Nicotine Modulates Growth Factors and MicroRNA to Promote Inflammatory and Fibrotic Processes

Abstract

Idiopathic pulmonary fibrosis (IPF) is a fatal disease that destroys the structure and function of the lungs. Risk factors include advanced age and genetic predisposition. However, tobacco use is the chief modifiable risk factor. The prevalence of tobacco use in IPF reaches up to 80%. Although tobacco smoke contains over 5000 chemicals, nicotine is a major component. Nicotine is a bioactive molecule that acts upon nicotinic acetylcholine receptors expressed on neuronal and non-neuronal cells including endothelial cells. Accordingly, it has a pleiotropic effect on cell proliferation and angiogenesis. The angiogenic effect is partly mediated by stimulation of growth factors including fibroblast, platelet-derived, and vascular endothelial growth factors. Nintedanib, a Food and Drug Administration-approved drug for IPF, works by inhibiting receptors for these growth factors, suggesting a pathobiologic role of the growth factors in IPF and a potential mechanism by which tobacco use may exacerbate the disease process; additionally, nicotine downregulates anti-inflammatory microRNAs (miRs) in lung cells. Here, we profiled the expression of miRs in lung tissues explanted from a lung injury model and examined the effect of nicotine on one of the identified miRs (miR-24) and its downstream targets. Our data show that miR-24 is downregulated during lung injury and is suppressed by nicotine. We also found that nicotine upregulates the expression of inflammatory cytokines targeted by miR-24. Finally, nicotine stimulated growth factors, fibroblast proliferation, collagen release, and expression of myofibroblast markers. Taken together, nicotine, alone or as a component of tobacco smoke, may accelerate the disease process in IPF through stimulation of growth factors and downregulation of anti-inflammatory miRs.

Dysregulated repair and inflammatory responses by e‐cigarette‐derived inhaled nicotine and humectant propylene glycol in a sex‐dependent manner in mouse lung

“…A recent study showed an additional role of nicotine‐induced dysregulated growth factors and microRNAs that contribute to the development of pulmonary fibrosis, possibly via altered target genes involved in myogenesis . We found significantly altered sex‐dependent expression of both lipogenic/myogenic and ECM remodeling markers in the lungs of the acute e‐cig exposed mice.…”

“…23,55,56 A recent study showed an additional role of nicotine-induced dysregulated growth factors and microRNAs that contribute to the development of pulmonary fibrosis, possibly via altered target genes involved in myogenesis. 57 We found significantly altered sex-dependent expression of both lipogenic/myogenic and ECM remodeling markers in the lungs of the acute e-cig exposed mice. Based on findings from this acute e-cig exposure model, we speculate that chronic exposure of PG and/or PG with nicotine would also cause lung remodeling as a result of altered lipogenesis/myogenesis, including the activation of ECM signaling.…”

Angiotensin II Type I Receptor Antagonism Attenuates Nicotine-Induced Cardiac Remodeling, Dysfunction, and Aggravation of Myocardial Ischemia-Reperfusion Injury in Rats

“…Severe fibrosis evident from increased collagen deposition in nicotine-administered rats, may therefore account for impaired cardiac function observed in this study. Several in vitro studies have shown that nicotine directly increases fibroblast proliferation and collagen deposition via modulation of pro-fibrotic cytokines such as TGFβ, microRNAs, and matrix metalloproteinases (Shan et al, 2009;Khoi et al, 2013;Ebrahimpour et al, 2018). Indeed, TGFβ was widely implicated as a key signaling molecule responsible for nicotine-induced fibrosis in various organs and cells (Rezonzew et al, 2012;Ateyya et al, 2017).…”

MiR-199a-3p/5p participated in TGF-β and EGF induced EMT by targeting DUSP5/MAP3K11 in pterygium

“…MiR-199a-3p/5p was reported to suppress EMT in various cancer, such as testicular germ cell tumor, non-small cell lung cancer, head and neck cancer, and so on [ 31 – 33 ]. But they were also reported to promote the EMT process in hepatic fibrosis and idiopathic pulmonary fibrosis (IPF) [ 15 , 34 , 35 ]. These contradictory results suggest that miR-199a-3p/5p might have different functions in different types of EMT in various diseases.…”