Influence of estrus cycle and timing of lipopolysaccharide (LPS)‐induced inflammation on inspiratory motor activity and the acute hypoxic ventilatory response (HVR) in urethane‐anesthetized spontaneously breathing adult female Sprague‐Dawley rat

Abstract

Accumulating evidence suggests that estrogens can exert anti‐inflammatory and neuroprotective effects, which have the capacity to influence the onset, magnitude, and time course of inflammatory processes. The most commonly used experimental approach for inducing inflammation involves systemic administration of the bacterial endotoxin lipopolysaccharide (LPS), and the progression of the LPS‐regulated pro‐inflammatory gene/protein expression response has been well characterized, with an induction phase of inflammation occurring at ~2–4 hours following LPS exposure, a peak inflammatory phase occurring at ~4–6 hours following LPS exposure, and a resolution phase at ~24 hours following LPS exposure. It is likely that time‐dependent changes in expression of the upregulated pro‐inflammatory cytokines underlie the progression of alterations in various physiological processes, including ventilatory control mechanisms. We have recently begun to examine the impact of inflammation on various aspects of ventilatory control, and the current study was undertaken to begin to evaluate the potential influence of the hormonal changes associated with the estrous cycle on inflammation‐induced alterations in ventilatory control during the induction and resolution phases of the early inflammatory response. For the current study, we examined basal inspiratory (diaphragm) motor (EMG) activity and the acute hypoxic ventilatory response (HVR; 12% O2 for 90s) in spontaneously breathing urethane‐anesthetized female Sprague‐Dawley rats at either ~2–4 hr or 24‐hr after systemic administration of LPS (3 mg/kg, ip) or vehicle (0.9% saline, ip) delivered during proestrus (high estrogen) or diestrus (low estrogen). We found that basal EMG burst timing and patterning features were slightly modified by LPS exposure at both time points albeit only trends were observed at the 24 hr time point. In contrast, at the 2–4 hr time point, significantly increased burst frequency, decreased TI, reduced TI/Ttot, and lower ApEn values were noted in diestrus LPS‐treated rats. We also found that in proestrus LPS‐, proestrus saline‐, and diestrus saline‐treated rats at 2–4 hr post administration, HVR increases in burst amplitude and frequency were similar, while in diestrus LPS‐treated rats, there was a markedly blunted increase in burst amplitude. In contrast at 24 hr post administration, in proestrus LPS‐, proestrus saline‐, diestrus LPS‐, and diestrus saline‐treated rats, we found that HVR increases in burst amplitude and frequency were comparable across all groups. These observations suggest that both LPS administration during different phases of the estrus cycle as well as time‐dependent phases of inflammation influence the impact of LPS‐induced inflammation on inspiratory motor activity and HVR ventilatory control.Support or Funding InformationNIH NS101737; Thomas Hartman Center for Parkinson’s Disease Research at Stony Brook University