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Role of Nitric Oxide Synthase Pathways in the Effects of Proinflammatory Cytokines on the Respiratory Pattern and Hypoxic Ventilatory Response

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Abstract

Interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) are the major proinflammatory cytokines. Cytokine receptors are expressed in the brainstem areas involved in respiratory control, as well as in the carotid bodies that control the O2 balance in arterial blood. We hypothesized that circulating proinflammatory cytokines are able to affect lung ventilation and modulate the respiratory response to hypoxia by activating NO-dependent pathways. The aim of our study was to compare the respiratory effects of IL-1β and TNF-α before and after pretreatment with L-NAME, a non-selective inhibitor of NO synthase (NOS). The ventilatory response to hypoxia was measured in anesthetized Wistar rats using the rebreathing method before and after intravenous administration of IL-1β (2 µg/kg) and TNF-α (40 µg/kg). It was found that an increase in the systemic level of proinflammatory cytokines increases lung ventilation under normoxia, while reducing respiratory sensitivity to hypoxia. Pretreatment with L-NAME (intraperitoneal administration) reduced these respiratory effects of both IL-1β and TNF-α. We believe that the activation of NOS pathways and an increase in NO synthesis, when cytokines interact with the corresponding receptors, mediate the respiratory effects of proinflammatory cytokines and underlies the effect of inflammation on respiratory function.

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Funding

This work was supported by the State Program of the Russian Federation (47 SP).

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Authors and Affiliations

  1. Pavlov Institute of Physiology, Russian Academy of Sciences, St. Petersburg, Russia

    A. A. Klinnikova, G. A. Danilova & N. P. Aleksandrova

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  1. A. A. Klinnikova
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  2. G. A. Danilova
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  3. N. P. Aleksandrova
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Contributions

Basic idea and experimental design (N.P.A., A.A.K.); data collection (A.A.K., G.A.D.); data processing (A.A.K., G.A.D.); writing and editing a manuscript (A.A.K., N.P.A., G.A.D.).

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Correspondence to A. A. Klinnikova.

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Translated by A. Polyanovsky

Russian Text © The Author(s), 2021, published in Rossiiskii Fiziologicheskii Zhurnal imeni I.M. Sechenova, 2021, Vol. 107, No. 11, pp. 1385–1394https://doi.org/10.31857/S0869813921110042.

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Klinnikova, A.A., Danilova, G.A. & Aleksandrova, N.P. Role of Nitric Oxide Synthase Pathways in the Effects of Proinflammatory Cytokines on the Respiratory Pattern and Hypoxic Ventilatory Response. J Evol Biochem Phys 57, 1373–1381 (2021). https://doi.org/10.1134/S0022093021060168

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