G P Livanos And M Simou Laboratories

Athens, Greece

G P Livanos And M Simou Laboratories

Athens, Greece

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Sigala I.,National and Kapodistrian University of Athens | Sigala I.,G P Livanos And M Simou Laboratories | Zacharatos P.,National and Kapodistrian University of Athens | Zacharatos P.,G P Livanos And M Simou Laboratories | And 12 more authors.
Journal of Applied Physiology | Year: 2012

Nitric oxide regulates cytokine induction in the diaphragm in response to inspiratory resistive breathing. J Appl Physiol 113: 1594-1603, 2012. First published September 6, 2012; doi:10.1152/japplphysiol.00233.2012.-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-kB (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-kB, whereas DETA triggered the opposite effect. NF-B and ERK1/2 inhibition in L-NAME-treated animals blunted the L-NAMEinduced 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-kB. © 2012 the American Physiological Society.


Sigala I.,National and Kapodistrian University of Athens | Sigala I.,G P Livanos And M Simou Laboratories | Zacharatos P.,G P Livanos And M Simou Laboratories | Toumpanakis D.,National and Kapodistrian University of Athens | And 10 more authors.
American Journal of Physiology - Regulatory Integrative and Comparative Physiology | Year: 2011

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 twoway 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. © 2011 the American Physiological Society.

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