mancilla-Ramírez, Javier; González-Canudas, Jorge; Alba, Erika; Santillán-Ballesteros, René; Morales-Barquet, Deneb; Sandoval-Plata, Gabriela; Galindo-Sevilla, Norma

    2016-01-01

    The response of the adaptive immune system is usually less intense in premature neonates than term neonates. The primary objective of this study was to determine whether immunological parameters vary between preterm (PT) neonates (≥32 weeks of gestational age) and very preterm (VPT) neonates (<32 weeks of gestational age). A cross-sectional study was designed to prospectively follow PT and VPT neonates at risk of developing sepsis. Plasma concentrations of IFN-γ, TNF-α, IL-6, IL-4, and IL-10 were detected using flow cytometry. C-reactive protein (C-RP) and the complex SC5b-9 were detected in the plasma using commercial kits. A total of 83 patients were included. The laboratory results and clinical histories showed that 26 patients had sepsis; 14 were VPT, and 12 were PT. The levels of C-RP, SC5b-9 (innate immune response mediators), and IL-10 or IL-4 (anti-inflammatory cytokines) were elevated during sepsis in both groups. IFN-γ, TNF-α, and IL-6 (proinflammatory cytokines) were differentially elevated only in PT neonates. The VPT neonates with sepsis presented increases in C-RP, SC5b-9, and anti-inflammatory cytokines but not in proinflammatory cytokines, whereas PT neonates showed increases in all studied mediators of inflammation. PMID:27293317

  3. Inhalation of concentrated ambient particulate matter near a heavily trafficked road stimulates antigen-induced airway responses in mice.

    PubMed

    Kleinman, Michael T; Hamade, Ali; Meacher, Dianne; Oldham, Michael; Sioutas, Constantinos; Chakrabarti, Bhabesh; Stram, Dan; Froines, John R; Cho, Arthur K

    2005-09-01

    The goal of this study was to test the following hypotheses: (1) exposure to mobile emissions from mobile sources close to a heavily trafficked roadway will exacerbate airway inflammation and allergic airway responses in a sensitized mouse model, and (2) the magnitude of allergic airway disease responses will decrease with increasing distance from the roadway. A particle concentrator and a mobile exposure facility were used to expose ovalbumin (OVA)-sensitized BALB/c mice to purified air and concentrated fine and concentrated ultrafine ambient particles at 50 m and 150 m downwind from a roadway that was heavily impacted by emissions from heavy duty diesel-powered vehicles. After exposure, we assessed interleukin (IL)-5, IL-13, OVA-specific immunoglobulin E, OVA-specific immunoglobulin G1, and eosinophil influx as biomarkers of allergic responses and numbers of polymorphonuclear leukocytes as a marker of inflammation. The study was performed over a two-year period, and there were differences in the concentrations and compositions of ambient particulate matter across those years that could have influenced our results. However, averaged over the two-year period, exposure to concentrated ambient particles (CAPs) increased the biomarkers associated with airway allergies (IL-5, immunoglobulin E, immunoglobulin G1 and eosinophils). In addition, mice exposed to CAPs 50 m downwind of the roadway had, on the average, greater allergic responses and showed greater indications of inflammation than did mice exposed to CAPs 150 m downwind. This study is consistent with the hypothesis that exposure to CAPs close to a heavily trafficked roadway influenced allergic airway responses. PMID:16259423

  4. Fine particulate matter from urban ambient and wildfire sources from California's San Joaquin Valley initiate differential inflammatory, oxidative stress, and xenobiotic responses in human bronchial epithelial cells.

    PubMed

    Nakayama Wong, L S; Aung, H H; Lamé, M W; Wegesser, T C; Wilson, D W

    2011-12-01

    Environmental particulate matter (PM) exposure has been correlated with pathogenesis of acute airway inflammatory disease such as asthma and COPD. PM size and concentration have been studied extensively, but the additional effects of particulate components such as biological material, transition metals, and polycyclic aromatic hydrocarbons could also impact initial disease pathogenesis. In this study, we compared urban ambient particulate matter (APM) collected from Fresno, California with wildfire (WF) particulate matter collected from Escalon, California on early transcriptional responses in human bronchial epithelial cells (HBE). Global gene expression profiling of APM treated HBE activated genes related to xenobiotic metabolism (CYP 1B1), endogenous ROS generation and response genes (DUOX1, SOD2, PTGS2) and pro-inflammatory responses associated with asthma or COPD such as IL-1α, IL-1β, IL-8, and CCL20. WF PM treatments also induced a pro-inflammatory gene response, but elicited a more robust xenobiotic metabolism and oxidative stress response. Inhibitor studies targeting endotoxin, ROS, and trace metals, found endotoxin inhibition had modest selective inhibition of inflammation while inhibition of hydrogen peroxide and transition metals had broad effects suggesting additional interactions with xenobiotic metabolism pathways. APM induced a greater inflammatory response while WF PM had more marked metabolism and ROS related responses. PMID:21703343

  5. A sensory neuronal ion channel essential for airway inflammation and hyperreactivity in asthma.

    PubMed

    Caceres, Ana I; Brackmann, Marian; Elia, Maxwell D; Bessac, Bret F; del Camino, Donato; D'Amours, Marc; Witek, JoAnn S; Fanger, Chistopher M; Chong, Jayhong A; Hayward, Neil J; Homer, Robert J; Cohn, Lauren; Huang, Xiaozhu; Moran, Magdalene M; Jordt, Sven-Eric

    2009-06-01

    Asthma is an inflammatory disorder caused by airway exposures to allergens and chemical irritants. Studies focusing on immune, smooth muscle, and airway epithelial function revealed many aspects of the disease mechanism of asthma. However, the limited efficacies of immune-directed therapies suggest the involvement of additional mechanisms in asthmatic airway inflammation. TRPA1 is an irritant-sensing ion channel expressed in airway chemosensory nerves. TRPA1-activating stimuli such as cigarette smoke, chlorine, aldehydes, and scents are among the most prevalent triggers of asthma. Endogenous TRPA1 agonists, including reactive oxygen species and lipid peroxidation products, are potent drivers of allergen-induced airway inflammation in asthma. Here, we examined the role of TRPA1 in allergic asthma in the murine ovalbumin model. Strikingly, genetic ablation of TRPA1 inhibited allergen-induced leukocyte infiltration in the airways, reduced cytokine and mucus production, and almost completely abolished airway hyperreactivity to contractile stimuli. This phenotype is recapitulated by treatment of wild-type mice with HC-030031, a TRPA1 antagonist. HC-030031, when administered during airway allergen challenge, inhibited eosinophil infiltration and prevented the development of airway hyperreactivity. Trpa1(-/-) mice displayed deficiencies in chemically and allergen-induced neuropeptide release in the airways, providing a potential explanation for the impaired inflammatory response. Our data suggest that TRPA1 is a key integrator of interactions between the immune and nervous systems in the airways, driving asthmatic airway inflammation following inhaled allergen challenge. TRPA1 may represent a promising pharmacological target for the treatment of asthma and other allergic inflammatory conditions. PMID:19458046

  6. Effect of different bronchodilators on airway smooth muscle responsiveness to contractile agents.

    PubMed

    Gustafsson, B; Persson, C G

    1991-05-01

    "Functional antagonism" is often used to describe the general relaxant effect of beta 2 agonists and xanthines and their ability to protect the airways against bronchoconstrictor stimuli. This study in guinea pig isolated trachea addresses the question of whether the capacity of these drugs to protect against constrictor stimuli is related to smooth muscle relaxation. Three antimuscarinic drugs were also examined to determine whether antagonism of mediators other than muscarinic agonists might contribute to bronchodilatation by these antimuscarinic drugs. Terbutaline (1.1 x 10(-7), 2.2 x 10(-7) M), theophylline (2.2 x 10(-4), 4.4 x 10(-4) M), and enprofylline (5.2 x 10(-5), 1.0 x 10(-4) M) relaxed the tracheal tension that remained after indomethacin treatment. They did not, however, alter the carbachol concentration-response curve significantly. In addition, neither theophylline (2.2 x 10(-4) M) nor terbutaline (1.1 x 10(-7) M) altered histamine induced contraction. Atropine sulphate, glycopyrrolate, and ipratropium bromide had EC50 values of 10(-9) - 10(-8) M for relaxation of carbachol induced contractions, whereas concentrations of 10(-6) - 10(-3) M or greater were required to relax contractions induced by allergen and nine other non-muscarinic mediators. It is suggested that bronchodilatation by antimuscarinic drugs in vivo is due to inhibition of acetylcholine induced bronchoconstriction alone and that beta 2 agonists and xanthines have poor ability to protect airway smooth muscle against constrictor stimuli. Hence mechanisms other than bronchodilatation and "functional antagonism" should be considered to explain the protection against constrictor stimuli in asthma seen with beta 2 agonists and xanthines. PMID:2068693

  7. Divergent immune responses to house dust mite lead to distinct structural-functional phenotypes.

    PubMed

    Johnson, Jill R; Swirski, Filip K; Gajewska, Beata U; Wiley, Ryan E; Fattouh, Ramzi; Pacitto, Stephanie R; Wong, Jonathan K; Stämpfli, Martin R; Jordana, Manel

    2007-09-01

    Asthma is a chronic airway inflammatory disease that encompasses three cardinal processes: T helper (Th) cell type 2 (Th2)-polarized inflammation, bronchial hyperreactivity, and airway wall remodeling. However, the link between the immune-inflammatory phenotype and the structural-functional phenotype remains to be fully defined. The objective of these studies was to evaluate the relationship between the immunologic nature of chronic airway inflammation and the development of abnormal airway structure and function in a mouse model of chronic asthma. Using IL-4-competent and IL-4-deficient mice, we created divergent immune-inflammatory responses to chronic aeroallergen challenge. Immune-inflammatory, structural, and physiological parameters of chronic allergic airway disease were evaluated in both strains of mice. Although both strains developed airway inflammation, the profiles of the immune-inflammatory responses were markedly different: IL-4-competent mice elicited a Th2-polarized response and IL-4-deficient mice developed a Th1-polarized response. Importantly, this chronic Th1-polarized immune response was not associated with airway remodeling or bronchial hyperresponsiveness. Transient reconstitution of IL-4 in IL-4-deficient mice via an airway gene transfer approach led to partial Th2 repolarization and increased bronchial hyperresponsiveness, along with full reconstitution of airway remodeling. These data show that distinct structural-functional phenotypes associated with chronic airway inflammation are strictly dependent on the nature of the immune-inflammatory response. PMID:17586699

  8. Respiratory responses of subjects with allergic rhinitis to ozone exposure and their relationship to nonspecific airway reactivity

    SciTech Connect

    McDonnell, W.F.; Horstman, D.H.; Abdul-Salaam, S.; Raggio, L.J.; Green, J.A.

    1987-12-01

    Ozone exposure in man produces changes in respiratory function and symptoms. There is a large degree of unexplained intersubject variability in the magnitude of these responses. There is concern that individuals with chronic respiratory diseases may also be more responsive to ozone than normal individuals. The purpose of this study was to describe the responses of subjects with allergic rhinitis to ozone exposure and to compare these responses to those previously observed in normal individuals. A further purpose was to measure the association of baseline nonspecific airway reactivity with changes in lung function and respiratory symptoms following ozone exposure. A group of 26 nonasthmatic subjects with allergic rhinitis performed a bronchial inhalation challenge with histamine and subsequently underwent two hour exposures to both clean air and to 0.18 part per million ozone with alternating periods of rest and heavy exercise. The airway reactivity of this group of subjects was no greater than that of a comparable group of subjects without allergic rhinitis. The respiratory responses of these subjects to ozone exposure were similar to those previously reported for subjects without allergic rhinitis with the exception that the allergic rhinitis subjects appeared to have a modestly increased bronchoconstrictor response compared to normals. Furthermore, we observed no significant relationships between nonspecific airway reactivity and response to ozone as measured by changes in lung function or the induction of symptoms.

  9. Cardiovascular and inflammatory response to cholecystokinin during endotoxemic shock.

    PubMed

    Saia, Rafael Simone; Bertozi, Giuliana; Mestriner, Fabíola Leslie; Antunes-Rodrigues, José; Queiróz Cunha, Fernando; Cárnio, Evelin Capellari

    2013-01-01

    Cholecystokinin (CCK) was first described as a gastrointestinal hormone, but its receptors have been located in cardiac and vascular tissues, as well as in immune cells. Our aims were to investigate the role of CCK on lipopolysaccharide (LPS)-induced hypotension and its ability to modulate previously reported inflammatory mediators, therefore affecting cardiovascular function. To conduct these experiments, rats had their jugular vein cannulated for drug administration, and also, the femoral artery cannulated for mean arterial pressure (MAP) and heart rate records. Endotoxemia induced by LPS from Escherichia coli (1.5 mg/kg; i.v.) stimulated the release of CCK, a progressive drop in MAP, and increase in heart rate. Plasma tumor necrosis factor α (TNF-α), interleukin 10 (IL-10), nitrate, vasopressin, and lactate levels were elevated in the endotoxemic rats. The pretreatment with proglumide (nonselective CCK antagonist; 30 mg/kg; i.p.) aggravated the hypotension and also increased plasma TNF-α and lactate levels. On the other hand, CCK (0.4 μg/kg; i.v.) administered before LPS significantly restored MAP, reduced aortic and hepatic inducible nitric oxide synthase (iNOS) production, and elevated plasma vasopressin and IL-10 concentrations; it did not affect TNF-α. Physiological CCK concentration reduced nitrite and iNOS synthesis by peritoneal macrophages, possibly through a self-regulatory IL-10-dependent mechanism. Together, these data suggest a new role for the peptide CCK in modulating MAP, possibly controlling the inflammatory response, stimulating the anti-inflammatory cytokine, IL-10, and reducing vascular and macrophage iNOS-derived nitric oxide production. Based on these findings, CCK could be used as an adjuvant therapeutic agent to improve cardiovascular function. PMID:23247127

  10. 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

  11. Biotin deficiency enhances the inflammatory response of human dendritic cells.

    PubMed

    Agrawal, Sudhanshu; Agrawal, Anshu; Said, Hamid M

    2016-09-01

    The water-soluble biotin (vitamin B7) is indispensable for normal human health. The vitamin acts as a cofactor for five carboxylases that are critical for fatty acid, glucose, and amino acid metabolism. Biotin deficiency is associated with various diseases, and mice deficient in this vitamin display enhanced inflammation. Previous studies have shown that biotin affects the functions of adaptive immune T and NK cells, but its effect(s) on innate immune cells is not known. Because of that and because vitamins such as vitamins A and D have a profound effect on dendritic cell (DC) function, we investigated the effect of biotin levels on the functions of human monocyte-derived DCs. Culture of DCs in a biotin-deficient medium (BDM) and subsequent activation with LPS resulted in enhanced secretion of the proinflammatory cytokines TNF-α, IL-12p40, IL-23, and IL-1β compared with LPS-activated DCs cultured in biotin-sufficient (control) and biotin-oversupplemented media. Furthermore, LPS-activated DCs cultured in BDM displayed a significantly higher induction of IFN-γ and IL-17 indicating Th1/Th17 bias in T cells compared with cells maintained in biotin control or biotin-oversupplemented media. Investigations into the mechanisms suggested that impaired activation of AMP kinase in DCs cultured in BDM may be responsible for the observed increase in inflammatory responses. In summary, these results demonstrate for the first time that biotin deficiency enhances the inflammatory responses of DCs. This may therefore be one of the mechanism(s) that mediates the observed inflammation that occurs in biotin deficiency. PMID:27413170

  12. Fracture initiates systemic inflammatory response syndrome through recruiting polymorphonuclear leucocytes.

    PubMed

    Li, Haipeng; Liu, Jia; Yao, Jianhua; Zhong, Jianfeng; Guo, Lei; Sun, Tiansheng

    2016-08-01

    Fracture, a common type injury in trauma patients, often results in the development of the systemic inflammatory response syndrome (SIRS). Though the mechanism of the fracture-initiated SIRS still remains not well characterized, it is well documented that the polymorphonuclear leucocytes (PMN) play an important role in the inflammatory process. We hypothesize that fractures recruit PMN to the local tissue, which is followed by an increase in the number of peripheral PMN and initiation of SIRS. In the current study, we established a closed femoral fracture rat model. We evaluated the levels of MPO, IL-1β and CINC-1 in fractured tissue homogenate, and we measured the levels of IL-6 and IL-10, the biomarkers for systemic inflammatory response, in the rat sera. In clinical part of the study, we collected blood from patients with isolated closed femoral fractures and evaluated PMN-related chemoattractants (IL-8, IL-1β and G-CSF) and the number of peripheral PMN. We further evaluated the level of mitochondrial DNA in the local haematoma of fracture and the circulating plasma of the patients with fracture. In the animal model of closed femoral fracture, we found a significant recruitment of PMN to the local tissue after fracture, which correlates with the elevated MPO level. We also showed that the concentration of IL-1β and CINC-1 in local tissue is significantly increased and might be responsible for the PMN recruitment. Recruitment of PMN to the local tissue was accompanied with a significant increase in the systemic levels of IL-6 and IL-10 in serum. In the patients with closed femoral fracture, we observed an increase in the number of peripheral PMN and PMN-related chemoattractants, including IL-8, IL-1β and G-CSF. The level of mitochondrial DNA in the local haematoma of fracture and the circulating plasma of patients were significantly higher compared to the healthy volunteers. Our data suggest that fracture released mitochondrial DNA into the local haematoma of

  13. Hyaluronidase Modulates Inflammatory Response and Accelerates the Cutaneous Wound Healing

    PubMed Central

    Fronza, Marcio; Caetano, Guilherme F.; Leite, Marcel N.; Bitencourt, Claudia S.; Paula-Silva, Francisco W. G.; Andrade, Thiago A. M.; Frade, Marco A. C.; Merfort, Irmgard; Faccioli, Lúcia H.

