Effects of Two‐Hit Lipopolysaccharide (LPS) Administration on Acute Intermittent Hypoxia (AIH)‐Induced Inspiratory Motor Behaviors in Urethane‐anesthetized Spontaneously Breathing Adult Male Sprague‐Dawley Rat
Authors: Bhatt Rashi C , Wadolowski Steven B , Thomas Selena C , Maqsood Anas , Solomon Irene C 
Published: June 2021

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.