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

Abstract

Evolving evidence suggests nicotine may contribute to impaired asthma control by stimulating expression of nerve growth factor (NGF), a neurotrophin associated with airway remodeling and airway hyperresponsiveness (AHR). 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 (ET-1), and collagen (COL1A1, and COL3A1) were measured in human LFs isolated from smoking donors, in mouse primary lung fibroblasts (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 to 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 in vitro and in lung homogenates in vivo. Treatment with anti-miR-98 alone was sufficient to recapitulate increases in NGF, FN1, and ET-1, while 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.

Cucurbitacin E ameliorates airway remodelling by inhibiting nerve growth factor expression in nicotine‐treated bronchial epithelial cells and mice: The key role of let‐7c‐5p up‐regulated expression

“…For example, miR-98 attenuates nicotine-induced airway remodelling by suppressing NGF. 14 In the current study, the expression of 78 miRs showed significant changes in nicotine-treated BECs in comparison with those in control BECs, which contributed to the alternatives in different biological functions. We selected let-7c-5p as a candidate target to mediate the function of CuE based on RT-qPCR detection.…”

“…Previous studies have demonstrated that the progression of airway remodelling is always associated with the down‐regulation of let‐7c‐5p 12,13,23 . Moreover, the downstream effector of let‐7c‐5p, NGF, is well characterized for its promotive effect on airway remodelling 14,24 . Thus, the level of let‐7c‐5p induced by CuE in nicotine‐treated BECs and mice may explain the protective effects of the compound: the up‐regulation of let‐7c‐5p contributed to the down‐regulation of NGF, which attenuated nicotine‐induced airway remodelling.…”

Nerve Growth Factor: A Potential Therapeutic Target for Lung Diseases

“…In lung fibroblasts, the pro-fibrotic effects of NGF are inhibited because transforming growth factor-β1 (TGF-β1)-induced miR-455-3p limits the production of NGF [24]. Moreover, the increase in the levels of NGF and other markers of nicotine-induced airway remodeling is negatively regulated by miRNA-98 [25]. Overexpression of miR-221 is related to maximal downregulation of NGF and its TrkA receptor at both the mRNA and protein levels [26].…”

The PPARα and PPARγ Epigenetic Landscape in Cancer and Immune and Metabolic Disorders

“…A well-known cause of asthma is exposure to nicotine. Human primary lung fibroblasts from smokers and mouse primary lung fibroblasts from mice exposed to nicotine both show reduced PPARγ protein levels [ 87 ]. In the nicotine-exposed mice, treatment with the PPARγ pathway activator rosiglitazone restores the expression level of miR-98, a miRNA that negatively regulates the expression of airway remodelling proteins associated with collagen deposition and fibrosis [ 87 ].…”

“…Human primary lung fibroblasts from smokers and mouse primary lung fibroblasts from mice exposed to nicotine both show reduced PPARγ protein levels [ 87 ]. In the nicotine-exposed mice, treatment with the PPARγ pathway activator rosiglitazone restores the expression level of miR-98, a miRNA that negatively regulates the expression of airway remodelling proteins associated with collagen deposition and fibrosis [ 87 ]. Similarly, pioglitazone-mediated PPARγ activation in rats inhibits airway smooth muscle cell proliferation and remodelling by supressing the Smad-TGFβ1-miR-21 signalling pathway [ 88 ].…”