    2014-01-01

    Hyaluronidases are enzymes that degrade hyaluronan an important constituent of the extracellular matrix. They have been used as a spreading agent, improving the absorption of drugs and facilitating the subcutaneous infusion of fluids. Here, we investigated the influence of bovine testes hyaluronidase (HYAL) during cutaneous wound healing in in vitro and in vivo assays. We demonstrated in the wound scratch assay that HYAL increased the migration and proliferation of fibroblasts in vitro at low concentration, e.g. 0.1 U HYAL enhanced the cell number by 20%. HYAL presented faster and higher reepithelialization in in vivo full-thickness excisional wounds generated on adult Wistar rats back skin already in the early phase at 2nd day post operatory compared to vehicle-control group. Wound closured area observed in the 16 U and 32 U HYAL treated rats reached 38% and 46% compared to 19% in the controls, respectively. Histological and biochemical analyses supported the clinical observations and showed that HYAL treated wounds exhibited increased granulation tissue, diminished edema formation and regulated the inflammatory response by modulating the release of pro and anti-inflammatory cytokines, growth factor and eicosanoids mediators. Moreover, HYAL increased gene expression of peroxisome proliferator-activated receptors (PPAR) γ and PPAR β/δ, the collagen content in the early stages of healing processes as well as angiogenesis. Altogether these data revealed that HYAL accelerates wound healing processes and might be beneficial for treating wound disorders. PMID:25393024

  14. Innate inflammatory responses in stroke: mechanisms and potential therapeutic targets

    PubMed Central

    Kim, Jong Youl; Kawabori, Masahito; Yenari, Midori A.

    2014-01-01

    Stroke is a frequent cause of long-term disability and death worldwide. Ischemic stroke is more commonly encountered compared to hemorrhagic stroke, and leads to tissue death by ischemia due to occlusion of a cerebral artery. Inflammation is known to result as a result of ischemic injury, long thought to be involved in initiating the recovery and repair process. However, work over the past few decades indicates that aspects of this inflammatory response may in fact be detrimental to stroke outcome. Acutely, inflammation appears to have a detrimental effect, and anti-inflammatory treatments have been been studied as a potential therapeutic target. Chronically, reports suggest that post-ischemic inflammation is also essential for the tissue repairing and remodeling. The majority of the work in this area has centered around innate immune mechanisms, which will be the focus of this review. This review describes the different key players in neuroinflammation and their possible detrimental and protective effects in stroke. A better understanding of the roles of the different immune cells and their temporal profile of damage versus repair will help to clarify more effective modulation of inflammation post stroke. Introduction Stroke refers to conditions caused by occlusion and/or rupture of blood vessels in the brain, and is a leading cause of death and disability in the industrialized world. PMID:24372209

  15. Hyaluronidase modulates inflammatory response and accelerates the cutaneous wound healing.

    PubMed

    Fronza, Marcio; Caetano, Guilherme F; Leite, Marcel N; Bitencourt, Claudia S; Paula-Silva, Francisco W G; Andrade, Thiago A M; Frade, Marco A C; Merfort, Irmgard; Faccioli, Lúcia H

    2014-01-01

    Hyaluronidases are enzymes that degrade hyaluronan an important constituent of the extracellular matrix. They have been used as a spreading agent, improving the absorption of drugs and facilitating the subcutaneous infusion of fluids. Here, we investigated the influence of bovine testes hyaluronidase (HYAL) during cutaneous wound healing in in vitro and in vivo assays. We demonstrated in the wound scratch assay that HYAL increased the migration and proliferation of fibroblasts in vitro at low concentration, e.g. 0.1 U HYAL enhanced the cell number by 20%. HYAL presented faster and higher reepithelialization in in vivo full-thickness excisional wounds generated on adult Wistar rats back skin already in the early phase at 2nd day post operatory compared to vehicle-control group. Wound closured area observed in the 16 U and 32 U HYAL treated rats reached 38% and 46% compared to 19% in the controls, respectively. Histological and biochemical analyses supported the clinical observations and showed that HYAL treated wounds exhibited increased granulation tissue, diminished edema formation and regulated the inflammatory response by modulating the release of pro and anti-inflammatory cytokines, growth factor and eicosanoids mediators. Moreover, HYAL increased gene expression of peroxisome proliferator-activated receptors (PPAR) γ and PPAR β/δ, the collagen content in the early stages of healing processes as well as angiogenesis. Altogether these data revealed that HYAL accelerates wound healing processes and might be beneficial for treating wound disorders. PMID:25393024

  16. Toll-like receptor 4 confers inflammatory response to Suilysin

    PubMed Central

    Bi, Lili; Pian, Yaya; Chen, Shaolong; Ren, Zhiqiang; Liu, Peng; Lv, Qingyu; Zheng, Yuling; Zhang, Shengwei; Hao, Huaijie; Yuan, Yuan; Jiang, Yongqiang

    2015-01-01

    Streptococcus suis serotype 2 (SS2) is an emerging human pathogen worldwide. A large outbreak occurred in the summer of 2005 in China. Serum samples from this outbreak revealed that levels of the main proinflammatory cytokines were significantly higher in patients with streptococcal toxic-shock-like syndrome (STSLS) than in patients with meningitis only. However, the mechanism underlying the cytokine storm in STSLS caused by SS2 remained unclear. In this study, we found that suilysin (SLY) is the main protein inflammatory stimulus of SS2 and that native SLY (nSLY) stimulated cytokines independently of its haemolytic ability. Interestingly, a small amount of SLY (Å Mol/L) induced strong, long-term TNF-α release from human PBMCs. We also found that nSLY stimulated TNF-α in wild-type macrophages but not in macrophages from mice that carried a spontaneous mutation in TLR4 (P712H). We demonstrated for the first time that SLY stimulates immune cells through TLR4. In addition, the Myd88 adaptor-p38-MAPK pathway was involved in this process. The present study suggested that the TLR4-dependent inflammatory responses induced by SLY in host might contribute to the STSLS caused by SS2 and that p38-MAPK could be used as a target to control the release of excess TNF-α induced by SS2. PMID:26167160

  17. Biomechanical changes in endothelial cells result from an inflammatory response

    NASA Astrophysics Data System (ADS)

    Vaitkus, Janina; Stroka, Kimberly; Aranda-Espinoza, Helim

    2012-02-01

    During periods of infection and disease, the immune system induces the release of TNF-α, an inflammatory cytokine, from a variety of cell types, such as macrophages. TNF-α, while circulating in the vasculature, binds to the apical surface of endothelial cells and causes a wide range of biological and mechanical changes to the endothelium. While the biological changes have been widely studied, the biomechanical aspects have been largely unexplored. Here, we investigated the biomechanical changes of the endothelium as a function of TNF-α treatment. First, we studied the traction forces applied by the endothelium, an effect that is much less studied than others. Through the use of traction force microscopy, we found that TNF-α causes an increase in traction forces applied by the endothelial cells as compared to non-treated cells. Then, we investigated cell morphology, cell mechanics, migration, and cytoskeletal dynamics. We found that in addition to increasing applied traction forces, TNF-α causes an increase in cell area and aspect ratio on average, as well as a shift in the organization of F-actin filaments within the cell. Combining these findings together, our results show that an inflammatory response heavily impacts the morphology, cell mechanics, migration, cytoskeletal dynamics, and applied traction forces of endothelial cells.

  18. The Role of Protein Arginine Methyltransferases in Inflammatory Responses

    PubMed Central

    Kim, Ji Hye; Yoo, Byong Chul; Yang, Woo Seok; Kim, Eunji; Hong, Sungyoul

    2016-01-01

    Protein arginine methyltransferases (PRMTs) mediate the methylation of a number of protein substrates of arginine residues and serve critical functions in many cellular responses, including cancer development, progression, and aggressiveness, T-lymphocyte activation, and hepatic gluconeogenesis. There are nine members of the PRMT family, which are divided into 4 types (types I–IV). Although most PRMTs do not require posttranslational modification (PTM) to be activated, fine-tuning modifications, such as interactions between cofactor proteins, subcellular compartmentalization, and regulation of RNA, via micro-RNAs, seem to be required. Inflammation is an essential defense reaction of the body to eliminate harmful stimuli, including damaged cells, irritants, or pathogens. However, chronic inflammation can eventually cause several types of diseases, including some cancers, atherosclerosis, rheumatoid arthritis, and periodontitis. Therefore, inflammation responses should be well modulated. In this review, we briefly discuss the role of PRMTs in the control of inflammation. More specifically, we review the roles of four PRMTs (CARM1, PRMT1, PRMT5, and PRMT6) in modulating inflammation responses, particularly in terms of modulating the transcriptional factors or cofactors related to inflammation. Based on the regulatory roles known so far, we propose that PRMTs should be considered one of the target molecule groups that modulate inflammatory responses. PMID:27041824

  19. The Role of Protein Arginine Methyltransferases in Inflammatory Responses.

    PubMed

    Kim, Ji Hye; Yoo, Byong Chul; Yang, Woo Seok; Kim, Eunji; Hong, Sungyoul; Cho, Jae Youl

    2016-01-01

    Protein arginine methyltransferases (PRMTs) mediate the methylation of a number of protein substrates of arginine residues and serve critical functions in many cellular responses, including cancer development, progression, and aggressiveness, T-lymphocyte activation, and hepatic gluconeogenesis. There are nine members of the PRMT family, which are divided into 4 types (types I-IV). Although most PRMTs do not require posttranslational modification (PTM) to be activated, fine-tuning modifications, such as interactions between cofactor proteins, subcellular compartmentalization, and regulation of RNA, via micro-RNAs, seem to be required. Inflammation is an essential defense reaction of the body to eliminate harmful stimuli, including damaged cells, irritants, or pathogens. However, chronic inflammation can eventually cause several types of diseases, including some cancers, atherosclerosis, rheumatoid arthritis, and periodontitis. Therefore, inflammation responses should be well modulated. In this review, we briefly discuss the role of PRMTs in the control of inflammation. More specifically, we review the roles of four PRMTs (CARM1, PRMT1, PRMT5, and PRMT6) in modulating inflammation responses, particularly in terms of modulating the transcriptional factors or cofactors related to inflammation. Based on the regulatory roles known so far, we propose that PRMTs should be considered one of the target molecule groups that modulate inflammatory responses. PMID:27041824

  20. Use of continuous positive airway pressure reduces airway reactivity in adults with asthma

    PubMed Central

    Busk, Michael; Busk, Nancy; Puntenney, Paula; Hutchins, Janet; Yu, Zhangsheng; Gunst, Susan J.; Tepper, Robert S.

    2015-01-01

    Asthma is characterised by airway hyperreactivity, which is primarily treated with β-adrenergic bronchodilators and anti-inflammatory agents. However, mechanical strain during breathing is an important modulator of airway responsiveness and we have previously demonstrated in animal models that continuous positive airway pressure (CPAP) resulted in lower in vivo airway reactivity. We now evaluated whether using nocturnal CPAP decreased airway reactivity in clinically-stable adults with asthma. Adults with stable asthma and normal spirometry used nocturnal CPAP (8–10 cmH2O) or sham treatment (0–2 cmH2O) for 7 days. Spirometry and bronchial challenges were obtained before and after treatment. The primary outcome was the provocative concentration of methacholine causing a 20% fall in forced expiratory volume in 1 s (PC20). The CPAP group (n=16) had a significant decrease in airway reactivity (change in (Δ)logPC20 0.406, p<0.0017) while the sham group (n=9) had no significant change in airway reactivity (ΔlogPC20 0.003, p=0.9850). There was a significant difference in the change in airway reactivity for the CPAP versus the sham group (ΔlogPC20 0.41, p<0.043). Our findings indicate that chronic mechanical strain of the lungs produced using nocturnal CPAP for 7 days reduced airway reactivity in clinically stable asthmatics. Future studies of longer duration are required to determine whether CPAP can also decrease asthma symptoms and/or medication usage. PMID:22835615

  1. Morphological features of the inflammatory response in molluscs.

    PubMed

    De Vico, G; Carella, F

    2012-12-01

    Over the last few years, there has been a large increase in studying the biology and pathology of molluscs, predominantly in addressing the molecular patterns involved in their immune-mediated and inflammatory responses. Conversely, the literature-based diagnostic criteria concerning the morphology of the above phenomena still involves pathogenetic confusion and conflicting terminology. A comparison of bibliographic resources, such as the Abridged Glossary of Terms Used in Invertebrate Pathology and the National Status manual for molluscan histopathological examination and analysis from the NOAA, have revealed variability in the definitions of superimposable lesions, emphasising the need for further efforts in establishing standard terminology and methodologies in this field of study. This review suggests some possible solutions for overcoming the use of parallel terminologies in diagnosing inflammation in molluscs and also highlights conflicting features requiring further discussion. PMID:22513124

  2. Engineering Immunomodulatory Biomaterials To Tune the Inflammatory Response.

    PubMed

    Vishwakarma, Ajaykumar; Bhise, Nupura S; Evangelista, Marta B; Rouwkema, Jeroen; Dokmeci, Mehmet R; Ghaemmaghami, Amir M; Vrana, Nihal Engin; Khademhosseini, Ali

    2016-06-01

    Current state-of-the-art biomedical implants and tissue engineering methods promise technologies to improve or even restore the function of diseased organs. However, one of the biggest challenges to clinical success is the lack of functional integration. A series of cellular and molecular events following biomaterial implantation poses an important bottleneck for developing breakthrough solutions. With inflammation increasingly recognized as a crucial component influencing regeneration, immunomodulation or immuno-engineering has emerged as a potential solution to overcome this key challenge in regenerative medicine. We postulate possibilities to utilize biomaterial physicochemical modifications to modulate the host inflammatory response and develop strategies for effective biomaterial integration. Biomaterial-based immunomodulation strategies can significantly ameliorate the outcomes of medical implants and tissue engineering therapies. PMID:27138899

  3. Particulate oil shale inhalation and pulmonary inflammatory response in rats

    SciTech Connect

    Wilson, J.S.; Holland, L.M.; Halleck, M.S.; Martinez, E.; Saunders, G.

    1983-01-01

    This experiment detrimetal that long-term inhalation of shale dusts by rats elicits a limited inflammatory response in the lung less profound than that observed in animals exposed to equivalent levels of quartz alone. This observation suggests that organic and inorganic constituents of shale may provide a protective effect. The implications for fibrogenic disease are two-fold: (1) inhalation of oil shale dusts appeared to be less detriemtal than the inhalation of quartz along, and (2) there was no apparent synergistic action of quartz and the complex of organic materials present in shale. Animals exposed to shale dusts failed to develop any significant lung lesions, while all of the animals exposed to quartz developed granulomas and some frank fibrosis.

  4. Down-regulation of 8-oxoguanine DNA glycosylase 1 expression in the airway epithelium ameliorates allergic lung inflammation.

    PubMed

    Bacsi, Attila; Aguilera-Aguirre, Leopoldo; Szczesny, Bartosz; Radak, Zsolt; Hazra, Tapas K; Sur, Sanjiv; Ba, Xueqing; Boldogh, Istvan

    2013-01-01

    Allergic airway inflammation is characterized by increased expression of pro-inflammatory mediators, inflammatory cell infiltration, mucus hypersecretion, and airway hyperresponsiveness, in parallel with oxidative DNA base and strand damage, whose etiological role is not understood. Our goal was to establish the role of 8-oxoguanine (8-oxoG), a common oxidatively damaged base, and its repair by 8-oxoguanine DNA glycosylase 1 (Ogg1) in allergic airway inflammatory processes. Airway inflammation was induced by intranasally administered ragweed (Ambrosia artemisiifolia) pollen grain extract (RWPE) in sensitized BALB/c mice. We utilized siRNA technology to deplete Ogg1 from airway epithelium; 8-oxoG and DNA strand break levels were quantified by Comet assays. Inflammatory cell infiltration and epithelial methaplasia were determined histologically, mucus and cytokines levels biochemically and enhanced pause was used as the main index of airway hyperresponsiveness. Decreased Ogg1 expression and thereby 8-oxoG repair in the airway epithelium conveyed a lower inflammatory response after RWPE challenge of sensitized mice, as determined by expression of Th2 cytokines, eosinophilia, epithelial methaplasia, and airway hyperresponsiveness. In contrast, 8-oxoG repair in Ogg1-proficient airway epithelium was coupled to an increase in DNA single-strand break (SSB) levels and exacerbation of allergen challenge-dependent inflammation. Decreased expression of the Nei-like glycosylases Neil1 and Neil2 that preferentially excise ring-opened purines and 5-hydroxyuracil, respectively, did not alter the above parameters of allergic immune responses to RWPE. These results show that DNA SSBs formed during Ogg1-mediated repair of 8-oxoG augment antigen-driven allergic immune responses. A transient modulation of OGG1 expression/activity in airway epithelial cells could have clinical benefits. PMID:23127499

  5. STUDIES TO ADDRESS THE ASSOCIATION BETWEEN PARTICULATE MATTER (PM) EXPOSURE AND DEVELOPMENT/EXACERBATION OF LUNG INJURY, INFLAMMATION, AND INCREASED AIRWAY RESPONSIVENESS.

