Effects of systemic infection on respiration vary with estrus cycle and between male and female Sprague Dawleys

Abstract

Little is known regarding gender differences in response to systemic infection. Progesterone peaks during proestrus and is associated with increased respiratory frequency and reduced cytokine expression during systemic infection compared to nonproestrus. We hypothesized that hormone fluctuations during the estrus cycle may not only affect respiration, but also the systemic inflammation impact on respiratory pattern. We compared baseline and changes in Ventilatory Pattern Variability (VPV, Autocorrelation coefficient (r at one‐cycle length), Mutual Information (MI), Sample Entropy (SampEn) and Nonlinear Complexity Index (NLCI)) in proestrus and nonproestrus in Sprague Dawley rats (n=44) during peritonitis and compared male (n=24) to females. CWRU IACUC approved all experiments. We tracked estrus cycle stage by characterizing vaginal epithelial cells and recorded ventilatory pattern in conscious unrestrained rats using whole‐body plethysmography. We sacrificed 10 females (n=5 proestrus and 5 nonproestrus) and 8 males (Naïve rats). In the remaining, we implanted clots containing 0 (D0) or 100x106 (D100) Escherichia coli cells. In addition to naïve groups, we studied: 1) D0 proestrus (n=7), 2) D100 proestrus (n=13), 3) D0 non‐proestrus (n=6), 4) D100 non‐proestrus (n=8), 5) D0 males (n=6) and 6) D100 males (n=10). We measured durations of inspiration (Ti), expiration (Te) and cycle (Ttot), r, MI, SampEn and NLCI. At D100, aside from SampEn between proestrus and nonproestrus (1.25±0.12 vs 1.13±0.05, p<0.01), the response to systemic infection was cycle independent. By 12h in infected rats compared to D0, MI increased and SampEn decreased in nonproestrus but not proestrus (0.69±0.09 vs 0.55±0.05, p=0.02; 1.13±0.05 vs 1.28±0.09, p=0.03); NLCI increased in proestrus but not in nonproestrus (0.21±0.12 vs 0.10±0.05 p=0.05). In naïve rats, r at one‐cycle length, CV, and MI varied between male and female (0.65±0.13 vs 0.40±0.15; p=0.006); (0.1±0.03 vs 0.19±0.05; p=0.04); (0.613±0.106 vs 0.45±0.08; p=0.02). Males responded to systemic infection more robustly than females; higher fR (122.4±31.2 vs 79.2±11.3, p<0.001); lower SampEn (1.08±0.15 vs 1.20±0.11, p=0.004); and higher NLCI (0.28±0.10 vs 0.19±0.12, p=0.009). In summary, proestrus effects on VPV are evident when comparing ventilatory patterns within the estrus cycle and against males during the development of peritonitis. SampEn was the variable that was consistently different. SampEn measures predictability of the pattern; a lower value implies more predictability. NLCI is derived from the difference in SampEn of the original dataset from the mean of 19 surrogate datasets. Stochastic variability is preserved in surrogate datasets while deterministic variability is disrupted. Thus, during proestrus lower NLCI indicates decreased deterministic variability in female rats, and perhaps, less sickness.