title: Nitric oxide regulates cytokine induction in the diaphragm in response to inspiratory resistive breathing.
abstract: Resistive breathing (encountered in chronic obstructive pulmonary disease and asthma) results in cytokine upregulation and decreased nitric oxide (NO) levels in the strenuously contracting diaphragm. NO can regulate gene expression. We hypothesized that endogenously produced NO downregulates cytokine production triggered by strenuous diaphragmatic contraction. Wistar rats treated with vehicle, the nonselective NO synthase inhibitor NG-nitro-l-arginine-methylester (l-NAME), or the NO donor diethylenetriamine-NONOate (DETA) were subjected to inspiratory resistive breathing (IRB; 50% of maximal inspiratory pressure) for 6 h or sham operation. Additional groups of rats were subjected to IRB for 6 h with concurrent administration of l-NAME and inhibitors of NF-κB (BAY-11-7082), ERK1/2 (PD98059), or P38 (SB203580). Inhibition of NO production (with l-NAME) resulted in upregulation of IRB-induced diaphragmatic IL-6, IL-10, IL-2, TNF-α, and IL-1β levels by 50%, 53%, 60%, 47%, and 45%, respectively. In contrast, the NO donor (DETA) attenuated the IRB-induced cytokine upregulation to levels characteristic of quietly breathing animals. l-NAME augmented IRB-induced activation of MAPKs (P38 and ERK1/2) and NF-κB, whereas DETA triggered the opposite effect. NF-κB and ERK1/2 inhibition in l-NAME-treated animals blunted the l-NAME-induced cytokine upregulation except IL-6, whereas P38 inhibition blunted all (including IL-6) cytokine upregulation. NO downregulates IRB-induced cytokine production in the strenuously contracting diaphragm through its action on MAPKs and NF-κB.
authors.affiliation: Department 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: Stavroula
authors.initials: S
authors.lastname: Boulia
authors.forename: Dimitris
authors.initials: D
authors.lastname: Toumpanakis
authors.forename: Tatiana
authors.initials: T
authors.lastname: Michailidou
authors.forename: Dimitris
authors.initials: D
authors.lastname: Parthenis
authors.forename: Charis
authors.initials: C
authors.lastname: Roussos
authors.forename: Andreas
authors.initials: A
authors.lastname: Papapetropoulos
authors.forename: Sabah N
authors.initials: SN
authors.lastname: Hussain
authors.forename: Theodoros
authors.initials: T
authors.lastname: Vassilakopoulos
mesh_terms: D000818:Animals; D016207:Cytokines / Q000378:metabolism*; D003964:Diaphragm / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007249:Inflammation / Q000276:immunology / Q000378:metabolism* / Q000503:physiopathology; D001239:Inhalation; D008173:Lung Diseases, Obstructive / Q000276:immunology / Q000378:metabolism* / Q000503:physiopathology; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009119:Muscle Contraction; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D010084:Oxidation-Reduction; D050050:Protein Carbonylation; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction; D013997:Time Factors; D014939:Work of Breathing
chemical_list: D016207:Cytokines; D004791:Enzyme Inhibitors; D016328:NF-kappa B; D020030:Nitric Oxide Donors; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D020928:Mitogen-Activated Protein Kinases