    EPA Science Inventory

    Asthma, an inflammatory airways disease, has become an urgent health problem affecting an estimated 17 million persons in the United States alone (CDC 1998 MMWR 47). Since 1979, the death rate from asthma has increased by almost 56%. Epidemiologic studies have demonstrated posit...

  6. Titanium dioxide nanoparticles increase inflammatory responses in vascular endothelial cells

    PubMed Central

    Han, Sung Gu; Newsome, Bradley; Hennig, Bernhard

    2013-01-01

    Atherosclerosis is a chronic inflammatory disease that remains the leading cause of death in the United States. Numerous risk factors for endothelial cell inflammation and the development of atherosclerosis have been identified, including inhalation of ultrafine particles. Recently, engineered nanoparticles (NPs) such as titanium (TiO2) NPs have attracted much attention due to their wide range of applications. However, there are also great concerns surrounding potential adverse health effects in vascular systems. Although TiO2 NPs are known to induce oxidative stress and inflammation, the associated signaling pathways have not been well studied. The focus of this work, therefore, deals with examination of the cellular signaling pathways responsible for TiO2 NP-induced endothelial oxidative stress and inflammation. In this study, primary vascular endothelial cells were treated with TiO2 NPs for 2–16 h at concentrations of 0–50 µg/mL. TiO2 NP exposure increased cellular oxidative stress and DNA binding of NF-κB. Further, phosphorylation of Akt, ERK, JNK and p38 was increased in cells exposed to TiO2 NPs. TiO2 NPs also significantly increased induction of mRNA and protein levels of vascular cell adhesion molecule-1 (VCAM-1) and mRNA levels of monocyte chemoattractant protein-1 (MCP-1). Pretreatment with inhibitors for NF-κB (pyrrolidine dithiocarbamate), oxidative stress (epigallocatechin gallate and apocynin), Akt (LY294002), ERK (PD98059), JNK (SP600125) and p38 (SB203580) significantly attenuated TiO2 NP-induced MCP-1 and VCAM-1 gene expression, as well as activation of NF-κB. These data indicate that TiO2 NPs can induce endothelial inflammatory responses via redox-sensitive cellular signaling pathways. PMID:23380242

  7. Inflammatory Response to Burn Trauma: Nicotine Attenuates Proinflammatory Cytokine Levels

    PubMed Central

    Papst, S.; Reimers, K.; Stukenborg-Colsman, C.; Steinstraesser, L.; Vogt, P. M.; Kraft, T.; Niederbichler, A. D.

    2014-01-01

    Objective: The immune response to an inflammatory stimulus is balanced and orchestrated by stimulatory and inhibitory factors. After a thermal trauma, this balance is disturbed and an excessive immune reaction with increased production and release of proinflammatory cytokines results. The nicotine-stimulated anti-inflammatory reflex offsets this. The goal of this study was to verify that transdermal administration of nicotine downregulates proinflammatory cytokine release after burn trauma. Methods: A 30% total body surface area full-thickness rat burn model was used in Sprague Dawley rats (n = 35, male). The experimental animals were divided into a control group, a burn trauma group, a burn trauma group with additional nicotine treatment, and a sham + nicotine group with 5 experimental animals per group. The last 2 groups received a transdermal nicotine administration of 1.75 mg. The concentrations of tumor necrosis factor alpha, interleukin 1 beta, and interleukin 6 were determined in homogenates of hearts, livers, and spleens 12 or 24 hours after burn trauma. Results: Experimental burn trauma resulted in a significant increase in cytokine levels in hearts, livers, and spleens. Nicotine treatment led to a decrease of the effect of the burn trauma with significantly lower concentrations of tumor necrosis factor alpha, interleukin 1 beta, and interleukin 6 compared to the trauma group. Conclusions: This study confirms in a standardized burn model that stimulation of the nicotinic acetylcholine receptor is involved in the regulation of effectory molecules of the immune response. Looking at the results of our study, further experiments designed to explore and evaluate the potency and mechanisms of the immunomodulating effects of this receptor system are warranted. PMID:25671045

  8. Ozone-induced oxygen radical release from bronchoalveolar lavage cells and airway hyper-responsiveness in dogs.

    PubMed Central

    Stevens, W H; Conlon, P D; O'Byrne, P M

    1995-01-01

    1. Ozone inhalation causes airway hyper-responsiveness and airway inflammation in dogs. The purpose of this study was to determine whether these effects are associated with increases in oxygen radical production from bronchoalveolar lavage (BAL) cells. 2. Twelve randomly selected dogs were studied twice, 4 weeks apart. On each study day, acetylcholine (ACh) airway responsiveness was measured before and 1 h after ozone (3 p.p.m., 30 min) or dry air inhalation, followed by BAL. The response to ACh was expressed as the concentration causing an increase in lung resistance of 5 cmH2O l-1 s-1 above baseline. Spontaneous and phorbol myristate acetate (PMA) (2.4 mumol l-1)-stimulated oxygen radical release from washed BAL cells (4 x 10(6) cells ml-1) was measured by luminol-enhanced chemiluminescence in a luminometer at 37 degrees C. 3. Ozone inhalation caused airway hyper-responsiveness. The concentration of ACh causing an increase in lung resistance of 5 cmH2O l-1 s-1 (the 'provocative' concentration) fell from 4.68 mg ml-1 (% S.E.M., 1.43) before, to 0.48 mg ml-1 (% S.E.M., 1.60) after ozone (P < 0.0001). Spontaneous chemiluminescence area under the curve (AUC) significantly increased after ozone from 4.08 mV (10 min) (% S.E.M., 1.28) after dry air to 8.25 mV (10 min; % S.E.M., 1.29) after ozone (P = 0.007). Ozone inhalation also increased PMA-stimulated chemiluminescence AUC from 18.97 mV (10 min; % S.E.M., 1.18) after dry air to 144.03 mV (10 min; % S.E.M., 1.45) after ozone (P = 0.0001). The increase in PMA-stimulated chemiluminescence was significantly correlated with ozone-induced ACh airway hyper-responsiveness (r = 0.83, P < 0.001). 4. These results indicate that inhaled ozone increases oxygen radical release from BAL cells and suggest that oxygen radicals are important in causing ozone-induced airway hyper-responsiveness. PMID:7562641

  9. The relationship between nasal index and nasal airway resistance, and response to a topical decongestant.

    PubMed

    Doddi, N M; Eccles, R

    2011-12-01

    The differences in the shape and size of the nose have been proposed to be an adaptation to climate with broad noses (platyrrhine) evolving in a warm humid environment where there was little need for air conditioning and narrow noses (leptorrhine) evolving in colder climates where the air needed more warming. The main aim of this research was to determine if there was any relationship between the shape of the nose as expressed in terms of nasal height and width (nasal index) and total nasal airway resistance (NAR), as one would predict that the narrower leptorrhine noses would have a greater resistance to air flow than the broader platyrrhine noses. It was also proposed that the narrow leptorrhine nose would have better developed vascular tissue than the broad platyrrhine nose in order to condition cold air, and would exhibit a greater response to nasal decongestion. No correlation was found between nasal index and NAR (r = -0.09) and similarly no correlation was found between nasal index and response to a topical nasal decongestant (r = 0.02). The absence of any physiological differences between the different nose types may be due to acclimatisation of participants to the area of recruitment. PMID:22125790

  10. Ets homologous factor regulates pathways controlling response to injury in airway epithelial cells.

    PubMed

    Fossum, Sara L; Mutolo, Michael J; Yang, Rui; Dang, Hong; O'Neal, Wanda K; Knowles, Michael R; Leir, Shih-Hsing; Harris, Ann

    2014-12-16

    Ets homologous factor (EHF) is an Ets family transcription factor expressed in many epithelial cell types including those lining the respiratory system. Disruption of the airway epithelium is central to many lung diseases, and a network of transcription factors coordinates its normal function. EHF can act as a transcriptional activator or a repressor, though its targets in lung epithelial cells are largely uncharacterized. Chromatin immunoprecipitation followed by deep sequencing (ChIP-seq), showed that the majority of EHF binding sites in lung epithelial cells are intergenic or intronic and coincide with putative enhancers, marked by specific histone modifications. EHF occupies many genomic sites that are close to genes involved in intercellular and cell-matrix adhesion. RNA-seq after EHF depletion or overexpression showed significant alterations in the expression of genes involved in response to wounding. EHF knockdown also targeted genes in pathways of epithelial development and differentiation and locomotory behavior. These changes in gene expression coincided with alterations in cellular phenotype including slowed wound closure and increased transepithelial resistance. Our data suggest that EHF regulates gene pathways critical for epithelial response to injury, including those involved in maintenance of barrier function, inflammation and efficient wound repair. PMID:25414352

  11. Simvastatin Inhibits Airway Hyperreactivity

    PubMed Central

    Zeki, Amir A.; Franzi, Lisa; Last, Jerold; Kenyon, Nicholas J.

    2009-01-01

    Rationale: Statin use has been linked to improved lung health in asthma and chronic obstructive pulmonary disease. We hypothesize that statins inhibit allergic airway inflammation and reduce airway hyperreactivity via a mevalonate-dependent mechanism. Objectives: To determine whether simvastatin attenuates airway inflammation and improves lung physiology by mevalonate pathway inhibition. Methods: BALB/c mice were sensitized to ovalbumin over 4 weeks and exposed to 1% ovalbumin aerosol over 2 weeks. Simvastatin (40 mg/kg) or simvastatin plus mevalonate (20 mg/kg) was injected intraperitoneally before each ovalbumin exposure. Measurements and Main Results: Simvastatin reduced total lung lavage leukocytes, eosinophils, and macrophages (P < 0.05) in the ovalbumin-exposed mice. Cotreatment with mevalonate, in addition to simvastatin, reversed the antiinflammatory effects seen with simvastatin alone (P < 0.05). Lung lavage IL-4, IL-13, and tumor necrosis factor-α levels were all reduced by treatment with simvastatin (P < 0.05). Simvastatin treatment before methacholine bronchial challenge increased lung compliance and reduced airway hyperreactivity (P = 0.0001). Conclusions: Simvastatin attenuates allergic airway inflammation, inhibits key helper T cell type 1 and 2 chemokines, and improves lung physiology in a mouse model of asthma. The mevalonate pathway appears to modulate allergic airway inflammation, while the beneficial effects of simvastatin on lung compliance and airway hyperreactivity may be independent of the mevalonate pathway. Simvastatin and similar agents that modulate the mevalonate pathway may prove to be treatments for inflammatory airway diseases, such as asthma. PMID:19608720

  12. Circulating progenitor epithelial cells traffic via CXCR4/CXCL12 in response to airway injury.

    PubMed

    Gomperts, Brigitte N; Belperio, John A; Rao, P Nagesh; Randell, Scott H; Fishbein, Michael C; Burdick, Marie D; Strieter, Robert M

    2006-02-01

    Recipient airway epithelial cells are found in human sex-mismatched lung transplants, implying that circulating progenitor epithelial cells contribute to the repair of the airway epithelium. Markers of circulating progenitor epithelial cells and mechanisms for their trafficking remain to be elucidated. We demonstrate that a population of progenitor epithelial cells exists in the bone marrow and the circulation of mice that is positive for the early epithelial marker cytokeratin 5 (CK5) and the chemokine receptor CXCR4. We used a mouse model of sex-mismatched tracheal transplantation and found that CK5+ circulating progenitor epithelial cells contribute to re-epithelialization of the airway and re-establishment of the pseudostratified epithelium. The presence of CXCL12 in tracheal transplants provided a mechanism for CXCR4+ circulating progenitor epithelial cell recruitment to the airway. Depletion of CXCL12 resulted in the epithelium defaulting to squamous metaplasia, which was derived solely from the resident tissue progenitor epithelial cells. Our findings demonstrate that CK5+CXCR4+ cells are markers of circulating progenitor epithelial cells in the bone marrow and circulation and that CXCR4/CXCL12-mediated recruitment of circulating progenitor epithelial cells is necessary for the re-establishment of a normal pseudostratified epithelium after airway injury. These findings support a novel paradigm for the development of squamous metaplasia of the airway epithelium and for developing therapeutic strategies for circulating progenitor epithelial cells in airway diseases. PMID:16424223

  13. Puerarin partly counteracts the inflammatory response after cerebral ischemia/reperfusion via activating the cholinergic anti-inflammatory pathway.

    PubMed

    Liu, Xiaojie; Mei, Zhigang; Qian, Jingping; Zeng, Yongbao; Wang, Mingzhi

    2013-12-01

    Puerarin, a major isoflavonoid derived from the Chinese medical herb radix puerariae (Gegen), has been reported to inhibit neuronal apoptosis and play an anti-inflammatory role in focal cerebral ischemia model rats. Recent findings regarding stroke pathophysiology have recognized that anti-inflammation is an important target for the treatment of ischemic stroke. The cholinergic anti-inflammatory pathway is a highly robust neural-immune mechanism for inflammation control. This study was to investigate whether activating the cholinergic anti-inflammatory pathway can be involved in the mechanism of inhibiting the inflammatory response during puerarin-induced cerebral ischemia/reperfusion in rats. Results showed that puerarin pretreatment (intravenous injection) reduced the ischemic infarct volume, improved neurological deficit after cerebral ischemia/reperfusion and decreased the levels of interleukin-1β, interleukin-6 and tumor necrosis factor-α in brain tissue. Pretreatment with puerarin (intravenous injection) attenuated the inflammatory response in rats, which was accompanied by janus-activated kinase 2 (JAK2) and signal transducers and activators of transcription 3 (STAT3) activation and nuclear factor kappa B (NF-κB) inhibition. These observations were inhibited by the alpha7 nicotinic acetylcholine receptor (α7nAchR) antagonist α-bungarotoxin (α-BGT). In addition, puerarin pretreatment increased the expression of α7nAchR mRNA in ischemic cerebral tissue. These data demonstrate that puerarin pretreatment strongly protects the brain against cerebral ischemia/reperfusion injury and inhibits the inflammatory response. Our results also indicated that the anti-inflammatory effect of puerarin may partly be mediated through the activation of the cholinergic anti-inflammatory pathway. PMID:25206641

  14. Effect of heparin on antigen-induced airway responses and pulmonary leukocyte accumulation in neonatally immunized rabbits

    PubMed Central

    Preuss, Janet M H; Page, Clive P

    2000-01-01

    The effect of single administrations of aerosolized heparin, low molecular weight heparin (LMWH) and the linear polyanionic molecule, polyglutamic acid (PGA) were examined on antigen-induced airway hyperresponsiveness and leukocyte accumulation in neonatally immunized rabbits.Adult litter-matched NZW rabbits immunized within 24 h of birth with Alternaria tenuis antigen were treated with heparin, LMWH or PGA prior to or following antigen challenge (Alternaria tenuis). For each drug-treated group, a parallel group of rabbits were treated with the appropriate vehicle. In all groups, airway responsiveness to inhaled histamine and bronchoalveolar lavage (BAL) was performed 24 h prior to and following antigen challenge.Basal lung function in terms of resistance (RL) and dynamic compliance (Cdyn) and acute bronchoconstriction was unaltered by pre-treatment with heparin, LMWH or PGA compared to their respective vehicles 24 h prior to or following antigen challenge.In vehicle-treated animals, airway hyperresponsiveness to inhaled histamine was indicated by an increase in the maximal responses of the cumulative concentration-effect curves to histamine and reductions in RLPC50 and CdynPC35 values 24 h following antigen challenge.Heparin and LMWH given prior to antigen challenge significantly inhibited the development of airway hyperresponsiveness, whereas PGA did not. When given following antigen challenge, all three drugs failed to inhibit the development of airway hyperresponsiveness.Eosinophil and neutrophil cell numbers in BAL fluid increased significantly 24 h following antigen challenge. Heparin, LMWH and PGA failed to inhibit the increase in cell numbers following antigen challenge whether given prior to or following antigen challenge. PMID:10780962

  15. Cohabitation with a sick partner increases allergic lung inflammatory response in mice.

    PubMed

    Hamasato, Eduardo Kenji; de Lima, Ana Paula Nascimento; de Oliveira, Ana Paula Ligeiro; dos Santos Franco, Adriana Lino; de Lima, Wothan Tavares; Palermo-Neto, João

    2014-11-01

    results suggest that allergic lung inflammatory response exacerbation in CSP mice is a consequence of the psychological stress induced by forced cohabitation with the sick partner. Strong involvement of the sympathetic nervous system (SNS) through adrenaline and noradrenaline release and a shift of the Th1/Th2 cytokine profile toward a Th2 response were considered to be the mechanisms underlying the cell recruitment to the animal's airways. PMID:24929194

  16. Inter- and intrasubject variability of the inflammatory response to segmental endotoxin challenge in healthy volunteers.

