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Resolvin D1 Inhibits IL-1beta Induced Alveolar Epithelial Cell Activation
Abstracts AB197
J ALLERGY CLIN IMMUNOL VOLUME 131, NUMBER 2
Resolvin D1 Inhibits IL-1beta Induced Alveolar Epithelial Cell Activation Ruan R. Cox, Jr1, Oluwakemi Phillips1, Jutaro Fukumoto, MD, PhD1, Itsuko Fukumoto, DMD1, Prasanna Tamarapu1, Tran Luong1, Richard F. Lockey, MD1,2, Narasaiah Kolliputi, PhD3; 1Morsani College of Medicine, University of South Florida, Tampa, FL, 2James A. Haley Veterans’ Hospital, Tampa, FL, 3Internal Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL. RATIONALE: Interleukin-1beta (IL-1b) is the most bioactive proinflammatory cytokine in acute lung injury (ALI). Secretion of IL-1b causes activation of alveolar epithelial cells which propagates this inflammatory response. Recently a lipid mediator, termed aspirin triggered resolvin D1 (AT-RvD1), attenuated inflammation in response to acute injury, however, the effects of AT-RVD1 on IL-1b induced epithelial cell activation has not been investigated. We hypothesize that AT-RvD1 decreases IL-1b induced alveolar epithelial cell activation. METHODS: Human alveolar epithelial cells were treated with IL-1b (10ng) in the presence or absence of AT-RVD1 (.01-.1mM) at varying time points. After each time point, Cells were harvested to assess the expression levels of protein and RNA by western blot and qPCR analysis respectively. Cell culture supernatants were collected to analyze cytokine secretion via ELISA. In a separate experiment, alveolar epithelial cells were fixed for immunocytochemical analysis. RESULTS: Results indicate that AT-RvD1 significantly inhibited IL-1b induced TGF-b and IL-6 secretion in alveolar epithelial cells. AT-RvD1 also inhibits IL-1b mediated p38 MAPK phosphorylation. Finally, IL-1b induced alveolar epithelial cell permeability was decreased in AT-RvD1 treated cells. CONCLUSIONS: Alveolar macrophages and epithelial cells are sentinel cells that sense and respond to injury as a result of cytokine signaling. During ALI, excessive secretion of IL-1b leads to an unregulated immune response hallmarked by activated macrophages, epithelial and endothelial cells. Therefore, AT-RvD1, by inhibiting epithelial cell activation, could be a useful therapeutic for ALI.
704
Interactions of Natural Killer (NK) Cells and Surfactant Protein D (SP-D) in Regulation of Ozone Induced Airway Inflammation: Involvement of NKp46 Moyar Q. Ge1,2, Jin Hwang1, Imre Redai1, Blerina Kokalari1, David M. Kemeny, PhD, FAAAAI2, Kerry S. Campbell, PhD3, Angela Haczku, MD, PhD, FAAAAI1; 1University of Pennsylvania, Philadelphia, PA, 2National University of Singapore, Singapore, 3Fox Chase Cancer Center, Philadelphia, PA. RATIONALE: Pulmonary NK cells and SP-D are both involved in IFN-g mediated host defense and immune regulation during acute lung inflammation. Whether SP-D can affect NK cells however is unclear. NKp46 is an activating receptor that mediates IFN-g production in NK cells. We aimed to study the role of SP-D and NKp46 in NK cell regulation during ozoneinduced lung inflammation. METHODS: Splenic and pulmonary NK cell phenotypes and SP-D binding to SP-D-/- pulmonary NK cells in vitro, were investigated by FACS analysis. Airway inflammation, cytokine and cellular profile and SP-D protein expression were assessed using in vivo models of ozone exposure (3ppm for 2hours) in C57BL/6, NKp46gfp/gfp (NKp46 deficient), SP-D-/-and wild type mice. RESULTS: Similarly to NKp46gfp/gfp mice, SP-D-/- mice had an enhanced and prolonged neutrophil granulocyte influx into the lung when compared with wild type mice after ozone exposure. Heightened airway inflammation was associated with an impaired IFN-g response 12 hour following ozone inhalation in mice lacking SP-D. SP-D-/- lung NK cells had enhanced CD107a, CD25 and CD69 but reduced intracellular IFN-g expression. In contrast, treatment with recombinant SP-D (0, 1, 10 mg/ml) increased IFN-g release from cultured splenocytes in vitro. SP-D-/-NKp46 positive lung NK cells bound recombinant SP-D in a dose-dependent fashion. CONCLUSIONS: These results suggest that SP-D is a likely regulator of lung resident NK cells promoting anti-inflammatory actions as well as host defense through IFN-g release. We speculate that the SP-D effects might be mediated through engaging NKp46.
