Pediatric obstructive sleep apnea (OSA) has been shown to not only affect the quality of sleep, but also overall health in general. Untreated or inadequately treated OSA can lead to long-term sequelae involving cardiovascular, endothelial, metabolic, endocrine, neurocognitive, and psychologicalconsequences. The physiological effects of pediatric OSA eventually become pathological. As the complex effects of pediatric OSA are discovered, they must be identified early so that healthcare providers can be better equipped to treat and even prevent them. Ultimately, adequate management of OSA improves overall quality of life.
Inflammation has been suggested to alter a variety of physiological processes by its effects on serotonergic (5‐HT) neurotransmission. In the respiratory neural control system, LPS‐induced neuroinflammation has been shown to affect multiple aspects of central ventilatory control, including serotonin2 (5‐HT2)‐dependent inspiratory motor behaviors. While numerous studies have focused on the role of 5‐HT2A receptors in neural control of breathing, the roles of other 5‐HT receptors are beginning to be appreciated. To this end, activation of 5‐HT1A receptors has been shown to exert marked effects on inspiratory motor activity; however, the impact of LPS‐induced neuroinflammation on 5‐HT1A receptor‐mediated inspiratory motor behaviors remains to be determined. To begin to address this issue, we studied the effects of systemic application of the 5‐HT1A receptor agonist 8‐hydroxy‐2‐(di‐npropylamino) tetralin (8‐OH DPAT) on basal inspiratory (diaphragm) EMG burst amplitude and frequency in spontaneously breathing urethane‐anesthetized adult male Sprague‐Dawley rats following a ‘two‐hit’ lipopolysaccharide (LPS) administration protocol in which systemic LPS (3 mg/kg, ip) was administered ~24 hr prior to an intratracheal LPS (0.5 mg/kg, IT) injection. Similar 8‐OH DPAT experiments were performed in control rats that were either untreated or received two‐hit saline injections. All rats used for this study had also undergone an acute intermittent hypoxia (AIH) exposure protocol that was completed at least 90 min prior to administration of 8‐OH DPAT. For this study, we compare diaphragm EMG burst activities before (baseline, BL) systemic administration of 8‐OH DPAT (0.3 mg/kg, iv) to those obtained at various time points for the 30 min period immediately following administration. We found that in both control and LPS‐treated rats, administration of 8‐OH DPAT similarly affected burst frequency but differentially affected burst amplitude. In both groups of rats, 8‐OH DPAT injection produced an ~50% increase in burst frequency above BL levels within 30–60s, but by 5 min post injection, this increase was attenuated to an ~30% increase above BL levels that persisted for the remainder of the 30 min recording period. While 8‐OH DPAT injection produced an initial ~15% increase in burst amplitude above BL levels within 60s in both groups of rats, a further increase in burst amplitude up to ~30% above BL was noted by 15 min post injection in control rats, and this increase persisted for the remainder of the 30 min recording period while in LPS‐treated rats, a slight attenuation of the burst amplitude increase was noted. These preliminary observations suggest that (compared to control rats) two‐hit LPS administration may differentially affect mechanisms by which 5‐HT1A receptor activation modulates inspiratory burst frequency and amplitude. Additional experiments will be needed to identify specific mechanisms underlying these differences.Support or Funding InformationNIH NS101737; Thomas Hartman Center for Parkinson's Disease Research at Stony Brook UniversityThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Ongoing studies designed to induce peripheral inflammation, and its accompanying neuroinflammation, have begun to examine various aspects of neural control of breathing. While most studies typically administer the bacterial endotoxin lipopolysaccharide (LPS) systemically or in an airway/lung targeted manner in order to produce models of systemic inflammatory response syndrome (SIRS)/sepsis and acute lung injury (ALI), a ‘two‐hit’ LPS administration protocol in which systemic LPS (ip, 3 mg/kg) is administered ~24 hr prior to an airway/lung targeted (intratracheal (IT); 0.5 mg/kg) LPS injection has been used to better reflect chronic (lung/airway) disease states. One of the most studied respiratory behaviors in which inflammation has been shown to negatively impact breathing is AIH‐induced inspiratory motor (phrenic) long‐term facilitation (pLTF), where in anesthetized, vagotomized, ventilated adult male rats, single‐hit systemic LPS administration attenuates AIH‐induced serotonin2‐dependent pLTF. Here, we examined the impact of two‐hit LPS administration in urethane‐anesthetized vagal intact spontaneously breathing adult male Sprague‐Dawley rats on AIH‐induced inspiratory motor behaviors using AIH composed of five 3‐min episodes of hypoxia (11% O2) separated by 3‐min