    PubMed

    Holz, O; Tan, L; Schaumann, F; Müller, M; Scholl, D; Hidi, R; McLeod, A; Krug, N; Hohlfeld, J M

    2015-12-01

    Segmental endotoxin challenge with lipopolysaccharide (LPS) can be used as a pharmacodynamic model to safely induce a transient airway inflammation in the peripheral lung of healthy subjects and to test the anti-inflammatory efficacy of investigational new drugs. In contrast to whole lung LPS challenge only a fraction of the dose is required that can be precisely administered to a specific lung region and a vehicle challenged segment as an intra-subject control can be included. The aim of this study was to assess the intra- and inter-individual variability of the response to segmental LPS challenge for the appropriate design and power calculation of future clinical trials. Two cohorts with 10 subjects each underwent two segmental LPS challenges within five weeks. The inflammatory response was evaluated in bronchoalveolar lavage (BAL) fluid at 6 (cohort 1) and 24 h (cohort 2) both in the LPS and in a vehicle challenged segment, as well as in plasma for up to 26 h post LPS challenge. While the cytokine response was more pronounced at 6 h, the influx of neutrophils and monocytes dominated at 24 h; e.g. neutrophils increased from a median (inter-quartile range, IQR) of 0.14 (0.16) and 0.09 (0.08)x10(4) cells/mL BAL fluid at baseline to 10.2 (17.1) and 19.3 (15.9)x10(4) cells/mL 24 h after the two separate challenges. The within-subject variability was higher than the between-subject variability for most of the markers. However, sample size estimations based on the variability of outcome variables found lower or equal numbers with cross-over designs compared to parallel group designs for cellular markers at 24 h and cytokine variables at 6 h. The segmental LPS challenge model was safe. Future study designs have to balance between burden to the study subjects (4 versus 2 bronchoscopies), variability (within-versus between-subject), and the desired outcome variable (cells versus chemo/cytokine). PMID:26545873

  17. Respiratory responses of subjects with allergic rhinitis to ozone exposure and their relationship to nonspecific airway reactivity

    SciTech Connect

    McDonnell, W.F.; Horstman, D.H.; Abdul-Salaam, S.; Raggio, L.J.; Green, J.A.

    1987-01-01

    Ozone exposure in man produces changes in respiratory function and symptoms. There is a large degree of unexplained intersubject variability in the magnitude of these responses. There is concern that individuals with chronic respiratory diseases may also be more responsive to ozone than normal individuals. The purpose of this study was to describe the responses of subjects with allergic rhinitis to ozone exposure and to compare these responses to those previously observed in normal individuals. A further purpose was to measure the association between baseline nonspecific airway reactivity and changes in lung function and respiratory symptoms following ozone exposure.

  18. Chlorine-induced injury to the airways in mice.

    PubMed

    Martin, James G; Campbell, Holly R; Iijima, Hiroaki; Gautrin, Denyse; Malo, Jean-Luc; Eidelman, David H; Hamid, Qutayba; Maghni, Karim

    2003-09-01

    Exposure to chlorine gas (Cl2) causes occupational asthma that we hypothesized occurs through the induction of airway inflammation and airway hyperresponsiveness by oxidative damage. Respiratory mechanics and airway responsiveness to methacholine were assessed in A/J mice 24 hours after a 5-minute exposure to 100, 200, 400, or 800 ppm Cl2 and 2 and 7 days after inhalation of 400 ppm Cl2. Airway responsiveness was higher 24 hours after 400 and 800 ppm Cl2. Responsiveness after inhalation of 400 ppm Cl2 returned to normal by 2 days but was again elevated at 7 days. Airway epithelial loss, patchy alveolar damage, proteinaceous exudates, and inflammatory cells within alveolar walls were observed in animals exposed to 800 ppm Cl2. Macrophages, granulocytes, epithelial cells, and nitrate/nitrite levels increased in lung lavage fluid. Increased inducible nitric oxide synthase expression and oxidation of lung proteins were observed. Epithelial cells and alveolar macrophages from mice exposed to 800 ppm Cl2 stained for 3-nitrotyrosine residues. Inhibition of inducible nitric oxide synthase with 1400W (1 mg/kg) abrogated the Cl2-induced changes in responsiveness. We conclude that chlorine exposure causes functional and pathological changes in the airways associated with oxidative stress. Inducible nitric oxide synthase is involved in the induction of changes in responsiveness to methacholine. PMID:12724121

  19. Imbalanced secondary mucosal antioxidant response in inflammatory bowel disease.

    PubMed

    Kruidenier, Laurens; Kuiper, Ineke; Van Duijn, Wim; Mieremet-Ooms, Marij A C; van Hogezand, Ruud A; Lamers, Cornelis B H W; Verspaget, Hein W

    2003-09-01

    cells that expressed CAT remained unchanged during inflammation and GPO was found in only a very low and constant number of epithelial cells. In addition, the inflamed epithelium displayed decreased expression of the hydroxyl radical (OH(*)) scavenger MT. In view of the high epithelial SOD levels in inflamed IBD epithelium, it is speculated that the efficient removal of excess H(2)O(2) is hampered in these cells, thereby increasing not only the risk of detrimental effects of H(2)O(2) directly, but also those of its extremely reactive derivatives such as OH(*). Taken together, the results suggest an imbalanced and inefficient endogenous antioxidant response in the intestinal mucosa of IBD patients, which may contribute to both the pathogenesis and the perpetuation of the inflammatory processes. PMID:12950013

  20. THE RESPONSE OF A HUMAN BRONCHIAL EPITHELIAL CELL LINE TO HISTAMINE: INTRACELLULAR CALCIUM CHANGES AND EXTRACELLULAR RELEASE OF INFLAMMATORY

    EPA Science Inventory

    The contribution of airway epithelium-derived factors to inflammation and tissue repair is unclear. ecause human airway epithelia are infrequently available for in vitro studies, transformed epithelial cell lines are of interest as models. e therefore investigated the response of...

  1. Emphysematous lung destruction by cigarette smoke. The effects of latent adenoviral infection on the lung inflammatory response.

    PubMed

    Meshi, Bernard; Vitalis, Timothy Z; Ionescu, Diana; Elliott, W Mark; Liu, Chun; Wang, Xiang-Dong; Hayashi, Shizu; Hogg, James C

    2002-01-01

    This study was designed to test the hypothesis that cigarette smoke-induced inflammation and emphysema are amplified by the presence of latent adenoviral (Ad) infection, and to determine whether this emphysematous process can be reversed by all-trans-retinoic acid (RA) treatment. The results confirm that in guinea pigs, chronic cigarette-smoke exposure caused lesions similar to human centrilobular emphysema. They also show that latent Ad infection combined with cigarette-smoke exposure caused an excess increase in lung volume (P < 0.001), air-space volume (P < 0.001), and lung weight (P < 0.01), and further decrease in surface-to-volume ratio (P < 0.001) compared with smoke exposure alone. RA treatment failed to reverse these emphysematous changes. Analysis of inflammatory response in parenchymal and airway tissue showed that smoking caused an increase of polymorphonuclear leukocytes (PMNs) (P < 0.0002), macrophages (P < 0.001), and CD4 cells (P < 0.0009), and that latent Ad infection independently increased PMNs (P < 0.001), macrophages (P = 0.003), and CD8 cells (P < 0.001). We conclude that latent Ad infection amplifies the emphysematous lung destruction and increases the inflammatory response produced by cigarette-smoke exposure. In this study, the increase in CD4 was associated with cigarette smoke and the increase in CD8 cells with latent Ad infection. PMID:11751203

  2. Increased Th2 cytokine secretion, eosinophilic airway inflammation, and airway hyperresponsiveness in neurturin-deficient mice.

    PubMed

    Michel, Tatiana; Thérésine, Maud; Poli, Aurélie; Domingues, Olivia; Ammerlaan, Wim; Brons, Nicolaas H C; Hentges, François; Zimmer, Jacques

    2011-06-01

    Neurotrophins such as nerve growth factor and brain-derived neurotrophic factor have been described to be involved in the pathogenesis of asthma. Neurturin (NTN), another neurotrophin from the glial cell line-derived neurotrophic factor family, was shown to be produced by human immune cells: monocytes, B cells, and T cells. Furthermore, it was previously described that the secretion of inflammatory cytokines was dramatically stimulated in NTN knockout (NTN(-/-)) mice. NTN is structurally similar to TGF-β, a protective cytokine in airway inflammation. This study investigates the implication of NTN in a model of allergic airway inflammation using NTN(-/-) mice. The bronchial inflammatory response of OVA-sensitized NTN(-/-) mice was compared with wild-type mice. Airway inflammation, Th2 cytokines, and airway hyperresponsiveness (AHR) were examined. NTN(-/-) mice showed an increase of OVA-specific serum IgE and a pronounced worsening of inflammatory features. Eosinophil number and IL-4 and IL-5 concentration in the bronchoalveolar lavage fluid and lung tissue were increased. In parallel, Th2 cytokine secretion of lung draining lymph node cells was also augmented when stimulated by OVA in vitro. Furthermore, AHR was markedly enhanced in NTN(-/-) mice after sensitization and challenge when compared with wild-type mice. Administration of NTN before challenge with OVA partially rescues the phenotype of NTN(-/-) mice. These findings provide evidence for a dampening role of NTN on allergic inflammation and AHR in a murine model of asthma. PMID:21508262

  3. Anti-inflammatory effects of Tat-Annexin protein on ovalbumin-induced airway inflammation in a mouse model of asthma

    SciTech Connect

    Lee, Sun Hwa; Kim, Dae Won; Kim, Hye Ri; Woo, Su Jung; Kim, So Mi; Jo, Hyo Sang; Jeon, Seong Gyu; Cho, Sung-Woo; Park, Jong Hoon; Won, Moo Ho; Park, Jinseu; Eum, Won Sik; Choi, Soo Young

    2012-01-20

    Highlights: Black-Right-Pointing-Pointer We construct a cell permeable Tat-ANX1 fusion protein. Black-Right-Pointing-Pointer We examined the protective effects of Tat-ANX1 protein on OVA-induced asthma in animal models. Black-Right-Pointing-Pointer Transduced Tat-ANX1 protein protects from the OVA-induced production of cytokines and eosinophils in BAL fluid. Black-Right-Pointing-Pointer Tat-ANX1 protein markedly reduced OVA-induced MAPK in lung tissues. Black-Right-Pointing-Pointer Tat-ANX1 protein could be useful as a therapeutic agent for lung disorders including asthma. -- Abstract: Chronic airway inflammation is a key feature of bronchial asthma. Annexin-1 (ANX1) is an anti-inflammatory protein that is an important modulator and plays a key role in inflammation. Although the precise action of ANX1 remains unclear, it has emerged as a potential drug target for inflammatory diseases such as asthma. To examine the protective effects of ANX1 protein on ovalbumin (OVA)-induced asthma in animal models, we used a cell-permeable Tat-ANX1 protein. Mice sensitized and challenged with OVA antigen had an increased amount of cytokines and eosinophils in their bronchoalveolar lavage (BAL) fluid. However, administration of Tat-ANX1 protein before OVA challenge significantly decreased the levels of cytokines (interleukin (IL)-4, IL-5, and IL-13) and BAL fluid in lung tissues. Furthermore, OVA significantly increased the activation of mitogen-activated protein kinase (MAPK) in lung tissues, whereas Tat-ANX1 protein markedly reduced phosphorylation of MAPKs such as extracellular signal-regulated protein kinase, p38, and stress-activated protein kinase/c-Jun N-terminal kinase. These results suggest that transduced Tat-ANX1 protein may be a potential protein therapeutic agent for the treatment of lung disorders including asthma.

  4. Interleukin-22 exacerbates airway inflammation induced by short-term exposure to cigarette smoke in mice

    PubMed Central

    Li, Jiu-rong; Zhou, Wei-xun; Huang, Ke-wu; Jin, Yang; Gao, Jin-ming

    2014-01-01

    Aim: Interleukin-22 (IL-22) exhibits both proinflammatory and anti-inflammatory properties in various biological processes. In this study we explored the effects of exogenous recombinant IL-22 (rIL-22) on cigarette smoke (CS)-induced airway inflammation in mice. Methods: Male C57BL/6 mice were divided into groups: (1) CS group exposed to tobacco smoke for 3 consecutive days, (2) rIL-22 group received rIL-22 (100 mg/kg, ip), and (3) CS plus rIL-22 group, received rIL-22 (100 mg/kg, ip) before the CS exposure. The airway resistance (Rn), lung morphology, inflammatory cells in the airways, and inflammatory cytokines and CXCR3 ligands in both bronchoalveolar lavage (BAL) fluids and lung tissues were analyzed. Results: CS alone significantly elevated IL-22 level in the BAL fluid. Both CS and rIL-22 significantly augmented airway resistance, an influx of inflammatory cells into the airways and lung parenchyma, and significantly elevated levels of pro-inflammatory cytokines (TGFβ1 and IL-17A) and CXCR3 chemokines (particularly CXCL10) at the mRNA and/or protein levels. Furthermore, the effects of rIL-22 on airway resistance and inflammation were synergistic with those of CS, as demonstrated by a further increased Rn value, infiltration of greater numbers of inflammatory cells into the lung, higher levels of inflammatory cytokines and chemokines, and more severe pathological changes in CS plus rIL-22 group as compared to those in CS group. Conclusion: Exogenous rIL-22 exacerbates the airway inflammatory responses to CS exposure in part by inducing expression of several proinflammatory cytokines and CXCR3 ligands. PMID:25345745

  5. Modulation of inflammatory response of wounds by antimicrobial photodynamic therapy

    PubMed Central

    Sharma, Mrinalini; Gupta, Pradeep Kumar

    2015-01-01

    Background and aims: Management of infections caused by Pseudomonas aeruginosa is becoming difficult due to the rapid emergence of multi-antibiotic resistant strains. Antimicrobial photodynamic therapy (APDT) has a lot of potential as an alternative approach for inactivation of antibiotic resistant bacteria. In this study we report results of our investigations on the effect of poly-L-lysine conjugate of chlorine p6 (pl-cp6) mediated APDT on the healing of P.aeruginosa infected wounds and the role of Nuclear Factor kappa B (NF-kB) induced inflammatory response in this process. Materials and method: Excisional wounds created in Swiss albino mice were infected with ∼107 colony forming units of P.aeruginosa. Mice with wounds were divided into three groups: 1) Uninfected, 2) Infected, untreated control (no light, no pl-cp6), 3) Infected, APDT. After 24 h of infection (day 1 post wounding), the wounds were subjected to APDT [pl-cp6 applied topically and exposed to red light (660 ± 25 nm) fluence of ∼ 60 J/cm2]. Subsequent to APDT, on day 2 and 5 post wounding (p.w), measurements were made on biochemical parameters of inflammation [toll like receptor-4 (TLR-4), NF-kB, Inteleukin (IL)-[1α, IL-β, and IL-2)] and cell proliferation [(fibroblast growth factor-2 (FGF-2), alkaline phosphatase (ALP)]. Results: In comparison with untreated control, while expression of TLR-4, NF-kB (p105 and p50), and proinflammatory interleukins (IL-1α, IL-1β,IL-2) were reduced in the infected wounds subjected to APDT, the levels of FGF-2 and ALP increased, on day 5 p.w. Conclusion: The measurements made on the inflammatory markers and cell proliferation markers suggest that APDT reduces inflammation caused by P.aeruginosa and promotes cell proliferation in wounds. PMID:26557735

  6. Eosinophil-mediated signalling attenuates inflammatory responses in experimental colitis

    PubMed Central

    Masterson, Joanne C; McNamee, Eóin N; Fillon, Sophie A; Hosford, Lindsay; Harris, Rachel; Fernando, Shahan D; Jedlicka, Paul; Iwamoto, Ryo; Jacobsen, Elizabeth; Protheroe, Cheryl; Eltzschig, Holger K; Colgan, Sean P; Arita, Makoto; Lee, James J; Furuta, Glenn T

    2015-01-01

    Objective Eosinophils reside in the colonic mucosa and increase significantly during disease. Although a number of studies have suggested that eosinophils contribute to the pathogenesis of GI inflammation, the expanding scope of eosinophil-mediated activities indicate that they also regulate local immune responses and modulate tissue inflammation. We sought to define the impact of eosinophils that respond to acute phases of colitis in mice. Design Acute colitis was induced in mice by administration of dextran sulfate sodium, 2,4,6-trinitrobenzenesulfonic acid or oxazolone to C57BL/6J (control) or eosinophil deficient (PHIL) mice. Eosinophils were also depleted from mice using antibodies against interleukin (IL)-5 or by grafting bone marrow from PHIL mice into control mice. Colon tissues were collected and analysed by immunohistochemistry, flow cytometry and reverse transcription PCR; lipids were analysed by mass spectroscopy. Results Eosinophil-deficient mice developed significantly more severe colitis, and their colon tissues contained a greater number of neutrophils, than controls. This compensatory increase in neutrophils was accompanied by increased levels of the chemokines CXCL1 and CXCL2, which attract neutrophils. Lipidomic analyses of colonic tissue from eosinophil-deficient mice identified a deficiency in the docosahexaenoic acid-derived anti-inflammatory mediator 10, 17- dihydroxydocosahexaenoic acid (diHDoHE), namely protectin D1 (PD1). Administration of an exogenous PD1-isomer (10S, 17S-DiHDoHE) reduced the severity of colitis in eosinophil-deficient mice. The PD1-isomer also attenuated neutrophil infiltration and reduced levels of tumour necrosis factor-α, IL-1β, IL-6 and inducible NO-synthase in colons of mice. Finally, in vitro assays identified a direct inhibitory effect of PD1-isomer on neutrophil transepithelial migration. Conclusions Eosinophils exert a protective effect in acute mouse colitis, via production of anti-inflammatory lipid

  7. Conquering the difficult airway.

    PubMed

    Gandy, William E

    2008-01-01

    Every medic should practice regularly for the inevitable difficult airway case. Practice should include review of the causes of difficult airways, as well as skill practice. Having a preassembled airway kit can make your response to an unexpected difficult situation easier. Of all the devices mentioned, the bougie is the airway practitioner's best friend. Using the BURP technique, if not contraindicated, together with the bougie will enable you to intubate many difficult patients with confidence. Remember, "If your patient cannot breathe, nothing else matters. PMID:18251307

  8. Platelet activation and apoptosis modulate monocyte inflammatory responses in dengue

    PubMed Central

    Hottz, Eugenio D.; Medeiros-de-Moraes, Isabel M.; Vieira-de-Abreu, Adriana; de Assis, Edson F.; Vals-de-Souza, Rogério; Castro-Faria-Neto, Hugo C.; Weyrich, Andrew S.; Zimmerman, Guy A.; Bozza, Fernando A.; Bozza, Patrícia T.

