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MicroRNA-98 reduces nerve growth factor expression in nicotine-induced airway remodeling
Journal article   Peer reviewed

MicroRNA-98 reduces nerve growth factor expression in nicotine-induced airway remodeling

Cherry Wongtrakool, Junsuk Ko, Andrew J Jang, Kora Grooms, Sarah Chang, Cory Sylber, Beata Kosmider, Karim Bahmed, Michael R Blackburn, Roy L Sutliff, …
The Journal of biological chemistry, Vol.295(52), pp.18051-18064
12/25/2020
DOI: 10.1074/jbc.RA119.012019
PMID: 33082140
url
https://doi.org/10.1074/jbc.RA119.012019View
Published (Version of record) Open Access

Abstract

Evolving evidence suggests that nicotine may contribute to impaired asthma control by stimulating expression of nerve growth factor (NGF), a neurotrophin associated with airway remodeling and airway hyperresponsiveness. We explored the hypothesis that nicotine increases NGF by reducing lung fibroblast (LF) microRNA-98 (miR-98) and PPARγ levels, thus promoting airway remodeling. Levels of NGF, miR-98, PPARγ, fibronectin 1 (FN1), endothelin-1 (EDN1, herein referred to as ET-1), and collagen (COL1A1 and COL3A1) were measured in human LFs isolated from smoking donors, in mouse primary LFs exposed to nicotine (50 μg/ml), and in whole lung homogenates from mice chronically exposed to nicotine (100 μg/ml) in the drinking water. In selected studies, these pathways were manipulated in LFs with miR-98 inhibitor (anti-miR-98), miR-98 overexpression (miR-98 mimic), or the PPARγ agonist rosiglitazone. Compared with unexposed controls, nicotine increased NGF, FN1, ET-1, COL1A1, and COL3A1 expression in human and mouse LFs and mouse lung homogenates. In contrast, nicotine reduced miR-98 levels in LFs and in lung homogenates Treatment with anti-miR-98 alone was sufficient to recapitulate increases in NGF, FN1, and ET-1, whereas treatment with a miR-98 mimic significantly suppressed luciferase expression in cells transfected with a luciferase reporter linked to the putative seed sequence in the NGF 3'UTR and also abrogated nicotine-induced increases in NGF, FN1, and ET-1 in LFs. Similarly, rosiglitazone increased miR-98 and reversed nicotine-induced increases in NGF, FN1, and ET-1. Taken together, these findings demonstrate that nicotine-induced increases in NGF and other markers of airway remodeling are negatively regulated by miR-98.
 Airway Remodeling Animals Fibroblasts - drug effects Fibroblasts - metabolism Fibroblasts - pathology Gene Expression Regulation - drug effects Humans Male Mice Mice, Inbred C57BL MicroRNAs - genetics Nerve Growth Factor - genetics Nerve Growth Factor - metabolism Nicotine - toxicity Nicotinic Agonists - toxicity PPAR gamma Respiratory Hypersensitivity - chemically induced Respiratory Hypersensitivity - metabolism Respiratory Hypersensitivity - pathology

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