title: MAPKs and NF-κB differentially regulate cytokine expression in the diaphragm in response to resistive breathing: the role of oxidative stress.
abstract: Inspiratory resistive breathing (IRB) induces cytokine expression in the diaphragm. The mechanism of this cytokine induction remains elusive. The roles of MAPKs and NF-κB and the impact of oxidative stress in IRB-induced cytokine upregulation in the diaphragm were studied. Wistar rats were subjected to IRB (50% of maximal inspiratory pressure) via a two-way nonrebreathing valve for 1, 3, or 6 h. Additional groups of rats subjected to IRB for 6 h were randomly assigned to receive either solvent or N-acetyl-cysteine (NAC) or inhibitors of NF-κB (BAY-11-7082), ERK1/2 (PD98059), and P38 MAPK (SB203580) to study the effect of oxidative stress, NF-κB, and MAPKs in IRB-induced cytokine upregulation in the diaphragm. Quietly breathing animals served as controls. IRB upregulated cytokine (IL-6, TNF-α, IL-10, IL-2, IL-1β) protein levels in the diaphragm and resulted in increased activation of MAPKs (P38, ERK1/2) and NF-κB. Inhibition of NF-κB and ERK1/2 blunted the upregulation of all cytokines except that of IL-6, which was further increased. P38 inhibition attenuated all cytokine (including IL-6) upregulation. Both P38 and ERK1/2 inhibition decreased NF-κB/p65 subunit phosphorylation. NAC pretreatment blunted IRB-induced cytokine upregulation in the diaphragm and resulted in decreased ERK1/2, P38, and NF-κB/p65 phosphorylation. In conclusion, IRB-induced cytokine upregulation in the diaphragm is under the regulatory control of MAPKs and NF-κB. IL-6 is regulated differently from all other cytokines through a P38-dependent and NF-κB independent pathway. Oxidative stress is a stimulus for IRB-induced cytokine upregulation in the diaphragm.
authors.affiliation: Dept. of Critical Care and Pulmonary Services, University of Athens Medical School, Evangelismos Hospital, 45-47 Ipsilandou Str., Athens, Greece.
authors.forename: Ioanna
authors.initials: I
authors.lastname: Sigala
authors.forename: Panayiotis
authors.initials: P
authors.lastname: Zacharatos
authors.forename: Dimitris
authors.initials: D
authors.lastname: Toumpanakis
authors.forename: Tatiana
authors.initials: T
authors.lastname: Michailidou
authors.forename: Olga
authors.initials: O
authors.lastname: Noussia
authors.forename: Stamatios
authors.initials: S
authors.lastname: Theocharis
authors.forename: Charis
authors.initials: C
authors.lastname: Roussos
authors.forename: Andreas
authors.initials: A
authors.lastname: Papapetropoulos
authors.forename: Theodoros
authors.initials: T
authors.lastname: Vassilakopoulos
mesh_terms: D000403:Airway Resistance; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001784:Blood Gas Analysis; D016207:Cytokines / Q000378:metabolism*; D003964:Diaphragm / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D001239:Inhalation; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D010766:Phosphorylation; D011312:Pressure; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors; D015854:Up-Regulation; D014939:Work of Breathing; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D000975:Antioxidants; D016207:Cytokines; D016328:NF-kappa B; D047428:Protein Kinase Inhibitors; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases