Systemic infection is a multi-billion dollar national health-care burden. Pre-term infants are particularly susceptible to bacterial infection and are at higher risk for the development of lung infections. While the majority of preterm infants suffer from disorders of respiratory control, these irregularities of breathing pattern are exacerbated by infection. The mechanism by which inflammation alters breathing control is still not well understood. With pulmonary tract infection, pro-inflammatory cytokines are released locally in the airways and lungs and the inflammatory signal is carried via the vagus nerve to the brainstem?inducing changes in the central nervous system to cause impaired breathing (tachypnea, apneas, and periodic breathing). Vagus nerve stimulation (VNS) has been shown to have an anti-inflammatory effect but the mechanism by which VNS changes inflammatory tone is unknown. In this proposal, we will induce an acute airway inflammatory response in neonatal rats texposed to endotoxin (lipopolysaccharide, or LPS via intra-tracheal injection). We will then use VNS to block the inflammatory signal to the brainstem. We hypothesize that LPS-induced increases in brainstem cytokine production and the subsequent impaired breathing can be blunted or blocked completely by VNS. Furthermore, we hypothesize that the neuroinflammatory changes to breathing control depend upon COX2 upregulation and prostaglandin (PGE2) release that alters synaptic activity in the nucleus tractus solitarii (nTS) and preBtzinger Complex (pBC)?regions critical to modulation and generation of breathing rhythm. To test this hypothesis, we will quantify changes in pro- inflammatory cytokines in nTS and pBC in response to acute LPS injection in the trachea with and without VNS. We will use VNS stimulation parameters that are used clinically and high-frequency VNS which has been shown to block c-fibers. To assess synaptic activity in nTS and pBC, we will use electrophysiology (whole-cell patch-clamp recording) in in vitro slices taken from animals that have been exposed to LPS and VNS. Our goal is to assess whether VNS can be used to reduce inflammation in neonates.

Public Health Relevance

Lung infection is a multi-billion dollar national health-care burden. Preterm infants are particularly susceptible to bacterial infection and are much more likely to develop sepsis, the most severe form of infection. Developing non-invasive therapies that have minimal complications and improve long-term outcome for preterm infants is a major goal of our work. Vagal nerve stimulation (VNS) may provide a safe, non-invasive alternative to anti-inflammatory drugs and antibiotics, which can cause complications in preterm babies. This project will provide foundational understanding of the mechanisms by which VNS can bock early infection in preterm babies.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Exploratory/Developmental Grants (R21)
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Respiratory Integrative Biology and Translational Research Study Section (RIBT)
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Bremer, Andrew
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Loma Linda University
Internal Medicine/Medicine
Schools of Medicine
Loma Linda
United States
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