Exposure to proinflammatory cytokines during early development appears to play a key role in initiating both neonatal lung and brain injury. Unfortunately, the pathways and mechanisms that link cytokine-mediated pathophysiology at these sites are not known. The goal of this proposal is to create a new developmental model to characterize the ability of an inflammatory response initiated in the lung to trigger a corresponding response in the brain and begin to utilize neonatal respiratory control as a physiologic measure of this lung/brain interaction. Specifically, we seek to test the hypothesis that an endotoxin induced inflammatory response in the immature lung triggers cytokine production in respiratory-related areas of the brainstem and resultant impairment of respiratory control. In our preliminary studies we demonstrated that rat pups exposed to intratracheal lipopolysaccharide (LPS) versus saline controls exhibited increased IL- 1b and IL-6 mRNA in the brainstem and that vagotomy decreased this brainstem response of IL- 1b mRNA to LPS exposure. We have additionally demonstrated the presence of IL-1b receptors in respiratory-related areas of the brainstem including the nucleus tractus solitarius, which serves as the first order central synapse for vagal afferents. Finally, we have documented a diminished ventilatory response to hypoxia in LPS versus saline exposed rat pups. In the current proposal we seek to characterize: the role of vagal afferents in modulation of brainstem cytokine expression in response to intrapulmonary LPS (Aim 1), the anatomical sites of cytokine message, protein and receptor expression in the brainstem (Aim 2) and the alteration of respiratory control associated with LPS-induced lung inflammation (Aim 3). All biochemical, anatomical, molecular and physiological studies will be performed in 10-12 day-old rat pups. The proposed studies will serve as the framework for future experiments to explore the role of brainstem cytokine production initiated by a peripheral inflammatory stimulus in modulating neurotransmitter pathways that regulate neonatal respiratory control.

Public Health Relevance

Inflammatory processes are a major cause of morbidity for both the developing brain and lung of preterm and term infants. In this proposal we seek to address the mechanism whereby lung inflammation in early life elicits an inflammatory response in the immature brain and resultant impairment of respiratory control.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21HL098628-02
Application #
8092652
Study Section
Respiratory Integrative Biology and Translational Research Study Section (RIBT)
Program Officer
Laposky, Aaron D
Project Start
2010-07-01
Project End
2012-06-30
Budget Start
2011-07-01
Budget End
2012-06-30
Support Year
2
Fiscal Year
2011
Total Cost
$196,250
Indirect Cost
Name
Case Western Reserve University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
Mayer, C A; Wilson, C G; MacFarlane, P M (2015) Changes in carotid body and nTS neuronal excitability following neonatal sustained and chronic intermittent hypoxia exposure. Respir Physiol Neurobiol 205:28-36
Jafri, Anjum; Belkadi, Abdelmadjid; Zaidi, Syed I A et al. (2013) Lung inflammation induces IL-1? expression in hypoglossal neurons in rat brainstem. Respir Physiol Neurobiol 188:21-8
Balan, Kannan V; Kc, Prabha; Mayer, Catherine A et al. (2012) Intrapulmonary lipopolysaccharide exposure upregulates cytokine expression in the neonatal brainstem. Acta Paediatr 101:466-71
Pozo, M E; Cave, A; Koroglu, O A et al. (2012) Effect of postnatal intermittent hypoxia on growth and cardiovascular regulation of rat pups. Neonatology 102:107-13
Balan, Kannan V; Kc, Prabha; Hoxha, Zana et al. (2011) Vagal afferents modulate cytokine-mediated respiratory control at the neonatal medulla oblongata. Respir Physiol Neurobiol 178:458-64
Martin, Richard J; Wang, Katherine; Koroglu, Ozge et al. (2011) Intermittent hypoxic episodes in preterm infants: do they matter? Neonatology 100:303-10
Gresham, Kenneth; Boyer, Brooke; Mayer, Catherine et al. (2011) Airway inflammation and central respiratory control: results from in vivo and in vitro neonatal rat. Respir Physiol Neurobiol 178:414-21