Supplemental oxygen (hyperoxia) administered to an immature respiratory system following preterm birth is a major risk factor for neonatal lung injury. For survivors of this critical period, the major short-term and long- term health problem remains chronic airway disease manifested as wheezing, asthma, and increased risk of respiratory infection. The long term goal of our studies is to understand mechanisms that contribute to hyperoxia-induced hyperresponsiveness of the immature airway. In previous grant cycles, we established that moderate (50%) hyperoxia in early postnatal development enhances bronchoconstriction, while impairing bronchodilation. The current proposal focuses on mechanisms underlying hyperoxia-induced enhancement of airway tone and constriction. Recent studies in adult airway suggest a role for the neurotrophin brain-derived neurotrophic factor (BDNF) and its receptor TrkB in local control of airway structure and function, especially via effects on airway smooth muscle (ASM). The role of BDNF in developing airway (or with insults such as hyperoxia) is still under investigation. Preliminary studies show that in developing airway, BDNF enhances [Ca2+]i/contractility of fetal ASM. Furthermore, hyperoxia increases BDNF generation/secretion by ASM, and enhances pro-contractile and pro-proliferative effects of BDNF. Accordingly, we believe that BDNF is a key player in hyperoxia-induced increase in tone and reactivity of developing airway. The current proposal focuses on understanding regulation of BDNF and its effects in developing airway. Here, cGMP and cAMP are proposed to normally have opposing effects on BDNF while hyperoxia alters cyclic nucleotide levels such that BDNF levels are allowed to rise. Based on preliminary data, we propose that hyperoxia and BDNF interact to enhance bronchoconstriction via the following mechanisms: 1) Hyperoxia decreases ASM cGMP but increases cAMP, disrupting normal cyclic nucleotide control of BDNF and allowing BDNF production/secretion to rise;2) via TrkB receptors, increased BDNF has autocrine/paracrine effects of enhancing bronchoconstriction by increasing ASM [Ca2+]i and sensitivity for force generation;3) separately, BDNF and hyperoxia enhance ASM cell proliferation contributing to airway remodeling;4) hyperoxia-triggered increase in BDNF serves to initiate and maintain increased airway tone and reactivity. We propose the following Specific Aims:
Aim 1 : In developing ASM, determine mechanisms by which hyperoxia increases BDNF;
Aim 2 : In developing ASM, determine role of BDNF in hyperoxia-induced enhancement of contractility;
Aim 3 : In developing ASM, determine role of BDNF in hyperoxia-induced enhancement of cell proliferation;
Aim 4 : In a mouse with altered TrkB signaling, determine role of BDNF in neonatal airway hyperresponsiveness. We will use novel in vitro models (human fetal ASM, neonatal mouse bronchial ring and living lung slice) and in vivo neonatal hyperoxia applied to a transgenic TrkB """"""""knock-in"""""""" (TrkB-KI) mouse. The clinical significance of our studies lies in focus on a novel mechanism with therapeutic potential for chronic lung diseases of newborns and beyond.

Public Health Relevance

Babies born prematurely often require substantial respiratory support to overcome the critical period while their immature lungs continue to develop. Supplemental oxygen (hyperoxia) administered to an immature respiratory system following preterm birth is a major risk factor for neonatal lung injury. Furthermore, for survivors of this critical period, chronic airway diseases such as wheezing and asthma remain major health problems throughout childhood and beyond. The primary goal of this proposal is to understand how the initial exposure to high levels of oxygen affects structure and function of the developing airway. We are focusing on the novel idea that growth factors called neurotrophins (specifically brain-derived neurotrophic factor) are key contributors. Our investigations will not only further our understanding of the role of such factors in early airway development, but also open up new therapeutic strategies to interfere with the detrimental effects of oxygen exposure.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
3R01HL056470-13S1
Application #
8849555
Study Section
Lung Cellular, Molecular, and Immunobiology Study Section (LCMI)
Program Officer
Lin, Sara
Project Start
1996-05-03
Project End
2016-07-31
Budget Start
2014-06-01
Budget End
2014-07-31
Support Year
13
Fiscal Year
2014
Total Cost
$6,486
Indirect Cost
$2,407
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
Cheon, In Su; Son, Young Min; Jiang, Li et al. (2018) Neonatal hyperoxia promotes asthma-like features through IL-33-dependent ILC2 responses. J Allergy Clin Immunol 142:1100-1112
Han, MeiLan K; Arteaga-Solis, Emilio; Blenis, John et al. (2018) Female Sex and Gender in Lung/Sleep Health and Disease. Increased Understanding of Basic Biological, Pathophysiological, and Behavioral Mechanisms Leading to Better Health for Female Patients with Lung Disease. Am J Respir Crit Care Med 198:850-858
Di Fiore, Juliann M; Dylag, Andrew M; Honomichl, Ryan D et al. (2018) Early inspired oxygen and intermittent hypoxemic events in extremely premature infants are associated with asthma medication use at 2 years of age. J Perinatol :
Martin, Richard J (2018) The unfortunate tale of immature respiratory control superimposed on an immature lung. Pediatr Res 84:153-154
Vogel, Elizabeth R; Britt Jr, Rodney D; Faksh, Arij et al. (2017) Moderate hyperoxia induces extracellular matrix remodeling by human fetal airway smooth muscle cells. Pediatr Res 81:376-383
Prakash, Y S; Pabelick, Christina M; Sieck, Gary C (2017) Mitochondrial Dysfunction in Airway Disease. Chest 152:618-626
Aravamudan, Bharathi; Goorhouse, Katelyn J; Unnikrishnan, Ghanashyam et al. (2017) Differential Expression of Estrogen Receptor Variants in Response to Inflammation Signals in Human Airway Smooth Muscle. J Cell Physiol 232:1754-1760
Freeman, Michelle R; Sathish, Venkatachalem; Manlove, Logan et al. (2017) Brain-derived neurotrophic factor and airway fibrosis in asthma. Am J Physiol Lung Cell Mol Physiol 313:L360-L370
Britt Jr, Rodney; Prakash, Y S (2017) The -Omic Approach to Understanding Glucocorticoid Effects in Smooth Muscle: Diving for Pearls. Am J Respir Cell Mol Biol 57:147-148
Aravamudan, Bharathi; Thompson, Michael; Sieck, Gary C et al. (2017) Functional Effects of Cigarette Smoke-Induced Changes in Airway Smooth Muscle Mitochondrial Morphology. J Cell Physiol 232:1053-1068

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