Perinatal Breathing Patterns and Survival in Mice Born Prematurely and at Term

Abstract

Infants born prematurely, often associated with maternal infection, frequently exhibit breathing instabilities that require resuscitation. We hypothesized that breathing patterns during the first hour of life would be predictive of survival in an animal model of prematurity. Using plethysmography, we measured breathing patterns during the first hour after birth in mice born at term (Term 19.5), delivered prematurely on gestational day 18.5 following administration of low-dose lipopolysaccharide (LPS; 0.14 mg/kg) to pregnant dams (LPS 18.5), or delivered on gestational day 18.7 or 17.5 by caesarian section (C-S 18.5 and C-S 17.5, respectively). Our experimental approach allowed us to dissociate effects caused by inflammation, from effects due to premature birth in the absence of an inflammatory response. C-S 17.5 mice did not survive, whereas mortality was not increased in C-S 18.5 mice. However, in premature pups born at the same gestational age (day 18.5) in response to maternal LPS injection, mortality was significantly increased. Overall, mice that survived had higher birth weights and showed eupneic or gasping activity that was able to transition to normal breathing. Some mice also exhibited a “saw tooth” breathing pattern that was able to transition into eupnea during the first hour of life. In contrast, mice that did not survive showed distinct, large amplitude, long-lasting breaths that occurred at low frequency and did not transition into eupnea. This breathing pattern was only observed during the first hour of life and was more prevalent in LPS 18.5 and C-S 18.5 mice. Indeed, breath tidal volumes were higher in inflammation-induced premature pups than in pups delivered via C-section at equivalent gestational ages, whereas breathing frequencies were low in both LPS-induced and C-section-induced premature pups. We conclude that a breathing pattern characterized by low frequency and large tidal volume is a predictor for the failure to survive, and that these characteristics are more often seen when prematurity occurs in the context of maternal inflammation. Further insights into the mechanisms that generate these breathing patterns and how they transition to normal breathing may facilitate development of novel strategies to manage premature birth in humans.

Leukocytes mediate disease pathogenesis in the Ndufs4(KO) mouse model of Leigh syndrome

“…We performed plethysmography in untreated and 300 mg/kg/d pexidartinib–treated mice to assess respiratory function (see ref. 24 for diagram and Supplemental Methods for details). Severe defects in respiratory function were present in untreated Ndufs4 (KO) mice at about P70 in respiratory frequency, incidence of amplitude and frequency irregularities, and responses to increased CO 2 ( Figure 2 ).…”

“…Impaired respiration, which is a brainstem function, is a proximal cause of death in LS patients and has been reported to be a proximal cause of death in Ndufs4(KO) mice not euthanized (23). We performed plethysmography in untreated and 300 mg/kg/day pexidartinib treated mice to assess respiratory function (see (24) for diagram, Methods for details). Severe defects in respiratory function were present in untreated Ndufs4(KO) mice at ~P70 in respiratory frequency, incidence of amplitude and frequency irregularities, and responses to increased CO2 (Figure 2I-L).…”

Low nephron endowment increases susceptibility to renal stress and chronic kidney disease

“…We generated mouse models of 30%–70% nephron reduction that simulate human premature kidneys by manipulating Ret tyrosine kinase activity or expression during late gestation. While early delivery would be an ideal experimental design to study prematurity related human kidney disease, delivering mice more than 2 days before natural birth does not yield viable animals ( 80 ). Mice delivered shortly prior to natural delivery results in mice with a 20% nephron deficit ( 28 ); however, this does not recapitulate the spectrum of nephron number seen in humans born preterm — particularly, the significant nephron reduction seen in extremely preterm infants ( 10 ).…”

Sex- and Region-Specific Differences in the Transcriptomes of Rat Microglia from the Brainstem and Cervical Spinal Cord

“…Rats were housed in facilities accredited by the Association for Assessment and Accreditation of Laboratory Animal Care on a 12:12 light:dark cycle, with food and water ad libitum. Because maternal inflammation can impact respiratory frequency and tidal volume in newborn pups (Ramirez et al, 2019) and maternal breathing dysfunction is thought to cause maternal inflammation that can cause fetal growth restriction, low birth weights, and premature birth in some human studies (reviewed in Izci Balserak (2015)), we used adult rats born from dams that were reared in controlled room air conditions during their pregnancy. Due to our interest in studying microglia from CNS regions involved in respiratory neural control, we housed timed pregnant Sprague-Dawley rats (arrived day E9; Charles River; Wilmington, MA) in environmentally controlled conditions from gestational day 10 to 21.…”