Airway remodeling in asthma involves increased fibrosis, airway smooth muscle (ASM) proliferation and migration. Inflammation drives remodeling, but ASM actively contributes by secreting factors, regulating extracellular matrix (ECM) composition and enhancing proliferation/migration. Accordingly, understanding mechanisms by which inflammation produces remodeling is key to novel therapeutic strategies. Our previous grant cycle highlighted the novel role of the neurotrophin brain-derived neurotrophic factor (BDNF), showing that BDNF enhances ASM [Ca2+]I and contractility, potentiating the effects of inflammation. Our studies now show that ASM is not only a target, but also a source of BDNF. The focus of the first renewal of this grant is to understand the autocrine/paracrine role of ASM-derived BDNF in inflammation-induced changes to airway structure and function in the context of asthma. Based on preliminary data, we believe that BDNF is a key player in remodeling. Here, BDNF may be linked to the matrix metalloproteinases (MMPs) MMP-2 and MMP-9, given their role in cleaving secreted BDNF, and limited data that BDNF conversely regulates MMPs. We propose that BDNF and MMPs form a mutually interactive, feed-forward loop stoked by inflammation, and that BDNF mediates and modulates inflammation effects on ECM production and ASM proliferation/migration. Relevant to asthma, preliminary data show that BDNF expression and effects on remodeling are enhanced in asthmatic human airway, and in a mouse model of allergic asthma. Accordingly, our overall hypothesis is that ASM-derived BDNF is central to inflammation-induced airway remodeling in asthma, affecting ECM composition and ASM proliferation and migration. In the proposed studies, we will test this theme via four Specific Aims:
Aim 1 : To examine mechanisms by which inflammation enhances expression and release in human airways;
Aim 2 : To examine the mechanisms by which potentiates inflammation effects on ECM production by human ASM;
Aim 3 : To examine ASM-derived BDNF ASM-derived BDNF the mechanisms by which ASM-derived BDNF potentiates inflammation effects on human ASM proliferation and migration;
Aim 4 : To examine in vivo effects of altered BDNF signaling on airway remodeling in a mixed allergen mouse model.
Aims 1 -3 will utilize human epithelium-denuded ASM tissues and cells from mild or moderate asthmatics vs. non-asthmatics to examine cytokine (TNF? vs. IL-13) enhancement of BDNF (Aim 1), overlapping vs. distinct signaling mechanisms by which mediates and modulates cytokine effects on MMP-2 and MMP-9, the ECM proteins fibronectin and collagen (Aim 2), and enhancement of ASM proliferation and migration in the setting of altered ECM composition (Aim 3). In vitro data will be integrated in vivo in Aim 4 in a mixed allergen mouse asthma model where BDNF receptor activation will be inhibited in a transgenic TrkB knockin mouse. The clinical significance of our studies lies in the potential that an "upstream" mechanism with pleiotropic effects on remodeling can be targeted to limit this irreversible feature of asthma. ASM-derived BDNF

Public Health Relevance

Diseases such as asthma involve complex, irreversible changes to the airway called remodeling. Such structural changes, driven by inflammation, involve increased deposition of proteins such as collagens, and increased cell number and distribution of smooth muscle cells. Our work suggests a critical role for a growth factor called brain-derived neurotrophic factor (BDNF) in mediating and modulating the effect of inflammation on remodeling. In this grant, we are proposing studies using human asthmatic airway tissue and animal models of asthma to study the mechanisms by which BDNF works on airway cells to enhance remodeling. We believe these studies are essential for development of novel therapeutic strategies to limit the detrimental effect of remodeling in diseases such as asthma and emphysema.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL088029-05A1
Application #
8634922
Study Section
Lung Cellular, Molecular, and Immunobiology Study Section (LCMI)
Program Officer
Banks-Schlegel, Susan P
Project Start
2007-04-01
Project End
2018-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
5
Fiscal Year
2014
Total Cost
$368,481
Indirect Cost
$136,732
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
Aravamudan, Bharathi; Thompson, Michael; Sieck, Gary C et al. (2016) Functional Effects of Cigarette Smoke-Induced Changes in Airway Smooth Muscle Mitochondrial Morphology. J Cell Physiol :
Vogel, Elizabeth R; Britt Jr, Rodney D; Faksh, Arij et al. (2016) Moderate hyperoxia induces extracellular matrix remodeling by human fetal airway smooth muscle cells. Pediatr Res :
Faksh, Arij; Britt Jr, Rodney D; Vogel, Elizabeth R et al. (2016) Effects of antenatal lipopolysaccharide and postnatal hyperoxia on airway reactivity and remodeling in a neonatal mouse model. Pediatr Res 79:391-400
Wang, Sheng-Yu; Freeman, Michelle R; Sathish, Venkatachalem et al. (2016) Sex Steroids Influence Brain-Derived Neurotropic Factor Secretion From Human Airway Smooth Muscle Cells. J Cell Physiol 231:1586-92
Britt Jr, Rodney D; Thompson, Michael A; Freeman, Michelle R et al. (2016) Vitamin D Reduces Inflammation-induced Contractility and Remodeling of Asthmatic Human Airway Smooth Muscle. Ann Am Thorac Soc 13 Suppl 1:S97-8
Sathish, Venkatachalem; Martin, Yvette N; Prakash, Y S (2015) Sex steroid signaling: implications for lung diseases. Pharmacol Ther 150:94-108
Wylam, Mark E; Sathish, Venkatachalem; VanOosten, Sarah Kay et al. (2015) Mechanisms of Cigarette Smoke Effects on Human Airway Smooth Muscle. PLoS One 10:e0128778
Martin, Yvette N; Manlove, Logan; Dong, Jie et al. (2015) Hyperoxia-induced changes in estradiol metabolism in postnatal airway smooth muscle. Am J Physiol Lung Cell Mol Physiol 308:L141-6
Britt Jr, Rodney D; Faksh, Arij; Vogel, Elizabeth R et al. (2015) Vitamin D attenuates cytokine-induced remodeling in human fetal airway smooth muscle cells. J Cell Physiol 230:1189-98
Britt Jr, Rodney D; Thompson, Michael A; Kuipers, Ine et al. (2015) Soluble guanylate cyclase modulators blunt hyperoxia effects on calcium responses of developing human airway smooth muscle. Am J Physiol Lung Cell Mol Physiol 309:L537-42

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