705
Association Between Dichlorophenol Exposure, Asthma Medication Use, and Serum Immunoglobulin E Purvi Parikh, MD1, Gabriele De Vos, MD2, Sunit Jariwala, MD3, David L. Rosenstreich, MD, FAAAAI4, Golda Hudes, MD, PhD5, Elina Jerschow, MD, MSc6; 1Albert Einstein / Montefiore Medical Center, 2Albert Einstein College of Medicine, Bronx, NY, 3Albert Einstein/Montefiore Medical Center, New York, NY, 4Albert Einstein/Montefiore Medical Center, NY, 5Albert Einstein/Montefiore Medical Center, New York, NY, 6Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY. RATIONALE: Phenols are used in bactericidal agents, herbicides, insecticides, and pesticides worldwide. Although phenols are associated with atopy, it is not known whether they are associated with asthma. We sought to test the association between the presence of five phenols (2,4dichlorophenol, 2,5-dichlorophenol, ortho-phenylphenol, 2,4,5-trichlorophenol, and 2,4,6-trichlorophenol) in urine and their association with prescriptions of asthma medications as well as total serum IgE levels. METHODS: Serum IgE and urine levels of phenols were examined from a national database with a representative sample of 2114 people in the U.S. of 6 years of age and older in the National Health and Nutrition Examination Survey (NHANES) 2005-2006. Associations between total log-IgE levels and log-transformed urinary phenol levels were tested in a linear regression model. Association between phenol levels and prescription asthma medications were tested in logistic regression models after adjustment for sample weights, urine creatinine, and other potential confounders. RESULTS: After multivariable adjustments, total IgE levels were positively associated with urine 2,5-dichlorophenol and 2,4-dichlorophenol levels (p values 0.02 and 0.04, respectively) but not with ortho-phenylphenol, 2,4,5-trichlorophenol, or 2,4,6-trichlorophenol. We also found that the presence of urinary 2,5-dichlorophenol was significantly associated with prescriptions of asthma medications (OR52.5, p value 5 0.03). CONCLUSIONS: Our findings suggest a positive association between total IgE and dichlorophenols (2,5-dichlorophenol and 2,4-dichlorophenol levels). In addition, there was a positive association between 2,5-dichlorophenol and prescriptions of asthma medications. Excessive use of chlorophenols may contribute to atopy and an increase in asthma medications.
MONDAY
703
J ALLERGY CLIN IMMUNOL VOLUME 131, NUMBER 2
Resolvin D1 Inhibits IL-1beta Induced Alveolar Epithelial Cell Activation Ruan R. Cox, Jr1, Oluwakemi Phillips1, Jutaro Fukumoto, MD, PhD1, Itsuko Fukumoto, DMD1, Prasanna Tamarapu1, Tran Luong1, Richard F. Lockey, MD1,2, Narasaiah Kolliputi, PhD3; 1Morsani College of Medicine, University of South Florida, Tampa, FL, 2James A. Haley Veterans’ Hospital, Tampa, FL, 3Internal Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL. RATIONALE: Interleukin-1beta (IL-1b) is the most bioactive proinflammatory cytokine in acute lung injury (ALI). Secretion of IL-1b causes activation of alveolar epithelial cells which propagates this inflammatory response. Recently a lipid mediator, termed aspirin triggered resolvin D1 (AT-RvD1), attenuated inflammation in response to acute injury, however, the effects of AT-RVD1 on IL-1b induced epithelial cell activation has not been investigated. We hypothesize that AT-RvD1 decreases IL-1b induced alveolar epithelial cell activation. METHODS: Human alveolar epithelial cells were treated with IL-1b (10ng) in the presence or absence of AT-RVD1 (.01-.1mM) at varying time points. After each time point, Cells were harvested to assess the expression levels of protein and RNA by western blot and qPCR analysis respectively. Cell culture supernatants were collected to analyze cytokine secretion via ELISA. In a separate experiment, alveolar epithelial cells were fixed for immunocytochemical analysis. RESULTS: Results indicate that AT-RvD1 significantly inhibited IL-1b induced TGF-b and IL-6 secretion in alveolar epithelial cells. AT-RvD1 also inhibits IL-1b mediated p38 MAPK phosphorylation. Finally, IL-1b induced alveolar epithelial cell permeability was decreased in AT-RvD1 treated cells. CONCLUSIONS: Alveolar macrophages and epithelial cells are sentinel cells that sense and respond to injury as a result of cytokine signaling. During ALI, excessive secretion of IL-1b leads to an unregulated immune response hallmarked by activated macrophages, epithelial and endothelial cells. Therefore, AT-RvD1, by inhibiting epithelial cell activation, could be a useful therapeutic for ALI.
