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Roflumilast N-oxide prevents cytokine secretion induced by cigarette smoke combined with LPS through JAK/STAT and ERK1/2 inhibition in airway epithelial cells.
PLoS One 2014; 9(1):e85243Plos

Abstract

Cigarette smoke is a major cause of chronic obstructive pulmonary disease (COPD). Airway epithelial cells and macrophages are the first defense cells against cigarette smoke and these cells are an important source of pro-inflammatory cytokines. These cytokines play a role in progressive airflow limitation and chronic airways inflammation. Furthermore, the chronic colonization of airways by Gram-negative bacteria, contributes to the persistent airways inflammation and progression of COPD. The current study addressed the effects of cigarette smoke along with lipolysaccharide (LPS) in airway epithelial cells as a representative in vitro model of COPD exacerbations. Furthermore, we evaluated the effects of PDE4 inhibitor, the roflumilast N-oxide (RNO), in this experimental model. A549 cells were stimulated with cigarette smoke extract (CSE) alone (0.4% to 10%) or in combination with a low concentration of LPS (0.1 µg/ml) for 2 h or 24 h for measurement of chemokine protein and mRNAs and 5-120 min for protein phosphorylation. Cells were also pre-incubated with MAP kinases inhibitors and Prostaglandin E2 alone or combined with RNO, before the addition of CSE+LPS. Production of cytokines was determined by ELISA and protein phosphorylation by western blotting and phospho-kinase array. CSE did not induce production of IL-8/CXCL8 and Gro-α/CXCL1 from A549 cells, but increase production of CCL2/MCP-1. However the combination of LPS 0.1 µg/ml with CSE 2% or 4% induced an important production of these chemokines, that appears to be dependent of ERK1/2 and JAK/STAT pathways but did not require JNK and p38 pathways. Moreover, RNO associated with PGE2 reduced CSE+LPS-induced cytokine release, which can happen by occur through of ERK1/2 and JAK/STAT pathways. We report here an in vitro model that can reflect what happen in airway epithelial cells in COPD exacerbation. We also showed a new pathway where CSE+LPS can induce cytokine release from A549 cells, which is reduced by RNO.

Authors+Show Affiliations

UMR991 INSERM/Université de Rennes 1, Rennes, France.UMR991 INSERM/Université de Rennes 1, Rennes, France.Laboratório de Reparo Tecidual, DHE/IBRAG/UERJ, Rio de Janeiro, Brasil.Nycomed GmbH, Konstanz, Germany.Laboratório de Reparo Tecidual, DHE/IBRAG/UERJ, Rio de Janeiro, Brasil.Laboratório de Reparo Tecidual, DHE/IBRAG/UERJ, Rio de Janeiro, Brasil.UMR991 INSERM/Université de Rennes 1, Rennes, France.UMR991 INSERM/Université de Rennes 1, Rennes, France.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

24416369

Citation

Victoni, Tatiana, et al. "Roflumilast N-oxide Prevents Cytokine Secretion Induced By Cigarette Smoke Combined With LPS Through JAK/STAT and ERK1/2 Inhibition in Airway Epithelial Cells." PloS One, vol. 9, no. 1, 2014, pp. e85243.
Victoni T, Gleonnec F, Lanzetti M, et al. Roflumilast N-oxide prevents cytokine secretion induced by cigarette smoke combined with LPS through JAK/STAT and ERK1/2 inhibition in airway epithelial cells. PLoS ONE. 2014;9(1):e85243.
Victoni, T., Gleonnec, F., Lanzetti, M., Tenor, H., Valença, S., Porto, L. C., ... Boichot, E. (2014). Roflumilast N-oxide prevents cytokine secretion induced by cigarette smoke combined with LPS through JAK/STAT and ERK1/2 inhibition in airway epithelial cells. PloS One, 9(1), pp. e85243. doi:10.1371/journal.pone.0085243.
Victoni T, et al. Roflumilast N-oxide Prevents Cytokine Secretion Induced By Cigarette Smoke Combined With LPS Through JAK/STAT and ERK1/2 Inhibition in Airway Epithelial Cells. PLoS ONE. 2014;9(1):e85243. PubMed PMID: 24416369.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Roflumilast N-oxide prevents cytokine secretion induced by cigarette smoke combined with LPS through JAK/STAT and ERK1/2 inhibition in airway epithelial cells. AU - Victoni,Tatiana, AU - Gleonnec,Florence, AU - Lanzetti,Manuella, AU - Tenor,Hermann, AU - Valença,Samuel, AU - Porto,Luis Cristovão, AU - Lagente,Vincent, AU - Boichot,Elisabeth, Y1 - 2014/01/08/ PY - 2013/04/05/received PY - 2013/12/03/accepted PY - 2014/1/14/entrez PY - 2014/1/15/pubmed PY - 2014/9/3/medline SP - e85243 EP - e85243 JF - PloS one JO - PLoS ONE VL - 9 IS - 1 N2 - Cigarette smoke is a major cause of chronic obstructive pulmonary disease (COPD). Airway epithelial cells and macrophages are the first defense cells against cigarette smoke and these cells are an important source of pro-inflammatory cytokines. These cytokines play a role in progressive airflow limitation and chronic airways inflammation. Furthermore, the chronic colonization of airways by Gram-negative bacteria, contributes to the persistent airways inflammation and progression of COPD. The current study addressed the effects of cigarette smoke along with lipolysaccharide (LPS) in airway epithelial cells as a representative in vitro model of COPD exacerbations. Furthermore, we evaluated the effects of PDE4 inhibitor, the roflumilast N-oxide (RNO), in this experimental model. A549 cells were stimulated with cigarette smoke extract (CSE) alone (0.4% to 10%) or in combination with a low concentration of LPS (0.1 µg/ml) for 2 h or 24 h for measurement of chemokine protein and mRNAs and 5-120 min for protein phosphorylation. Cells were also pre-incubated with MAP kinases inhibitors and Prostaglandin E2 alone or combined with RNO, before the addition of CSE+LPS. Production of cytokines was determined by ELISA and protein phosphorylation by western blotting and phospho-kinase array. CSE did not induce production of IL-8/CXCL8 and Gro-α/CXCL1 from A549 cells, but increase production of CCL2/MCP-1. However the combination of LPS 0.1 µg/ml with CSE 2% or 4% induced an important production of these chemokines, that appears to be dependent of ERK1/2 and JAK/STAT pathways but did not require JNK and p38 pathways. Moreover, RNO associated with PGE2 reduced CSE+LPS-induced cytokine release, which can happen by occur through of ERK1/2 and JAK/STAT pathways. We report here an in vitro model that can reflect what happen in airway epithelial cells in COPD exacerbation. We also showed a new pathway where CSE+LPS can induce cytokine release from A549 cells, which is reduced by RNO. SN - 1932-6203 UR - https://www.unboundmedicine.com/medline/citation/24416369/Roflumilast_N_oxide_prevents_cytokine_secretion_induced_by_cigarette_smoke_combined_with_LPS_through_JAK/STAT_and_ERK1/2_inhibition_in_airway_epithelial_cells_ L2 - http://dx.plos.org/10.1371/journal.pone.0085243 DB - PRIME DP - Unbound Medicine ER -