    2014-01-01

    Background Dengue is the most prevalent human arbovirus disease in the world. Dengue infection has a large spectrum of clinical manifestations from self-limited febrile illness to severe syndromes accompanied by bleeding and shock. Thrombocytopenia and vascular leak with altered cytokine profiles in plasma are features of severe dengue. Although monocytes have been recognized as important sources of cytokines in dengue, the contributions of platelet-monocyte interactions to inflammatory responses in dengue have not been addressed. Patients/Methods Patients with dengue were investigated for platelet-monocyte aggregate formation and markers of monocyte activation. Platelet-induced cytokine responses by monocytes and underlying mechanisms were also investigated in vitro. Results We observed increased levels of platelet-monocyte aggregates in blood samples from patients with dengue, especially patients with thrombocytopenia and increased vascular permeability. Moreover, the exposure of monocytes from healthy volunteers to platelets from patients with dengue induced the secretion of the cytokines IL-1β, IL-8, IL-10 and MCP-1, while the exposure to platelets from healthy volunteers only induced the secretion of MCP-1. In addition to the well-established modulation of monocyte cytokine responses by activated platelets through P-selectin binding, we found that interaction of monocytes with apoptotic platelets mediate IL-10 secretion through phosphatidylserine recognition in platelet-monocyte aggregates. Moreover, IL-10 secretion required platelet-monocyte contact but not phagocytosis. Conclusions Together, our results demonstrate that activated and apoptotic platelets aggregate with monocytes during dengue infection and signal specific cytokine responses that may contribute to the pathogenesis of dengue. PMID:25015827

  9. Cerebral analgesic response to nonsteroidal anti-inflammatory drug ibuprofen.

    PubMed

    Hodkinson, Duncan J; Khawaja, Nadine; OʼDaly, Owen; Thacker, Michael A; Zelaya, Fernando O; Wooldridge, Caroline L; Renton, Tara F; Williams, Steven C R; Howard, Matthew A

    2015-07-01

    Nonopioid agents, such as nonsteroidal anti-inflammatory drugs (NSAIDs), are the most commonly used class of analgesics. Increasing evidence suggests that cyclooxygenase (COX) inhibition at both peripheral and central sites can contribute to the antihyperalgesic effects of NSAIDs, with the predominant clinical effect being mediated centrally. In this study, we examined the cerebral response to ibuprofen in presurgical and postsurgical states and looked at the analgesic interaction between surgical state and treatment. We used an established clinical pain model involving third molar extraction, and quantitative arterial spin labelling (ASL) imaging to measure changes in tonic/ongoing neural activity. Concurrent to the ASL scans, we presented visual analogue scales inside the scanner to evaluate the subjective experience of pain. This novel methodology was incorporated into a randomized double-blind placebo-controlled design, with an open method of drug administration. We found that independent of its antinociceptive action, ibuprofen has no effect on regional cerebral blood flow under pain-free conditions (presurgery). However, in the postsurgical state, we observed increased activation of top-down modulatory circuits, which was accompanied by decreases in the areas engaged because of ongoing pain. Our findings demonstrate that ibuprofen has a measurable analgesic response in the human brain, with the subjective effects of pain relief reflected in two distinct brain networks. The observed activation of descending modulatory circuits warrants further investigation, as this may provide new insights into the inhibitory mechanisms of analgesia that might be exploited to improve safety and efficacy in pain management. PMID:25851460

  10. A pneumococcal pilus influences virulence and host inflammatory responses.

    PubMed

    Barocchi, M A; Ries, J; Zogaj, X; Hemsley, C; Albiger, B; Kanth, A; Dahlberg, S; Fernebro, J; Moschioni, M; Masignani, V; Hultenby, K; Taddei, A R; Beiter, K; Wartha, F; von Euler, A; Covacci, A; Holden, D W; Normark, S; Rappuoli, R; Henriques-Normark, B

    2006-02-21

    Streptococcus pneumoniae (pneumococcus) is a major cause of morbidity and mortality world-wide. The initial event in invasive pneumococcal disease is the attachment of encapsulated pneumococci to epithelial cells in the upper respiratory tract. This work provides evidence that initial bacterial adhesion and subsequent ability to cause invasive disease is enhanced by pili, long organelles able to extend beyond the polysaccharide capsule, previously unknown to exist in pneumococci. These adhesive pili-like appendages are encoded by the pneumococcal rlrA islet, present in some, but not all, clinical isolates. Introduction of the rlrA islet into an encapsulated rlrA-negative isolate allowed pilus expression, enhanced adherence to lung epithelial cells, and provided a competitive advantage upon mixed intranasal challenge of mice. Furthermore, a pilus-expressing rlrA islet-positive clinical isolate was more virulent than a nonpiliated deletion mutant, and it out-competed the mutant in murine models of colonization, pneumonia, and bacteremia. Additionally, piliated pneumococci evoked a higher TNF response during systemic infection, compared with nonpiliated derivatives, suggesting that pneumococcal pili not only contribute to adherence and virulence but also stimulate the host inflammatory response. PMID:16481624

  11. Acute Pelvic Inflammatory Disease and Clinical Response to Parenteral Doxycycline

    PubMed Central

    Chow, Anthony W.; Malkasian, Kay L.; Marshall, John R.; Guze, Lucien B.

    1975-01-01

    The bacteriology of acute pelvic inflammatory disease (PID) and clinical response to parenteral doxycycline were evaluated in 30 patients. Only 3 of 21 cul-de-sac cultures from PID patients were sterile, whereas all 8 normal control subjects yielded negative results (P< 0.005). Poor correlation was observed between cervical and cul-de-sac cultures. Neisseria gonorrhoeae, isolated from the cervix in 17 patients (57%), was recovered from the cul-de-sac only once. Streptococcus, Peptococcus, Peptostreptococcus, coliforms, and other organisms normally present in the vagina were the predominant isolates recovered from the cul-de-sac. Parenteral doxycycline resulted in rapid resolution of signs and symptoms (within 48 h) in 20 of 27 evaluable patients (74%). In five others, signs and symptoms of infection abated within 4 days. The remaining two patients failed to respond; in both cases, adnexal masses developed during doxycycline therapy. Gonococci were eradicated from the cervix in all but one patient who, nevertheless, had a rapid defervescence of symptoms. There was no clear-cut correlation between the clinical response and in vitro susceptibility of cul-de-sac isolates to doxycycline. These data confirm the usefulness of broad-spectrum antibiotics in acute PID. Culdocentesis is a reliable means of obtaining material for the bacteriological diagnosis of acute PID; however, the pathogenetic role and relative importance of gonococci and various other bacteria in acute PID need to be clarified further. PMID:1169908

  12. Histone deacetylase 5 regulates the inflammatory response of macrophages

    PubMed Central

    Poralla, Lukas; Stroh, Thorsten; Erben, Ulrike; Sittig, Marie; Liebig, Sven; Siegmund, Britta; Glauben, Rainer

    2015-01-01

    Modifying the chromatin structure and interacting with non-histone proteins, histone deacetylases (HDAC) are involved in vital cellular processes at different levels. We here specifically investigated the direct effects of HDAC5 in macrophage activation in response to bacterial or cytokine stimuli. Using murine and human macrophage cell lines, we studied the expression profile and the immunological function of HDAC5 at transcription and protein level in over-expression as well as RNA interference experiments. Toll-like receptor-mediated stimulation of murine RAW264.7 cells significantly reduced HDAC5 mRNA within 7 hrs but presented baseline levels after 24 hrs, a mechanism that was also found for Interferon-γ treatment. If treated with lipopolysaccharide, RAW264.7 cells transfected for over-expression only of full-length but not of mutant HDAC5, significantly elevated secretion of tumour necrosis factor α and of the monocyte chemotactic protein-1. These effects were accompanied by increased nuclear factor-κB activity. Accordingly, knock down of HDAC5-mRNA expression using specific siRNA significantly reduced the production of these cytokines in RAW264.7 or human U937 cells. Taken together, our results suggest a strong regulatory function of HDAC5 in the pro-inflammatory response of macrophages. PMID:26059794

  13. A pneumococcal pilus influences virulence and host inflammatory responses

    PubMed Central

    Barocchi, M. A.; Ries, J.; Zogaj, X.; Hemsley, C.; Albiger, B.; Kanth, A.; Dahlberg, S.; Fernebro, J.; Moschioni, M.; Masignani, V.; Hultenby, K.; Taddei, A. R.; Beiter, K.; Wartha, F.; von Euler, A.; Covacci, A.; Holden, D. W.; Normark, S.; Rappuoli, R.; Henriques-Normark, B.

    2006-01-01

    Streptococcus pneumoniae (pneumococcus) is a major cause of morbidity and mortality world-wide. The initial event in invasive pneumococcal disease is the attachment of encapsulated pneumococci to epithelial cells in the upper respiratory tract. This work provides evidence that initial bacterial adhesion and subsequent ability to cause invasive disease is enhanced by pili, long organelles able to extend beyond the polysaccharide capsule, previously unknown to exist in pneumococci. These adhesive pili-like appendages are encoded by the pneumococcal rlrA islet, present in some, but not all, clinical isolates. Introduction of the rlrA islet into an encapsulated rlrA-negative isolate allowed pilus expression, enhanced adherence to lung epithelial cells, and provided a competitive advantage upon mixed intranasal challenge of mice. Furthermore, a pilus-expressing rlrA islet-positive clinical isolate was more virulent than a nonpiliated deletion mutant, and it out-competed the mutant in murine models of colonization, pneumonia, and bacteremia. Additionally, piliated pneumococci evoked a higher TNF response during systemic infection, compared with nonpiliated derivatives, suggesting that pneumococcal pili not only contribute to adherence and virulence but also stimulate the host inflammatory response. PMID:16481624

  14. Dose response relation to oral theophylline in severe chronic obstructive airways disease.

    PubMed Central

    Chrystyn, H.; Mulley, B. A.; Peake, M. D.

    1988-01-01

    OBJECTIVE--To evaluate measurement of the trapped gas volume as a measure of respiratory function in patients with chronic obstructive airways disease and their response to treatment with theophylline. DESIGN--Patients able to produce consistent results on testing of respiratory function spent two weeks having dosage of theophylline adjusted to give individual pharmacokinetic data. This was followed by random assignment to four consecutive two month treatment periods--placebo and low, medium, and high dose, as assessed by serum concentrations of theophylline. Respiratory function and exercise performance was assessed at the end of each two month period. SETTING--Chest unit in district hospital. PATIENTS--Thirty eight patients with chronic bronchitis and moderate to severe chronic obstruction to airflow were recruited; 33 aged 53-73 years completed the study. INTERVENTIONS--Dosage of oral theophylline increased during two week optimisation period to 800 mg daily unless toxicity was predicted, when 400 mg was given. Targets for the steady state serum theophylline concentrations were 5-10 mg/l in the low dose period, 10-15 mg/l in the medium dose, and 15-20 mg/l in the high dose period. ENDPOINTS--Respiratory function as measured by forced expiratory volume in one second, forced vital capacity, peak expiratory flow rate, slow vital capacity, and static lung volumes using helium dilution and body plethysmography from which trapped gas volume was derived. Exercise performance assessed by six minute walking test and diary cards using visual analogue scale. MEASUREMENTS AND MAIN RESULTS--The forced expiratory volume in one second, forced vital capacity, and peak expiratory flow rate changed only slightly (about 13%) over the range of doses. There was a linear dose dependent fall of trapped gas volume from 1.84 l (SE 0.157) to 1.42 l (0.152), 1.05 l (0.128), and 0.67 l (0.102) during the placebo and low, medium, and high dose treatment periods. Mean walking distance

  15. Human Airway Epithelial Cell Responses to Single Walled Carbon Nanotube Exposure: Nanorope-Residual Body Formation

    SciTech Connect

    Panessa-Warren, Barbara J.; Warren, John B.; Kisslinger, Kim; Crosson, Kenya; Maye, Mathew M.

    2012-11-01

    This investigation examines the 'first contact responses' of in vitro human epithelial airway cells exposed to unrefined single walled carbon nanotubes (SWCNTs) [containing metal catalyst, carbon black, amorphous carbon, graphitic shells, and SWCNTs], and refined acid/peroxide cleaned and cut SWCNTs at low and high dose exposures (0.16 ug/L and 1.60 ug/L) for 2, 3 and 3.5 hours. FTIR, X-ray compositional analysis, morphological TEM analysis and UV-Vis were used to physicochemically characterize the SWCNTs in this study. Following SWCNT exposure to human lung NCI-H292 epithelial monolayers, the airway cells were prepared for light microscopy vital staining, or fixed in glutaraldehyde for SEM/TEM imaging to determine SWCNT binding, uptake, intracellular processing and organellar/SWCNT fate within the exposure period. At 2 hr exposures to both unrefined Carbolex, and refined SWCNTs (at both high and low doses), there were no increases in lung cell necrosis compared to controls. However high dose, 3 hr exposures to unrefined Carbolex material produced severe cell damage (apical and basal plasma membrane holes, decreased mitochondria, numerous intracellular vesicles containing nanomaterial and membrane fragments) and increased cell necrosis. The refined SWCNTs exposed for 3 hr at low dose produced no increase in cell death, although high dose exposure produced significant cell death. By TEM, Acid/peroxide cleaned SWCNT 3 hr exposures at high and low doses, revealed SWCNTs attachment to cell surface mucin, and SWCNT uptake into the cells during membrane recycling. Membranes and SWCNTs were seen within cytoplasmic lamellar body-type vesicles, where vesicular contents were bio-degraded, eventually forming long SWCNT-nanoropes, which were subsequently released into the cytoplasm as clusters of attached nanoropes, as the vesicle membranes fragmented. These Nanorope-Residual Bodies did not cause damage to the surrounding organelles or cytoplasm, and seemed very stabile in the

  16. Direct particle-to-cell deposition of coarse ambient particulate matter increases the production of inflammatory mediators from cultured human airway epithelial cells

    PubMed Central

    Volckens, John; Dailey, Lisa; Walters, Glenn; Devlin, Robert B.