exposures to hyperoxia (40% O2) with all rats being continuously supplied with 2% CO2. Similar experiments were performed in control rats that were either untreated or received two‐hit saline injections. We found that in control rats, exposure to the repetitive bouts of hypoxia elicited increases in both diaphragm EMG burst frequency (~18% increase) and amplitude (IH1, ~22% to IH5, ~31%) that resulted in progressive augmentation (PA) and LTF inspiratory burst amplitude that persisted for ~75 min post‐AIH (sustained ~12–18% increase above baseline levels); no frequency LTF and a robust post hypoxic frequency decline (PHFD) after each hypoxic exposure and for up to 25 min post‐AIH were also observed. In contrast, in LPS‐treated rats, exposure to the repetitive bouts of hypoxia elicited a more robust increase in diaphragm EMG burst frequency (~25–30% increase) and a blunted or absent amplitude response (IH1, ≤8%). Moreover, in these rats, PA of burst amplitude was absent, inspiratory burst amplitude LTF was highly variable with an overall amplitude increase of ~10% above baseline levels that subsided by 20 min post‐AIH, and PHFD after each hypoxic exposure slightly increased in magnitude and persisted for up to 50 min post‐AIH. These preliminary observations suggest that (compared to control rats) two‐hit LPS administration affects mechanisms underlying multiple components responsible for inspiratory burst frequency and amplitude plasticity in response to hypoxic exposure(s) and following AIH exposure. Additional experiments, including those using other AIH protocols, will be needed to confirm these observations and identify specific mechanisms underlying these differences.Support or Funding InformationNIH NS101737; Thomas Hartman Center for Parkinson's Disease Research at Stony Brook UniversityThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Accumulating evidence indicates that inflammation and serotonergic (5‐HT) neurotransmission interact thereby affecting a variety of physiological processes. Ongoing studies in our laboratory are examining the effects of peripheral inflammation, and its accompanying neuroinflammation, on the neural control of breathing, including the impact of LPS‐induced neuroinflammation on 5‐HT1A receptor‐mediated inspiratory motor behaviors. Here, we examined the effects of systemic administration of the 5‐HT1A receptor agonist 8‐hydroxy‐2‐(di‐npropylamino) tetralin (8‐OH DPAT) on the (diaphragm) EMG burst amplitude and frequency response to a single bout of acute hypoxia (HVR; 11% O2 for 90s) in spontaneously breathing urethane‐anesthetized adult male Sprague‐Dawley rats following a ‘two‐hit’ lipopolysaccharide (LPS) administration protocol in which systemic LPS (3 mg/kg, ip) was administered ~24 hr prior to an intratracheal LPS (0.5 mg/kg, IT) injection. Similar HVR experiments were performed in control rats that were either untreated or received two‐hit saline injections. All rats used for this study had also undergone an acute intermittent hypoxia (AIH) exposure protocol that was completed at least 90 min prior to administration of 8‐OH DPAT, and they were continuously supplied with 2% CO2 throughout the recording protocol. Following baseline (BL; 40% O2) recording of diaphragm EMG activity, 8‐OH DPAT (0.3 mg/kg, iv) was administered and allowed to exert its effects for 30 min, after which a 30s HVR challenge was performed (11% O2) followed by recovery under BL conditions. Data from these experiments were also compared to our previous observations in two‐hit LPS‐ and vehicle‐treated male rats that had not undergone an AIH exposure protocol or received 8‐OH DPAT (to serve as a control for two‐hit LPS HVR behaviors). In brief, we had reported that two‐hit LPS administration blunts the HVR amplitude response such that it increases by ≤10% above BL levels (versus ≥30% increase in vehicle‐treated rats) and produces an exaggerated frequency HVR response such that it increases by ≥30% above BL levels (versus~15–20% increase in vehicle‐treated rats). In contrast to these observations, in the current study, we found that following 8‐OH DPAT administration, the HVR exhibited similar increases in both burst frequency and amplitude in both control and LPS‐treated rats. In this case, HVR amplitude and frequency increased on average by ~23% and ~25%, respectively, although LPS‐treated rats exhibited variable magnitude HVR responses. Regardless, following 8‐OH DPAT administration, HVR inspiratory motor activity appeared to be indistinguishable between control and LPS‐treated rats. These observations suggest that following pharmacological activation of 5‐HT1A receptors, amplitude and frequency HVR behaviors are improved in two‐hit LPS‐treated rats. The specific mechanisms underlying these differences remain to be identified.Support or Funding InformationNIH NS101737; Thomas Hartman Center for Parkinson's Disease Research at Stony Brook UniversityThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
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