704
Interactions of Natural Killer (NK) Cells and Surfactant Protein D (SP-D) in Regulation of Ozone Induced Airway Inflammation: Involvement of NKp46 Moyar Q. Ge1,2, Jin Hwang1, Imre Redai1, Blerina Kokalari1, David M. Kemeny, PhD, FAAAAI2, Kerry S. Campbell, PhD3, Angela Haczku, MD, PhD, FAAAAI1; 1University of Pennsylvania, Philadelphia, PA, 2National University of Singapore, Singapore, 3Fox Chase Cancer Center, Philadelphia, PA. RATIONALE: Pulmonary NK cells and SP-D are both involved in IFN-g mediated host defense and immune regulation during acute lung inflammation. Whether SP-D can affect NK cells however is unclear. NKp46 is an activating receptor that mediates IFN-g production in NK cells. We aimed to study the role of SP-D and NKp46 in NK cell regulation during ozoneinduced lung inflammation. METHODS: Splenic and pulmonary NK cell phenotypes and SP-D binding to SP-D-/- pulmonary NK cells in vitro, were investigated by FACS analysis. Airway inflammation, cytokine and cellular profile and SP-D protein expression were assessed using in vivo models of ozone exposure (3ppm for 2hours) in C57BL/6, NKp46gfp/gfp (NKp46 deficient), SP-D-/-and wild type mice. RESULTS: Similarly to NKp46gfp/gfp mice, SP-D-/- mice had an enhanced and prolonged neutrophil granulocyte influx into the lung when compared with wild type mice after ozone exposure. Heightened airway inflammation was associated with an impaired IFN-g response 12 hour following ozone inhalation in mice lacking SP-D. SP-D-/- lung NK cells had enhanced CD107a, CD25 and CD69 but reduced intracellular IFN-g expression. In contrast, treatment with recombinant SP-D (0, 1, 10 mg/ml) increased IFN-g release from cultured splenocytes in vitro. SP-D-/-NKp46 positive lung NK cells bound recombinant SP-D in a dose-dependent fashion. CONCLUSIONS: These results suggest that SP-D is a likely regulator of lung resident NK cells promoting anti-inflammatory actions as well as host defense through IFN-g release. We speculate that the SP-D effects might be mediated through engaging NKp46.
705
Association Between Dichlorophenol Exposure, Asthma Medication Use, and Serum Immunoglobulin E Purvi Parikh, MD1, Gabriele De Vos, MD2, Sunit Jariwala, MD3, David L. Rosenstreich, MD, FAAAAI4, Golda Hudes, MD, PhD5, Elina Jerschow, MD, MSc6; 1Albert Einstein / Montefiore Medical Center, 2Albert Einstein College of Medicine, Bronx, NY, 3Albert Einstein/Montefiore Medical Center, New York, NY, 4Albert Einstein/Montefiore Medical Center, NY, 5Albert Einstein/Montefiore Medical Center, New York, NY, 6Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY. RATIONALE: Phenols are used in bactericidal agents, herbicides, insecticides, and pesticides worldwide. Although phenols are associated with atopy, it is not known whether they are associated with asthma. We sought to test the association between the presence of five phenols (2,4dichlorophenol, 2,5-dichlorophenol, ortho-phenylphenol, 2,4,5-trichlorophenol, and 2,4,6-trichlorophenol) in urine and their association with prescriptions of asthma medications as well as total serum IgE levels. METHODS: Serum IgE and urine levels of phenols were examined from a national database with a representative sample of 2114 people in the U.S. of 6 years of age and older in the National Health and Nutrition Examination Survey (NHANES) 2005-2006. Associations between total log-IgE levels and log-transformed urinary phenol levels were tested in a linear regression model. Association between phenol levels and prescription asthma medications were tested in logistic regression models after adjustment for sample weights, urine creatinine, and other potential confounders. RESULTS: After multivariable adjustments, total IgE levels were positively associated with urine 2,5-dichlorophenol and 2,4-dichlorophenol levels (p values 0.02 and 0.04, respectively) but not with ortho-phenylphenol, 2,4,5-trichlorophenol, or 2,4,6-trichlorophenol. We also found that the presence of urinary 2,5-dichlorophenol was significantly associated with prescriptions of asthma medications (OR52.5, p value 5 0.03). CONCLUSIONS: Our findings suggest a positive association between total IgE and dichlorophenols (2,5-dichlorophenol and 2,4-dichlorophenol levels). In addition, there was a positive association between 2,5-dichlorophenol and prescriptions of asthma medications. Excessive use of chlorophenols may contribute to atopy and an increase in asthma medications.
MONDAY
703