    2010-01-01

    Exposure of cultured cells to particulate matter air pollution is usually accomplished by collecting particles on a solid matrix, extracting the particles from the matrix, suspending them in liquid, and applying the suspension to cells grown on plastic and submerged in medium. The objective of this work was to develop a more physiologically and environmentally relevant model of air pollutant deposition on cultures of human primary airway epithelial cells. We hypothesize that the toxicology of inhaled particulate matter depends strongly on both the particulate dispersion state and the mode of delivery to cells. Our exposure system employs a combination of unipolar charging and electrostatic force to deposit particles directly from the air onto cells grown at an air-liquid interface in a heated, humidified exposure chamber. Normal human bronchial epithelial cells exposed to concentrated, coarse ambient particulate matter in this system expressed increased levels of inflammatory biomarkers at 1 hour following exposure and relative to controls exposed to particle-free air. More importantly, these effects are seen at particulate loadings that are 1-2 orders of magnitude lower than levels applied using traditional in vitro systems. PMID:19603682

  17. Spatial and temporal traction response in human airway smooth muscle cells

    NASA Technical Reports Server (NTRS)

    Tolic-Norrelykke, Iva Marija; Butler, James P.; Chen, Jianxin; Wang, Ning

    2002-01-01

    Tractions that cells exert on their substrates are essential in cell spreading, migration, and contraction. These tractions can be determined by plating the cells on a flexible gel and measuring the deformation of the gel by using fluorescent beads embedded just below the surface of the gel. In this article we describe the image correlation method (ICM) optimized for determining the displacement field of the gel under a contracting cell. For the calculation of the traction field from the displacement field we use the recently developed method of Fourier transform traction cytometry (FTTC). The ICM and FTTC methods are applied to human airway smooth muscle cells during stimulation with the contractile agonist histamine or the relaxing agonist isoproterenol. The overall intensity of the cell contraction (the median traction magnitude, the energy transferred from the cell to the gel, and the net contractile moment) increased after activation with histamine, and decreased after treatment with isoproterenol. Cells exhibited regional differences in the time course of traction during the treatment. Both temporal evolution and magnitude of traction increase induced by histamine varied markedly among different cell protrusions, whereas the nuclear region showed the smallest response. These results suggest that intracellular mediators of cell adhesion and contraction respond to contractile stimuli with different rates and intensities in different regions of the cell.

  18. An overview of asthma and airway hyper-responsiveness in Olympic athletes.

    PubMed

    Fitch, Kenneth D

    2012-05-01

    Data from the past five Olympic Games obtained from athletes seeking to inhale β2 adrenoceptor agonists (IBA) have identified those athletes with documented asthma and airway hyper-responsiveness (AHR). With a prevalence of about 8%, asthma/AHR is the commonest chronic medical condition experienced by Olympic athletes. In Summer and Winter athletes, there is a marked preponderance of asthma/AHR in endurance-trained athletes. The relatively late onset of asthma/AHR in many older athletes is suggestive that years of endurance training may be a contributory cause. Inspiring polluted or cold air is considered a significant aetiological factor in some but not all sports. During the last five Olympic Games, there has been improved management of athletes with asthma/AHR with a much higher proportion of athletes combining inhaled corticosteroids (ICS) with IBA and few using long-acting IBA as monotherapy. Athletes with asthma/AHR have consistently outperformed their peers, which research suggests is not due to their treatment enhancing sports performance. Research is necessary to determine how many athletes will continue to experience asthma/AHR in the years after they cease intensive endurance training. PMID:22228581

  19. So-Cheong-Ryong-Tang, a herbal medicine, modulates inflammatory cell infiltration and prevents airway remodeling via regulation of interleukin-17 and GM-CSF in allergic asthma in mice

    PubMed Central

    Kim, Hyung-Woo; Lim, Chi-Yeon; Kim, Bu-Yeo; Cho, Su-In

    2014-01-01

    Background: So-Cheong-Ryong-Tang (SCRT), herbal medicine, has been used for the control of respiratory disease in East Asian countries. However, its therapeutic mechanisms, especially an inhibitory effect on inflammatory cell infiltration and airway remodeling in allergic asthma are unclear. Objective: The present study investigated the mechanism of antiasthmatic effects of SCRT in allergic asthma in mice. Materials and Methods: We investigated the influence of SCRT on levels of interleukin-17 (IL-17), granulocyte/macrophage colony-stimulating factor (GM-CSF), IL-4, and interferon gamma (IFN-γ) in bronchoalveolar lavage fluid (BALF), ovalbumin (OVA)-specific IgE in serum, and histopathological changes in allergen-induced asthma. Results: So-Cheong-Ryong-Tang decreased levels of IL-17 and GM-CSF in BALF. IL-4, a Th2-driven cytokine, was also decreased by SCRT, but IFN-γ, a Th1-driven cytokine, was not changed. Levels of OVA-specific IgE in serum were also decreased by SCRT. With SCRT treatment, histopathological findings showed reduced tendency of inflammatory cell infiltration, and prevention from airway remodeling such as epithelial hyperplasia. Conclusion: In this study, we firstly demonstrated that regulation of IL-17 and GM-CSF production may be one of the mechanism contributed to a reduction of inflammatory cell infiltration and prevention from airway remodeling. PMID:25298667

  20. Effects of cessation of terbutaline treatment on airway obstruction and responsiveness in patients with chronic obstructive pulmonary disease.

    PubMed Central

    de Jong, J. W.; Koëter, G. H.; van der Mark, T. W.; Postma, D. S.

    1996-01-01

    BACKGROUND: Cessation of regular therapy with inhaled beta 2 agonists in patients with asthma may lead to a temporary deterioration of lung function and airway responsiveness. Few such studies have been reported in patients with chronic obstructive pulmonary disease (COPD), so an investigation was carried out to determine whether rebound airway responsiveness and rebound bronchoconstriction also occurs in COPD and if there is any relationship with the dose of beta 2 agonist being used. METHODS: Lung function (forced expiratory volume in one second (FEV1) and peak expiratory flow (PEF)), airway responsiveness (PC20 methacholine (PC20)) and symptoms were assessed in a double blind, placebo controlled crossover study during and after cessation of two weeks regular treatment with placebo, and low dose (250 micrograms) and high dose (1000 micrograms) inhaled terbutaline via a dry powder inhaler (Turbohaler) all given three times a day. Sixteen non-allergic patients with COPD of mean (SD) age 58.7 (6.5) years, FEV1 57.1 (12.8)% of predicted, and reversibility on 1000 micrograms terbutaline of 4.5 (3.5)% predicted were studied. PC20 and FEV1 were measured 10, 14, 34 and 82 hours after the last inhalation of terbutaline or placebo. Measurements performed at 10, 14, and 34 hours were expressed relative to 82 hour values in each period, transformed into an area under the curve (AUC) value and analysed by ANOVA. RESULTS: Mean morning and evening PEF increased during terbutaline treatment. PC20 and FEV1 did not change after cessation of terbutaline treatment. CONCLUSIONS: Cessation of regular treatment with both low and high dose inhaled terbutaline does not result in a rebound bronchoconstriction and rebound airway responsiveness in patients with COPD. PMID:8882073

  1. Nonadrenergic, noncholinergic responses stabilize smooth muscle tone, with and without parasympathetic activation, in guinea-pig isolated airways.

    PubMed

    Lindén, A; Löfdahl, C G; Ullman, A; Skoogh, B E

    1993-03-01

    In guinea-pig isolated airways, nonadrenergic, noncholinergic (NANC) neural responses converge towards a similar level of smooth muscle tone, via a contraction when the tone is low prior to stimulation, and via a relaxation when the tone is high prior to stimulation. We wanted to assess the effect of simultaneous parasympathetic activation on these converging NANC responses, with and without the addition of sympathetic activation. In guinea-pig isolated airways, the spontaneous airway tone was initially abolished by indomethacin (10 microM). In one series, adrenergic depletion by guanethidine (10 microM) was then established, with and without cholinergic blockade by atropine (1 microM). In another series, either cholinergic blockade by atropine (1 microM) or no blockade was utilized. Responses to electrical field stimulation (1,200 mA, 0.5 ms, 3 Hz for 240 s) were studied with no induced tone, at a moderate (0.3 microM) and at a near-maximum (6 microM), histamine-induced tone. The mean level of the tonus equilibrium (% of maximum tone) was higher with the simultaneous NANC and parasympathetic activation than with NANC activation alone (75% compared with 44%, in the main bronchus, n = 8). The level of the tonus equilibrium was also higher with the simultaneous NANC, sympathetic and parasympathetic activation than with NANC and sympathetic activation only (49% compared with 21%, in the main bronchus, n = 8). The pattern was similar in the distal trachea. In conclusion, NANC neural responses can stabilize smooth muscle tone, and this stabilizing effect can be modulated by both parasympathetic and sympathetic activation, in guinea-pig isolated airways. PMID:8472834

  2. Apoptosis of resident and inflammatory macrophages before and during the inflammatory response of the virgin bovine mammary gland

    PubMed Central

    2010-01-01

    Background Macrophages may play a prominent role in defense of the bovine mammary gland, and their functionality is necessary for successful eradication of bacterial pathogens. In contrast to necrosis, however, apoptosis has not yet been studied in macrophages from bovine mammary glands. Therefore, the aim of this study was to confirm the occurrence of apoptosis in macrophages from resting heifer mammary glands and during the inflammatory response. Methods Inflammatory response was induced by phosphate buffered saline (PBS) and by lipopolysaccharide (LPS). Resident macrophages (RESMAC) were obtained before and inflammatory macrophages (INFMAC) 24, 48, 72 and 168 hours after inducing inflammatory response in mammary glands of unbred heifers. Cell samples were analyzed for differential counts, apoptosis and necrosis using flow cytometry. Results Populations of RESMAC and INFMAC contained monocyte-like cells and vacuolized cells. Apoptosis was detected differentially in both morphologically different types of RESMAC and INFMAC and also during initiation and resolution of the inflammatory response. In the RESMAC population, approximately one-tenth of monocyte-like cells and one-third of vacuolized cells were apoptotic. In the INFMAC population obtained 24 h after PBS treatment, approximately one-tenth of monocyte-like cells and almost one-quarter of vacuolized cells were apoptotic. At the same time following LPS, however, we observed a significantly lower percentage of apoptotic cells in the population of monocyte-like INFMAC and vacuolized INFMAC. Moreover, a higher percentage of apoptotic cells in INFMAC was detected during all time points after PBS in contrast to LPS. Comparing RESMAC and INFMAC, we observed that vacuolized cells from populations of RESMAC and INFMAC underwent apoptosis more intensively than did monocyte-like cells. Conclusions We conclude that apoptosis of virgin mammary gland macrophages is involved in regulating their lifespan, and it is involved

  3. Regulation of cyclooxygenase-2 expression by cAMP response element and mRNA stability in a human airway epithelial cell line exposed to zinc

    EPA Science Inventory

    Exposure to zinc-laden particulate matter in ambient and occupational settings has been associated with proinflammatory responses in the lung. Cyclooxygenase 2-derived eicosanoids are important modulators of airway inflammation. In this study, we characterized the transcriptional...

  4. Exposure Assessment and Inflammatory Response Among Workers Producing Calcium Carbonate Nanomaterials

    NASA Astrophysics Data System (ADS)

    Cui, Ling

    . Modification is thought to be the primary emission source. It is discovered nanoparticles in the size range of 20-300nm dominate in this workplace, which consists of 90-98% of particle counts in the respirable fraction. Based on the sampling results from 2012, there was a strong relationship between number concentration in 5-25um range and the respirable mass concentration (r= 0.908); however, no such correlation was found between number concentration in nanoscale and respirable mass (r= 0.018). The deposited surface area in TB (r=0.66) and alveolar region (r=0.46) was modestly correlated with number concentration of particles in the nanoscale. A reduced FEV1 and increased BP were consistently found among medium-mass exposure compared to low-mass exposure, however no statistical significance was found. When comparing the four exposure metrics, we found number concentration and surface area concentration in general produce effects in similar direction, however opposite to mass concentration. Such observation is consistent with the correlation among these exposure metrics. Airway inflammatory responses presented a dose-response relationship using mass as exposure metric. The concentrations of IL1beta (p =0.043) and IL8 (p=0.008) in sputum among high mass-exposure group were statistically greater than that in low-mass exposure group. It suggested the inflammatory responses were associated with mass concentration of inhaled nanoparticle particles, which are mainly made up by agglomerated form of nanoparticles. At current stage, with limited understanding of the toxicological perspective of nanoparticle, a complete exposure assessment in nanoparticle facility needs to be conducted in both bulk- and nano-form.

  5. DISREGULATION OF INFLAMMATORY RESPONSES BY CHRONIC CIRCADIAN DISRUPTION

    PubMed Central

    Castanon-Cervantes, Oscar; Wu, Mingwei; Ehlen, J. Christopher; Paul, Ketema; Gamble, Karen L.; Johnson, Russell L.; Besing, Rachel C.; Menaker, Michael; Gewirtz, Andrew T.; Davidson, Alec J.

    2010-01-01

    Circadian rhythms modulate nearly every mammalian physiological process. Chronic disruption of circadian timing in shift work or during chronic jet lag in animal models leads to a higher risk of several pathologies. Many of these conditions in both shift workers and experimental models share the common risk factor of inflammation. Here we show that experimentally-induced circadian disruption altered innate immune responses. Endotoxemic shock induced by LPS was magnified leading to hypothermia and death after 4 consecutive weekly 6h phase-advances of the light-dark schedule, with 89% mortality compared with 21% in unshifted control mice. This may be due to a heightened release of pro-inflammatory cytokines in response to LPS treatment in shifted animals. Isolated peritoneal macrophages harvested from shifted mice exhibited a similarly heightened response to LPS in vitro, indicating that these cells are a target for jet lag. Sleep deprivation and stress are known to alter immune function and are potential mediators of the effects we describe. However polysomnographic recording in mice exposed to the shifting schedule revealed no sleep loss, and stress measures were not altered in shifted mice. In contrast, we observed altered or abolished rhythms in the expression of clock genes in the central clock, liver, thymus and peritoneal macrophages in mice after chronic jet lag. We conclude that circadian disruption, but not sleep loss or stress, are associated with jet lag-related disregulation of the innate immune system. Such immune changes might be a common mechanism for the myriad negative health effects of shift work. PMID:20944004

  6. Distinct Tlr4-expressing cell compartments control neutrophilic and eosinophilic airway inflammation.

    PubMed

    McAlees, J W; Whitehead, G S; Harley, I T W; Cappelletti, M; Rewerts, C L; Holdcroft, A M; Divanovic, S; Wills-Karp, M; Finkelman, F D; Karp, C L; Cook, D N

    2015-07-01

    Allergic asthma is a chronic, inflammatory lung disease. Some forms of allergic asthma are characterized by T helper type 2 (Th2)-driven eosinophilia, whereas others are distinguished by Th17-driven neutrophilia. Stimulation of Toll-like receptor 4 (TLR4) on hematopoietic and airway epithelial cells (AECs) contributes to the inflammatory response to lipopolysaccharide (LPS) and allergens, but the specific contribution of TLR4 in these cell compartments to airway inflammatory responses remains poorly understood. We used novel, conditionally mutant Tlr4(fl/fl) mice to define the relative contributions of AEC and hematopoietic cell Tlr4 expression to LPS- and allergen-induced airway inflammation. We found that Tlr4 expression by hematopoietic cells is critical for neutrophilic airway inflammation following LPS exposure and for Th17-driven neutrophilic responses to the house dust mite (HDM) lysates and ovalbumin (OVA). Conversely, Tlr4 expression by AECs was found to be important for robust eosinophilic airway inflammation following sensitization and challenge with these same allergens. Thus, Tlr4 expression by hematopoietic and airway epithelial cells controls distinct arms of the immune response to inhaled allergens. PMID:25465099

  7. Acute response of airway muscle to extreme temperature includes disruption of actin-myosin interaction.

    PubMed

    Dyrda, Peter; Tazzeo, Tracy; DoHarris, Lindsay; Nilius, Berndt; Roman, Horia Nicolae; Lauzon, Anne-Marie; Aziz, Tariq; Lukic, Dusan; Janssen, Luke J

    2011-02-01

    Despite the emerging use of bronchial thermoplasty in asthma therapy, the response of airway smooth muscle (ASM) to extreme temperatures is unknown. We investigated the immediate effects of exposing ASM to supraphysiologic temperatures. Isometric contractions were studied in bovine ASM before and after exposure to various thermal loads and/or pharmacologic interventions. Actin-myosin interactions were investigated using a standard in vitro motility assay. We found steep thermal sensitivity for isometric contractions evoked by acetylcholine, with threshold and complete inhibition at less than 50°C and greater than 55°C, respectively. Contractile responses to serotonin or KCl were similarly affected, whereas isometric relaxations evoked by the nitric oxide donor S-nitrosyl-N-acetylpenicillamine or the β-agonist isoproterenol were unaffected. This thermal sensitivity developed within 15 minutes, but did not evolve further over the course of several days (such a rapid time-course rules out heat shock proteins, apoptosis, autophagy, and necrosis). Although heat-sensitive transient receptor potential (TRPV2) channels and the calmodulin-dependent (Cam) kinase-II-induced inactivation of myosin light chain kinase are both acutely thermally sensitive, with a temperature producing half-maximal effect (T(1/2)) of 52.5°C, the phenomenon we describe was not prevented by blockers of TRPV2 channels (e.g., ruthenium red, gadolinium, zero-Ca(2+) or zero-Na(+)/zero-Ca(2+) media, and cromakalim) or of Cam kinase-II (e.g., W7, trifluoperazine, and KN-93). However, direct measurements of actin-myosin interactions showed the same steep thermal profile. The functional changes preceded any histologic evidence of necrosis or apoptosis. We conclude that extreme temperatures (such as those used in bronchial thermoplasty) directly disrupt actin-myosin interactions, likely through a denaturation of the motor protein, leading to an immediate loss of ASM cell function. PMID:20395634

  8. Pulpal inflammatory responses following non-carious class V restorations.

    PubMed

    About, I; Murray, P E; Franquin, J C; Remusat, M; Smith, A J

    2001-01-01

    The effects of inflammatory activity following surgical intervention can injure pulp tissues; in severe cases it can lead to pulpal complications. With this article, the authors report on the effects of cavity preparation and restoration events and how they can interact together to reduce or increase the severity of pulpal inflammatory activity in 202 restored Class V cavities. Although some inflammatory activity was observed in the absence of bacteria, the severity of pulpal inflammatory activity was increased when cavity restorations became infected. Zinc oxide eugenol and resin-modified glass ionomer cement prevented bacterial microleakage in cavity restorations, with no severe inflammatory activity observed with these materials. Bacteria were observed in cavities restored with enamel bonding resin and adhesive bonded composites and were associated with severe grades of inflammatory activity. The cavity remaining dentin thickness influenced the grade of inflammatory activity. In the absence of infection, the grade of inflammatory activity decreased after 20 weeks post-operatively. In the presence of infection, the grade of pulpal inflammation remained stable until a minimum of 30 weeks had elapsed. PMID:11504432

  9. The Role of COX-2 in the Inflammatory and Fibrotic Response in the Lung Following Exposure to Multi-Walled Carbon Nanotubes

    NASA Astrophysics Data System (ADS)

    Sayers, Brian C.

