Influence of Estrus Cycle on Lipopolysaccharide (LPS)‐induced Modulation of Basal Inspiratory Motor Activity and 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 this approach is often used in ongoing studies addressing the impact of inflammation on various aspects of ventilatory control. The potential influence of the hormonal changes associated with the estrous cycle on inflammation‐induced alterations in ventilatory control, however, have not been identified. To begin to address this issue, we examined basal inspiratory (diaphragm) motor (EMG) activity and the acute hypoxic ventilatory response (HVR; 12% O2 for 90s) during proestrus (high estrogen) and diestrus (low estrogen) in urethane‐anesthetized spontaneously breathing female Sprague‐Dawley rats after acute (2–4 hrs post) administration of LPS (3 mg/kg, ip); saline administration served as a control in aditional groups of rats. For basal diaphragm EMG burst characteristics, we quantified burst frequency, burst duration (TI), time between bursts (TE), inspiratory duty cycle (TI/Ttot), time‐to‐peak (Tpeak/TI), and inspiratory burst complexity (ApEn) from 20 consecutive breathing cycles. We found that in proestrus, LPS‐ and saline‐treated rats exhibited similar timing and patterning features with the exception of TI/Ttot (P=0.0385) and TI (P=0.0694) which both tended to be shorter in LPS‐treated rats while in diestrus, LPS‐treated rats (compared to saline‐treated rats) exhibited increased burst frequency (P=0.0399) and decreased TI (P=0.0087). In addition, ApEn was significantly lower in diestrus than in proestrus (P=0.0421). For the HVR, we quantified burst amplitude and frequency for 5 consecutive breathing cycles at 30s intervals for 90s before, during, immediately following, and 5 min after the hypoxic gas exposure. We found that in proestrus LPS‐, proestrus saline‐, and diestrus saline‐treated rats, HVR burst amplitude and frequency responses were similar, with burst amplitude increasing by 30–35% above BL levels and burst frequency increasing by 35–41% above BL levels. While diestrus LPS‐treated rats exhibited an ~48% increase in burst frequency above BL levels, they had a markedly blunted increase in burst amplitude (~14% above BL levels), yielding a significantly different response than that noted for the other groups (P=0.009). It should also be noted that in a subset of diestrus LPS‐treated rats, the HVR challenge was terminated early due to development of severe respiratory depression. These observations demonstrate that LPS administration during diestrus slightly alters basal inspiratory motor activity and impairs the HVR in a manner similar to what we have seen in LPS‐treated male rats. Moreover, these observations may be taken to support a potential protective role for estrogen in ventilatory control.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.