Gestational intermittent hypoxia increases susceptibility to neuroinflammation and alters respiratory motor control in neonatal rats

Abstract

Sleep disordered breathing (SDB) and obstructive sleep apnea (OSA) during pregnancy are growing health concerns because these conditions are associated with adverse outcomes for newborn infants. SDB/OSA during pregnancy exposes the mother and the fetus to intermittent hypoxia. Direct exposure of adults and neonates to IH causes neuroinflammation and neuronal apoptosis, and exposure to IH during gestation (GIH) causes long-term deficits in offspring respiratory function. However, the role of neuroinflammation in CNS respiratory control centers of GIH offspring has not been investigated. Thus, the goal of this hybrid review/research article is to comprehensively review the available literature both in humans and experimental rodent models of SDB in order to highlight key gaps in knowledge. To begin to address some of these gaps, we also include data demonstrating the consequences of GIH on respiratory rhythm generation and neuroinflammation in CNS respiratory control regions. Pregnant rats were exposed to daily intermittent hypoxia during gestation (G10-G21). Neuroinflammation in brainstem and cervical spinal cord was evaluated in P0-P3 pups that were injected with saline or lipopolysaccharide (LPS; 0.1mg/kg, 3h). In CNS respiratory control centers, we found that GIH attenuated the normal CNS immune response to LPS challenge in a gene-, sex-, and CNS region-specific manner. GIH also altered normal respiratory motor responses to LPS in newborn offspring brainstem-spinal cord preparations. These data underscore the need for further study of the long-term consequences of maternal SDB on the relationship between inflammation and the respiratory control system, in both neonatal and adult offspring.

One bout of neonatal inflammation impairs adult respiratory motor plasticity in male and female rats

“…Low-levels of cytokines are important for neurodevelopment (Bilbo and Schwarz, 2009), and perturbing the balance of neonatal cytokines during development leads to lasting aberrant effects on neural circuits and developing cells (Reemst et al, 2016). Furthermore, while many components of the respiratory system begin developing in utero (Prakash et al, 2000; Pagliardini et al, 2003; Mantilla and Sieck, 2008; Johnson et al, 2018), the respiratory control system undergoes significant postnatal maturation. In these studies, we induced systemic inflammation with LPS at P4, similar to other studies showing long-term consequences of neonatal inflammation in other physiological systems (Shanks et al, 2000; Walker et al, 2006; Fan et al, 2008; Kohman et al, 2008; Bilbo, 2010), supporting the idea that important neural changes occur within the first week of life.…”

Pulmonary arterial hypertension-associated changes in gut pathology and microbiota

“…Our previous studies and those of others have challenged this central dogma and suggested that PAH could be a systemic disease, where coordinated interactions of multiple organ systems may be involved in the initiation and establishment of PAH pathophysiology [ 1 , 3 –]. For example, our recent studies have demonstrated that microglia activation and neuroinflammation in autonomic brain regions in association with enhanced sympathetic activity play key roles in the development of PAH [ 1 , 3 ] This led us to propose the concept of dysfunctional brain–lung communication in PAH, consistent with evidence of increased sympathetic nerve activity (SNA) in PAH patients [ 4 , 5 ] and involvement of neuroinflammation in many pulmonary and hypoxic pathophysiological conditions [ 6 , 7 ].…”

Spermidine Prevents Heart Injury in Neonatal Rats Exposed to Intrauterine Hypoxia by Inhibiting Oxidative Stress and Mitochondrial Fragmentation

“…In clinical studies, CIH was found to be an important pathophysiological change induced by obstructive sleep apnea-hypopnea syndrome (OSAHS). Evidence shows that OSAHS affects up to one-third of women by the third trimester [76]. OSAHS leads to the upregulation of oxidative stress and pathways of inflammation [77], which are also mechanisms of chronic hypoxia.…”