A Comparative Assessment of Effects of Major Mediators of Acute Phase Response (IL-1, TNF-α, IL-6) on Breathing Pattern and Survival Rate in Rats with Acute Progressive Hypoxia

Abstract

A pressing issue of the day is the identification of therapeutic targets to suppress the “cytokine storm” in COVID-19 complicated by acute respiratory distress syndrome (ARDS) with concomitant hypoxemia. However, the key cytokine and its relative contribution to the pathogenesis of ARDS, which leads to high mortality, are unknown. A comparative assessment of the effect of elevated systemic levels of pro-inflammatory cytokines IL-1β, TNF-1α and IL-6 on the respiratory patterns and survival rate in rats was carried out under progressively increasing acute hypoxia. Increasing hypoxia was simulated by a rebreathing method (from normoxia to apnea). The recorded parameters were the breathing pattern components (tidal volume and respiratory rate), minute ventilation (MV), oxygen saturation, apnea onset time, and posthypoxic survival rate. A comparative analysis was carried out under mild, moderate and severe hypoxia (at F I O 2 = 15, 12 and 8%, respectively). It was shown that increasing hypoxia was accompanied by an acute suppression of the compensatory elevation of MV in rats with increased systemic levels of IL-1β and TNF-1α. By contrast, IL-6 caused an intensive elevation of MV with increasing hypoxia. Acute hypoxia (F I O 2 < 8%), in all experimental series, was accompanied by an impairment of the respiratory rhythm up to the development of apnea. Posthypoxic breathing restoration (survival rate) was 50% with IL-1β and TNF-1α and only 10% with IL-6. The obtained results indicate that the elevated IL-6 level, despite the absence of respiratory disorders at the initial stage of the developing pathologic process, leads to a higher mortality in rats compared to IL-1β and TNF-1α. This allows considering IL-6 as an early prognostic biomarker of a high risk of mortality under severe hypoxemia.

Microglial reactivity in brainstem chemosensory nuclei in response to hypercapnia

“…Similarly, normoxic hypercapnia (15% CO 2 , 20% O 2 , 65%N 2 ) for 24 h did not increase IL1β in BV2 microglial cells in culture (Ding et al, 2018). However, hypercapnia under hypoxic conditions was effective in increasing IL1β both in vivo and in vitro (Ding et al, 2018). Differences with our in vitro results, might be related with the different species (rat vs. mouse), the use of BV2 cell lines instead of primary microglia, distinct stimulation intensity (10% vs. 15% CO 2 ) and duration (2 h vs. 24 h), or perhaps different basal microglial functional states (Paolicelli et al, 2022).…”

“…By contrast, i. v. IL1β injection increases f R in conscious rats ( Graff and Gozal, 1999 ) and i. p. IL1β injection increases the amplitude of respiratory cycle in anesthetized rats ( Hocker and Huxtable, 2018 ). In urethane-anesthetized normoxic rats, i. v. administration of IL1β increases V T , f R , and V E ( Donina et al, 2021 ).…”

“…Hypercapnia in normoxic in vivo conditions (5% CO 2 , 21% O 2 , 74% N 2 ) for 3 h was unable to increase the expression of IL1β in microglia of adult rat hippocampal CA1 area examined by double immunofluorescence (Ding et al, 2018). Similarly, normoxic hypercapnia (15% CO 2 , 20% O 2 , 65%N 2 ) for 24 h did not increase IL1β in BV2 microglial cells in culture (Ding et al, 2018).…”

Identification of Inflammatory Mediators in Saliva Samples From Hospitalized Newborns: Potential Biomarkers?

“…IL1b, being one of the most studied pleiotropic cytokines, shares similar effects to TNF-α, also referring to the main pro-inflammatory cytokines, which stimulate the production of other cytokines, including IL-6 (Hsieh et al, 2020). To date, it is suggested that IL1b and TNF are involved in neuroimmune interactions in brain regions responsible for central regulation of respiration (Donina et al, 2021). Therefore, it is possible that neuroimmune interactions mediated by IL1b and TNF-α also play a role in peripheral mechanisms of respiratory control that modulate the response to hypoxia and arterial blood oxygen saturation (Donina et al, 2021).…”

“…To date, it is suggested that IL1b and TNF are involved in neuroimmune interactions in brain regions responsible for central regulation of respiration (Donina et al, 2021). Therefore, it is possible that neuroimmune interactions mediated by IL1b and TNF-α also play a role in peripheral mechanisms of respiratory control that modulate the response to hypoxia and arterial blood oxygen saturation (Donina et al, 2021). In addition, an association between IL1b levels and moderate to severe neonatal asphyxia is mentioned in the literature (Agustina & Kosim, 2021; Boskabadi et al, 2023).…”