    Exposure to multiwalled carbon nanotubes (MWCNT) has been demonstrated to exacerbate airway inflammation and fibrosis in allergen-challenged mouse model. These data have led to concern that individuals with asthma could represent a susceptible population to adverse health effects following exposure to MWCNT, and possibly other engineered nanoparticles. Asthma pathogenesis is caused by the interaction of a complex genetic predisposition and environmental exposures. Because chronic airway inflammation is common to all asthma phenotypes, it is logical to investigate genes that are involved in inflammatory pathways in order to understand the genetic basis of asthma. The metabolism of arachidonic acid by cyclooxygenase (COX) enzymes is the rate-determining step in the synthesis of prostanoids, which are biologically active lipids that are important modulators of inflammation. Based on the role of COX enzymes in inflammatory pathways, we sought to investigate how COX enzymes are involved in the inflammatory response following MWCNT exposure in asthmatic airways. We report that MWCNT significantly exacerbated allergen-induced airway inflammation and mucus cell metaplasia in COX-2 deficient mice compared to wild type mice. In addition, MWCNTs significantly enhanced allergen-induced cytokines involved in Th2 (IL-13, IL-5), Th1 (CXCL10), and Th17 (IL-17A) inflammatory responses in COX-2 deficient mice but not in WT mice. We conclude that exacerbation of allergen-induced airway inflammation and mucus cell metaplasia by MWCNTs is enhanced by deficiency in COX-2 and associated with activation of a mixed Th1/Th2/Th17 immune response. Based on our observation that COX-2 deficient mice developed a mixed Th immune response following MWCNT exposure, we sought to evaluate how cytokines associated with different Th immune responses alter COX expression following MWCNT exposure. For this study, a mouse macrophage cell line (RAW264.7) was used because MWCNT were largely sequestered

  10. Triggering of inflammatory response by myeloperoxidase-oxidized LDL.

    PubMed

    Boudjeltia, Karim Zouaoui; Legssyer, Ilham; Van Antwerpen, Pierre; Kisoka, Roger Lema; Babar, Sajida; Moguilevsky, Nicole; Delree, Paul; Ducobu, Jean; Remacle, Claude; Vanhaeverbeek, Michel; Brohee, Dany

    2006-10-01

    The oxidation theory proposes that LDL oxidation is an early event in atherosclerosis and that oxidized LDL contributes to atherogenesis in triggering inflammation. In contrast to the copper-modified LDL, there are few studies using myeloperoxidase-modified LDL (Mox-LDL) as an inflammation inducer. Our aim is to test whether Mox-LDL could constitute a specific inducer of the inflammatory response. Albumin, which is the most abundant protein in plasma and which is present to an identical concentration of LDL in the intima, was used for comparison. The secretion of IL-8 by endothelial cells (Ea.hy926) and TNF-alpha by monocytes (THP-1) was measured in the cell medium after exposure of these cells to native LDL, native albumin, Mox-LDL, or Mox-albumin. We observed that Mox-LDL induced a 1.5- and 2-fold increase (ANOVA; P < 0.001) in IL-8 production at 100 microg/mL and 200 microg/mL, respectively. The incubation of THP-1 cells with Mox-LDL (100 microg/mL) increased the production of TNF-alpha 2-fold over the control. Native LDL, albumin, and Mox-albumin showed no effect in either cellular types. The myeloperoxidase-modified LDL increase in cytokine release by endothelial and monocyte cells and by firing both local and systemic inflammation could induce atherogenesis and its development. PMID:17167545

  11. Acute inflammatory response in spinal cord following impact injury.

    PubMed

    Carlson, S L; Parrish, M E; Springer, J E; Doty, K; Dossett, L

    1998-05-01

    Numerous factors are involved in the spread of secondary damage in spinal cord after traumatic injury, including ischemia, edema, increased excitatory amino acids, and oxidative damage to the tissue from reactive oxygen species. Neutrophils and macrophages can produce reactive oxygen species when activated and thus may contribute to the lipid peroxidation that is known to occur after spinal cord injury. This study examined the rostral-caudal distribution of neutrophils and macrophages/microglia at 4, 6, 24, and 48 h after contusion injury to the T10 spinal cord of rat (10 g weight, 50 mm drop). Neutrophils were located predominantly in necrotic regions, with a time course that peaked at 24 h as measured with assays of myeloperoxidase activity (MPO). The sharpest peak of MPO activity was localized between 4 mm rostral and caudal to the injury. Macrophages/microglia were visualized with antibodies against ED1 and OX-42. Numerous cells with a phagocytic morphology were present by 24 h, with a higher number by 48 h. These cells were predominantly located within the gray matter and dorsal funiculus white matter. The number of cells gradually declined through 6 mm rostral and caudal to the lesion. OX-42 staining also revealed reactive microglia with blunt processes, particularly at levels distant to the lesion. The number of macrophages/microglia was significantly correlated with the amount of tissue damage at each level. Treatments to decrease the inflammatory response are likely to be beneficial to recovery of function after traumatic spinal cord injury. PMID:9582256

  12. Role of Fiber Length on Phagocytosis & Inflammatory Response

    NASA Astrophysics Data System (ADS)

    Turkevich, Leonid; Stark, Carahline; Champion, Julie

    2014-03-01

    Asbestos fibers have long been associated with lung cancer death. The inability of immune cells (e.g. macrophages) to effectively remove asbestos leads to chronic inflammation and disease. This study examines the role of fiber length on toxicity at the cellular level using model glass fibers. A major challenge is obtaining single diameter fibers but differing in length. Samples of 1 micron diameter fibers with different length distributions were prepared: short fibers (less than 15 microns) by aggressive crushing, and long fibers (longer than 15 microns) by successive sedimentation. Time-lapse video microscopy monitored the interaction of MH-S murine alveolar macrophages with the fibers: short fibers were easily internalized by the macrophages, but long fibers resisted internalization over many hours. Production of TNF- α (tumor necrosis factor alpha), a general inflammatory secreted cytokine, and Cox-2 (cyclo-oxygenase-2), an enzyme that produces radicals, each exhibited a dose-dependence that was greater for long than for short fibers. These results corroborate the importance of fiber length in both physical and biochemical cell response and support epidemiological observations of higher toxicity for longer fibers.

  13. Role of Small Airways in Asthma.

    PubMed

    Finkas, Lindsay K; Martin, Richard

    2016-08-01

    Asthma is an inflammatory condition of both the small and large airways. Recently the small airways have gained attention as studies have shown significant inflammation in the small airways in all severities of asthma. This inflammation has correlated with peripheral airway resistance and as a result, noninvasive methods to reliably measure small airways have been pursued. In addition, recent changes in asthma inhalers have led to alterations in drug formulations and the development of extrafine particle inhalers that improve delivery to the distal airways. PMID:27401620

  14. Acute hypoxemia in humans enhances the neutrophil inflammatory response.

    PubMed

    Tamura, Douglas Y; Moore, Ernest E; Partrick, David A; Johnson, Jeffrey L; Offner, Patrick J; Silliman, Christopher C

    2002-04-01

    The neutrophil (PMN) is regarded as a key component in the hyperinflammatory response known as the systemic inflammatory response syndrome. Acute respiratory distress syndrome (ARDS) and subsequent multiple organ failure (MOF) are related to the severity of this hyperinflammation. ICU patients who are at highest risk of developing MOF may have acute hypoxic events that complicate their hospital course. This study was undertaken to evaluate the effects of acute hypoxia and subsequent hypoxemia on circulating PMNs in human volunteers. Healthy subjects were exposed to a changing O2/N2 mixture until their O2 saturation (SaO2) reached a level of 68% saturation. These subjects were then exposed to room air and then returned to their baseline SaO2. PMNs were isolated from pre- and post-hypoxemic arterial blood samples and were then either stimulated with N-formyl-methionyl-leucyl-phenylalanine (fMLP) or PMA alone, or they were primed with L-alpha-phosphatidylcholine, beta-acetyl-gamma-O-alkyl (PAF) followed by fMLP activation. Reactive oxygen species generation as measured by superoxide anion production was enhanced in primed PMNs after hypoxemia. Protease degranulation as measured by elastase release was enhanced in both quiescent PMNs and primed PMNs after fMLP activation following the hypoxemic event. Adhesion molecule upregulation as measured by CD11b/CD18, however, was not significantly changed after hypoxemia. Apoptosis of quiescent PMNs was delayed after the hypoxemic event. TNFalpha, IL-1, IL-6, and IL-8 cytokine levels were unchanged following hypoxemia. These results indicate that relevant acute hypoxemic events observed in the clinical setting enhance several PMN cytotoxic functions and suggest that a transient hypoxemic insult may promote hyperinflammation. PMID:11954825

  15. Helicobacter hepaticus Induces an Inflammatory Response in Primary Human Hepatocytes

    PubMed Central

    Kleine, Moritz; Worbs, Tim; Schrem, Harald; Vondran, Florian W. R.; Kaltenborn, Alexander; Klempnauer, Jürgen; Förster, Reinhold; Josenhans, Christine; Suerbaum, Sebastian; Bektas, Hüseyin

    2014-01-01

    Helicobacter spp. on human liver cells, resulting in an inflammatory response with increased synthesis of inflammatory mediators and consecutive monocyte activation. PMID:24932686

  16. Burn size determines the inflammatory and hypermetabolic response

    PubMed Central

    Jeschke, Marc G; Mlcak, Ronald P; Finnerty, Celeste C; Norbury, William B; Gauglitz, Gerd G; Kulp, Gabriela A; Herndon, David N

    2007-01-01

    Background Increased burn size leads to increased mortality of burned patients. Whether mortality is due to inflammation, hypermetabolism or other pathophysiologic contributing factors is not entirely determined. The purpose of the present study was to determine in a large prospective clinical trial whether different burn sizes are associated with differences in inflammation, body composition, protein synthesis, or organ function. Methods Pediatric burned patients were divided into four burn size groups: <40% total body surface area (TBSA) burn, 40–59% TBSA burn, 60–79% TBSA burn, and >80% TBSA burn. Demographic and clinical data, hypermetabolism, the inflammatory response, body composition, the muscle protein net balance, serum and urine hormones and proteins, and cardiac function and changes in liver size were determined. Results One hundred and eighty-nine pediatric patients of similar age and gender distribution were included in the study (<40% TBSA burn, n = 43; 40–59% TBSA burn, n = 79; 60–79% TBSA burn, n = 46; >80% TBSA burn, n = 21). Patients with larger burns had more operations, a greater incidence of infections and sepsis, and higher mortality rates compared with the other groups (P < 0.05). The percentage predicted resting energy expenditure was highest in the >80% TBSA group, followed by the 60–79% TBSA burn group (P < 0.05). Children with >80% burns lost the most body weight, lean body mass, muscle protein and bone mineral content (P < 0.05). The urine cortisol concentration was highest in the 80–99% and 60–79% TBSA burn groups, associated with significant myocardial depression and increased change in liver size (P < 0.05). The cytokine profile showed distinct differences in expression of IL-8, TNF, IL-6, IL-12p70, monocyte chemoattractant protein-1 and granulocyte–macrophage colony-stimulating factor (P < 0.05). Conclusion Morbidity and mortality in burned patients is burn size dependent, starts at a 60% TBSA burn and is due to an

  17. Resistin-Like Molecule–α Regulates IL-13–Induced Chemokine Production but Not Allergen-Induced Airway Responses

    PubMed Central

    Munitz, Ariel; Cole, Eric T.; Karo-Atar, Danielle; Finkelman, Fred D.

    2012-01-01

    Resistin-like molecule α (Relm-α) is one of the most up-regulated gene products in allergen- and parasite-associated Th2 responses. Localized to alternatively activated macrophages, Relm-α was shown to exert an anti-inflammatory effect in parasite-induced Th2 responses, but its role in experimental asthma remains unexplored. Here, we analyzed the cellular source, the IL-4 receptors required to stimulate Relm-α production, and the role of Relm-α after experimental asthma induction by IL-4, IL-13, or multiple experimental regimes, including ovalbumin and Aspergillus fumigatus immunization. We demonstrate that Relm-α was secreted into the airway lumen, dependent on both the IL-13 receptor–α1 chain and likely the Type I IL-4 receptor, and differentially localized to epithelial cells and myeloid cells, depending on the specific cytokine or aeroallergen trigger. Studies performed with Retnla gene–targeted mice demonstrate that Relm-α was largely redundant in terms of inducing the infiltration of Th2 cytokines, mucus, and inflammatory cells into the lung. These results mirror the dispensable role that other alternatively activated macrophage products (such as arginase 1) have in allergen-induced experimental asthma and contrast with their role in the setting of parasitic infections. Taken together, our findings demonstrate the distinct utilization of IL-4/IL-13 receptors for the induction of Relm-α in the lungs. The differential regulation of Relm-α expression is likely determined by the relative expression levels of IL-4, IL-13, and their corresponding receptors, which are differentially expressed by divergent cells (i.e., epithelial cells and macrophages.) Finally, we identify a largely redundant functional role for Relm-α in acute experimental models of allergen-associated Th2 immune responses. PMID:22246861

  18. Induction of Tachykinin Production in Airway Epithelia in Response to Viral Infection

    PubMed Central

    Stewart, James P.; Kipar, Anja; Cox, Helen; Payne, Catherine; Vasiliou, Sylvia; Quinn, John P.

    2008-01-01

    Background The tachykinins are implicated in neurogenic inflammation and the neuropeptide substance P in particular has been shown to be a proinflammatory mediator. A role for the tachykinins in host response to lung challenge has been previously demonstrated but has been focused predominantly on the release of the tachykinins from nerves innervating the lung. We have previously demonstrated the most dramatic phenotype described for the substance P encoding gene preprotachykinin-A (PPT-A) to date in controlling the host immune response to the murine gammaherpesvirus 68, in the lung. Methodology/Principal Findings In this study we have utilised transgenic mice engineered to co-ordinately express the beta-galactosidase marker gene along with PPT-A to facilitate the tracking of PPT-A expression. Using a combination of these mice and conventional immunohistology we now demonstrate that PPT-A gene expression and substance P peptide are induced in cells of the respiratory tract including tracheal, bronchiolar and alveolar epithelial cells and macrophages after viral infection. This induction was observed 24h post infection, prior to observable inflammation and the expression of pro-inflammatory chemokines in this model. Induced expression of the PPT-A gene and peptide persisted in the lower respiratory tract through day 7 post infection. Conclusions/Significance Non-neuronal PPT-A expression early after infection may have important clinical implications for the progression or management of lung disease or infection aside from the well characterised later involvement of the tachykinins during the inflammatory response. PMID:18320026

  19. Epithelial injury and repair in airways diseases.

    PubMed

    Grainge, Christopher L; Davies, Donna E

    2013-12-01

    Asthma is a common chronic disease characterized by variable respiratory distress with underlying airway inflammation and airflow obstruction. The incidence of asthma has risen inexorably over the past 50 years, suggesting that environmental factors are important in its etiology. All inhaled environmental stimuli interact with the lung at the respiratory epithelium, and it is a testament to the effectiveness of the airway innate defenses that the majority of inhaled substances are cleared without the need to elicit an inflammatory response. However, once this barrier is breached, effective communication with immune and inflammatory cells is required to protect the internal milieu of the lung. In asthma, the respiratory epithelium is known to be structurally and functionally abnormal. Structurally, the epithelium shows evidence of damage and has more mucus-producing cells than normal airways. Functionally, the airway epithelial barrier can be more permeable and more sensitive to oxidants and show a deficient innate immune response to respiratory virus infection compared with that in normal individuals. The potential of a susceptible epithelium and the underlying mesenchyme to create a microenvironment that enables deviation of immune and inflammatory responses to external stimuli may be crucial in the development and progression of asthma. In this review, we consider three important groups of environmental stimuli on the epithelium in asthma: oxidants, such as environmental pollution and acetaminophen; viruses, including rhinovirus; and agents that cause barrier disruption, such as house dust mite allergens. The pathology associated with each stimulus is considered, and potential future treatments arising from research on their effects are presented. PMID:24297122

  20. Heme oxygenase-1 exerts a protective role in ovalbumin-induced neutrophilic airway inflammation by inhibiting Th17 cell-mediated immune response.

    PubMed

    Zhang, Yanjie; Zhang, Liya; Wu, Jinhong; Di, Caixia; Xia, Zhenwei

    2013-11-29

    Allergic asthma is conventionally considered as a Th2 immune response characterized by eosinophilic inflammation. Recent investigations revealed that Th17 cells play an important role in the pathogenesis of non-eosinophilic asthma (NEA), resulting in steroid-resistant neutrophilic airway inflammation. Heme oxygenase-1 (HO-1) has anti-inflammation, anti-oxidation, and anti-apoptosis functions. However, its role in NEA is still unclear. Here, we explore the role of HO-1 in a mouse model of NEA. HO-1 inducer hemin or HO-1 inhibitor tin protoporphyrin IX was injected intraperitoneally into ovalbumin-challenged DO11.10 mice. Small interfering RNA (siRNA) was delivered into mice to knock down HO-1 expression. The results show that induction of HO-1 by hemin attenuated airway inflammation and decreased neutrophil infiltration in bronchial alveolar lavage fluid and was accompanied by a lower proportion of Th17 cells in mediastinal lymph nodes and spleen. More importantly, induction of HO-1 down-regulated Th17-related transcription factor retinoic acid-related orphan receptor γt (RORγt) expression and decreased IL-17A levels, all of which correlated with a decrease in phosphorylated STAT3 (p-STAT3) level and inhibition of Th17 cell differentiation. Consistently, the above events could be reversed by tin protoporphyrin IX. Also, HO-1 siRNA transfection abolished the effect of hemin induced HO-1 in vivo. Meanwhile, the hemin treatment promoted the level of Foxp3 expression and enhanced the proportion of regulatory T cells (Tregs). Collectively, our findings indicate that HO-1 exhibits anti-inflammatory activity in the mouse model of NEA via inhibition of the p-STAT3-RORγt pathway, regulating kinetics of RORγt and Foxp3 expression, thus providing a possible novel therapeutic target in asthmatic patients. PMID:24097973

  1. Classification of childhood asthma phenotypes and long-term clinical responses to inhaled anti-inflammatory medications

    PubMed Central

    Howrylak, Judie A.; Fuhlbrigge, Anne L.; Strunk, Robert C.; Zeiger, Robert S.; Weiss, Scott T.; Raby, Benjamin A.

    2014-01-01

    Background Although recent studies have identified the presence of phenotypic clusters in asthmatic patients, the clinical significance and temporal stability of these clusters have not been explored. Objective Our aim was to examine the clinical relevance and temporal stability of phenotypic clusters in children with asthma. Methods We applied spectral clustering to clinical data from 1041 children with asthma participating in the Childhood Asthma Management Program. Posttreatment randomization follow-up data collected over 48 months were used to determine the effect of these clusters on pulmonary function and treatment response to inhaled anti-inflammatory medication. Results We found 5 reproducible patient clusters that could be differentiated on the basis of 3 groups of features: atopic burden, degree of airway obstruction, and history of exacerbation. Cluster grouping predicted long-term asthma control, as measured by the need for oral prednisone (P < .0001) or additional controller medications (P = .001), as well as longitudinal differences in pulmonary function (P < .0001). We also found that the 2 clusters with the highest rates of exacerbation had different responses to inhaled corticosteroids when compared with the other clusters. One cluster demonstrated a positive response to both budesonide (P = .02) and nedocromil (P = .01) compared with placebo, whereas the other cluster demonstrated minimal responses to both budesonide (P = .12) and nedocromil (P = .56) compared with placebo. Conclusion Phenotypic clustering can be used to identify longitudinally consistent and clinically relevant patient subgroups, with implications for targeted therapeutic strategies and clinical trials design. PMID:24892144

  2. MUC4 involvement in ErbB2/ErbB3 phosphorylation and signaling in response to airway cell mechanical injury.

    PubMed

    Theodoropoulos, George; Carraway, Coralie A Carothers; Carraway, Kermit L

    2009-05-01

    The receptor tyrosine kinases ErbB2 and ErbB3 are phosphorylated in response to injury of the airway epithelium. Since we have shown that the membrane mucin MUC4 can act as a ligand/modulator for ErbB2, affecting its localization in polarized epithelial cells and its phosphorylation, we questioned whether Muc4 was involved, along with ErbB2 and ErbB3, in the damage response of airway epithelia. To test this hypothesis, we first examined the localization of MUC4 in human airway samples. Both immunocytochemistry and immunofluorescence showed a co-localization of MUC4 and ErbB2 at the airway luminal surface. Sequential immunoprecipitation and immunoblotting from airway cells demonstrated that the MUC4 and ErbB2 are present as a complex in airway epithelial cells. To assess the participation of MUC4 in the damage response, cultures of NCI-H292 or airway cells were scratch-wounded, then analyzed for association of phospho-ErbB2 and -ErbB3 with MUC4 by sequential immunoprecipitation and immunoblotting. Wounded cultures exhibited increased phosphorylation of both receptors in complex with MUC4. Scratch wounding also increased activation of the downstream pathway through Akt, as predicted from our previous studies on Muc4 effects on ErbB2 and ErbB3. The participation of MUC4 in the phosphorylation response was also indicated by siRNA repression of MUC4 expression, which resulted in diminution of the phosphorylation of ErbB2 and ErbB3. These studies provide a new model for the airway epithelial damage response, in which the MUC4-ErbB2 complex is a key element in the sensor mechanism and phosphorylation of the receptors. PMID:19288496

  3. Plasma exudation in the airways: mechanisms and function.

    PubMed

    Persson, C G

    1991-11-01

    Inflammatory challenges of tracheobronchial and nasal mucosa produce prompt extravasation or exudation of plasma from the well developed microcirculation just beneath the epithelial base. Plasma exudation is not an exaggeration of the normal capilliary exchange of fluid and solutes but a specific inflammatory response of post-capilliary venules. The exuded plasma may not produce oedema. By a rapid, undirectional, unfiltered and yet non-injurious process, plasma exudates cross the mucosal lining to appear on the airway surface at the site of challenge. In vitro data suggests the possibility that a slightly increased hydrostatic pressure moves the acellular exudate through valve-like openings between epithelial cells. By the venular-mucosal exudation mechanism all the potent protein systems of circulating plasma will operate in respiratory defence on the surface of an intact mucosa. A further inference is that exudative indices obtained from the airway surface quantitatively reflect the intensity and time course of mucosal/submucosal inflammatory processes. Irrespective of which particular cellular mechanism happens to fuel the inflammation. Mucosal exudation of plasma characteristically occurs in health and disease also when there is no airway oedema, no epithelial disruption, and no increased absorbtion ability. However, exuded plasma and its derived peptide mediators potentially contribute to several pathophysical and pathophysiological characteristics of inflammatory airway diseases. PMID:1804675

  4. Prokineticin 1 Induces Inflammatory Response in Human Myometrium

    PubMed Central

    Gorowiec, Marta R.; Catalano, Rob D.; Norman, Jane E.; Denison, Fiona C.; Jabbour, Henry N.

    2011-01-01

    The infiltration of human myometrium and cervix with leukocytes and the formation of a pro-inflammatory environment within the uterus have been associated with the initiation of both term and preterm parturition. The mechanism regulating the onset of this pro-inflammatory cascade is not fully elucidated. We demonstrate that prokineticin 1 (PROK1) is up-regulated in human myometrium and placenta during labor. The expression of PROK1 receptor remains unchanged during labor and is abundantly expressed in the myometrium. Gene array analysis identified 65 genes up-regulated by PROK1 in human myometrium, mainly cytokines and chemokines, including IL-1β, chemokine C-C motif ligand 3, and colony-stimulating factor 3. In addition, we demonstrate that PROK1 increases the expression of chemokine C-C motif ligand 20, IL-6, IL-8, prostaglandin synthase 2, and prostaglandin E2 and F2α secretion. The treatment of myometrial explants with 100 ng/mL of lipopolysaccharide up-regulates the expression of PROK1, PROK1 receptor, and inflammatory mediators. The infection of myometrial explants with lentiviral microRNA targeting PROK1, preceding treatment with lipopolysaccharide, reduces the expression of inflammatory genes. We propose that PROK1 is a novel inflammatory mediator that can contribute to the onset of human parturition at term and partially mediate premature onset of inflammatory pathways during bacterial infection. PMID:21983634

  5. Early inflammatory response in epithelial ovarian tumor cyst fluids.

    PubMed

    Kristjánsdóttir, Björg; Partheen, Karolina; Fung, Eric T; Yip, Christine; Levan, Kristina; Sundfeldt, Karin

    2014-10-01

    Mortality rates for epithelial ovarian cancer (EOC) are high, mainly due to late-stage diagnosis. The identification of biomarkers for this cancer could contribute to earlier diagnosis and increased survival rates. Given that chronic inflammation plays a central role in cancer initiation and progression, we selected and tested 15 cancer-related cytokines and growth factors in 38 ovarian cyst fluid samples. We used ovarian cyst fluid since it is found in proximity to the pathology and mined it for inflammatory biomarkers suitable for early detection of EOC. Immunoprecipitation and high-throughput sample fractionation were obtained by using tandem antibody libraries bead and mass spectrometry. Two proteins, monocyte chemoattractant protein-1 (MCP-1/CCL2) and interleucin-8 (IL-8/CXCL8), were significantly (P < 0.0001) higher in the malignant (n = 16) versus benign (n = 22) tumor cysts. Validation of MCP-1, IL-8, and growth-regulated protein-α (GROα/CXCL1) was performed with ELISA in benign, borderline, and malignant cyst fluids (n = 256) and corresponding serum (n = 256). CA125 was measured in serum from all patients and used in the algorithms performed. MCP-1, IL-8, and GROα are proinflammatory cytokines and promoters of tumor growth. From 5- to 100-fold higher concentrations of MCP-1, IL-8 and GROα were detected in the cyst fluids compared to the serum. Significant (P < 0.001) cytokine response was already established in borderline cyst fluids and stage I EOC. In serum a significant (P < 0.01) increase of IL-8 and GROα was found, but not until stage I and stage III EOC, respectively. These findings confirm that early events in tumorigenesis can be analyzed and detected in the tumor environment and we conclude that ovarian cyst fluid is a promising source in the search for new biomarkers for early ovarian tumors. PMID:24947406

  6. Lactic acid delays the inflammatory response of human monocytes

    SciTech Connect

    Peter, Katrin; Rehli, Michael; Singer, Katrin; Renner-Sattler, Kathrin; Kreutz, Marina

    2015-02-13

    Lactic acid (LA) accumulates under inflammatory conditions, e.g. in wounds or tumors, and influences local immune cell functions. We previously noted inhibitory effects of LA on glycolysis and TNF secretion of human LPS-stimulated monocytes. Here, we globally analyze the influence of LA on gene expression during monocyte activation. To separate LA-specific from lactate- or pH-effects, monocytes were treated for one or four hours with LPS in the presence of physiological concentrations of LA, sodium lactate (NaL) or acidic pH. Analyses of global gene expression profiles revealed striking effects of LA during the early stimulation phase. Up-regulation of most LPS-induced genes was significantly delayed in the presence of LA, while this inhibitory effect was attenuated in acidified samples and not detected after incubation with NaL. LA targets included genes encoding for important monocyte effector proteins like cytokines (e.g. TNF and IL-23) or chemokines (e.g. CCL2 and CCL7). LA effects were validated for several targets by quantitative RT-PCR and/or ELISA. Further analysis of LPS-signaling pathways revealed that LA delayed the phosphorylation of protein kinase B (AKT) as well as the degradation of IκBα. Consistently, the LPS-induced nuclear accumulation of NFκB was also diminished in response to LA. These results indicate that the broad effect of LA on gene expression and function of human monocytes is at least partially caused by its interference with immediate signal transduction events after activation. This mechanism might contribute to monocyte suppression in the tumor environment. - Highlights: • Lactic acid broadly delays LPS-induced gene expression in human monocytes. • Expression of important monocyte effector molecules is affected by lactic acid. • Interference of lactic acid with TLR signaling causes the delayed gene expression. • The profound effect of lactic acid might contribute to immune suppression in tumors.

  7. Exposure to cigarette smoke impacts myeloid-derived regulatory cell function and exacerbates airway hyper-responsiveness

    PubMed Central

    Wang, Yong; Jin, Tong Huan; Farhana, Aisha; Freeman, Jason; Estell, Kim; Zmijewski, Jaroslaw; Gaggar, Amit; Thannickal, Victor J; Schwiebert, Lisa M; Steyn, Adrie JC; Deshane, Jessy S

    2014-01-01

    Cigarette smoking enhances oxidative stress and airway inflammation in asthma, the mechanisms of which are largely unknown. Myeloid-derived regulatory cells (MDRC) are free radical producing immature myeloid cells with immunoregulatory properties which have recently been demonstrated as critical regulators of allergic airway inflammation. NO (nitric oxide)-producing immunosuppressive MDRC suppress T cell proliferation and airway-hyper responsiveness (AHR), while the O2•− (superoxide)-producing MDRC are proinflammatory. We hypothesized that cigarette smoke (CS) exposure may impact MDRC function and contribute to exacerbations in asthma. Exposure of bone marrow (BM) derived NO-producing MDRC to CS reduced the production of NO and its metabolites and inhibited their potential to suppress T cell proliferation. Production of immunoregulatory cytokine IL-10 was significantly inhibited, while proinflammatory cytokines IL-6, IL-1β, TNF-α and IL-33 were enhanced in CS exposed BMMDRC. Additionally, CS exposure increased NF-κB activation and induced BM-MDRC-mediated production of O2•−, via NF-κB dependent pathway. Intratracheal transfer of smoke exposed MDRC producing proinflammatory cytokines increased NF-κB activation, reactive oxygen species and mucin production in vivo and exacerbated AHR in C57BL/6 mice, mice deficient in Type I IFNR and MyD88, both with reduced numbers of endogenous MDRC. Thus, CS exposure modulates MDRC function and contributes to asthma exacerbation and identifies MDRC as potential targets for asthma therapy. PMID:25365203

  8. Exposure to cigarette smoke impacts myeloid-derived regulatory cell function and exacerbates airway hyper-responsiveness.

    PubMed

    Wang, Yong; Jin, Tong Huan; Farhana, Aisha; Freeman, Jason; Estell, Kim; Zmijewski, Jaroslaw W; Gaggar, Amit; Thannickal, Victor J; Schwiebert, Lisa M; Steyn, Adrie J C; Deshane, Jessy S

    2014-12-01

    Cigarette smoking enhances oxidative stress and airway inflammation in asthma, the mechanisms of which are largely unknown. Myeloid-derived regulatory cells (MDRC) are free radical producing immature myeloid cells with immunoregulatory properties that have recently been demonstrated as critical regulators of allergic airway inflammation. NO (nitric oxide)-producing immunosuppressive MDRC suppress T-cell proliferation and airway-hyper responsiveness (AHR), while the O2(•-) (superoxide)-producing MDRC are proinflammatory. We hypothesized that cigarette smoke (CS) exposure may impact MDRC function and contribute to exacerbations in asthma. Exposure of bone marrow (BM)-derived NO-producing MDRC to CS reduced the production of NO and its metabolites and inhibited their potential to suppress T-cell proliferation. Production of immunoregulatory cytokine IL-10 was significantly inhibited, while proinflammatory cytokines IL-6, IL-1β, TNF-α and IL-33 were enhanced in CS-exposed BM-MDRC. Additionally, CS exposure increased NF-κB activation and induced BM-MDRC-mediated production of O2(•-), via NF-κB-dependent pathway. Intratracheal transfer of smoke-exposed MDRC-producing proinflammatory cytokines increased NF-κB activation, reactive oxygen species and mucin production in vivo and exacerbated AHR in C57BL/6 mice, mice deficient in Type I IFNR and MyD88, both with reduced numbers of endogenous MDRC. Thus CS exposure modulates MDRC function and contributes to asthma exacerbation and identifies MDRC as potential targets for asthma therapy. PMID:25365203