Deficiency of α7 Nicotinic Acetylcholine Receptor Attenuates Bleomycin-Induced Lung Fibrosis in Mice

Sun, Ping; Li, Ling; Zhao, Chengcheng; Pan, Mengyao; Zhou, Qian; Su, Xiao

doi:10.2119/molmed.2016.00083

Cited by 24 publications

(24 citation statements)

References 69 publications

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“…In our previous study, we found that ACh treatment in keratocytes activates mAChRs rather than nAChRs, in order to enhance keratocyte proliferation. Perhaps, the activation of mAChRs, rather than nAChRs, in keratocytes and corneal myofibroblasts leads to an anti‐fibrotic response, rather than a pro‐fibrotic one, as it has been reported for airways that activation of α7 nAChR is involved in the progression of lung fibrosis . Studies have shown contradicting results regarding the role of the mAChR antagonist atropine in fibrosis.…”

Section: Discussioncontrasting

confidence: 53%

“…The role of ACh in fibrosis has been investigated in airway diseases and in liver fibrosis, for which it has been shown that ACh is involved in ECM remodelling and proliferation of myofibroblasts, but no data exist on its possible role in corneal fibrosis. We have adapted an in vitro human corneal fibrosis model from Karamichos et al in order to study the role of ACh in the onset of fibrosis and its effect on the transition of fibroblasts to myofibroblasts.…”

Section: Discussionmentioning

confidence: 99%

“…We have also demonstrated that ACh induces proliferation of keratocytes and that it decreases keratocyte apoptosis in a Fas‐ligand apoptosis model . Research on the role of ACh in fibrosis has been mostly conducted on its role in airway diseases, for which it has been shown that stimulation of mAChRs may be involved in remodelling processes in chronic airway diseases and that α7 nAChR is a key regulator of lung fibrogenesis . It has also been shown that ACh induced collagen expression and proliferation of myofibroblasts in hepatic stellate cells …”

Section: Introductionmentioning

confidence: 99%

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Acetylcholine decreases formation of myofibroblasts and excessive extracellular matrix production in an in vitro human corneal fibrosis model

Słoniecka

Danielson

2020

J Cellular Molecular Medi

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Acetylcholine (ACh) has been reported to play various physiological roles, including wound healing in the cornea. Here, we study the role of ACh in the transition of corneal fibroblasts into myofibroblasts, and in consequence its role in the onset of fibrosis, in an in vitro human corneal fibrosis model. Primary human keratocytes were obtained from healthy corneas. Vitamin C (VitC) and transforming growth factor-β1 (TGF-β1) were used to induce fibrosis in corneal fibroblasts. qRT-PCR and ELISA analyses showed that gene expression and production of collagen I, collagen III, collagen V, lumican, fibronectin (FN) and alpha-smooth muscle actin (α-SMA) were reduced by ACh in quiescent keratocytes. ACh treatment furthermore decreased gene expression and production of collagen I, collagen III, collagen V, lumican, FN and α-SMA during the transition of corneal fibroblasts into myofibroblasts, after induction of fibrotic process. ACh inhibited corneal fibroblasts from developing contractile activity during the process of fibrosis, as assessed with collagen gel contraction assay. Moreover, the effect of ACh was dependent on activation of muscarinic ACh receptors. These results show that ACh has an anti-fibrotic effect in an in vitro human corneal fibrosis model, as it negatively affects the transition of corneal fibroblasts into myofibroblasts. Therefore, ACh might play a role in the onset of fibrosis in the corneal stroma.

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Section: Discussioncontrasting

confidence: 53%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Acetylcholine decreases formation of myofibroblasts and excessive extracellular matrix production in an in vitro human corneal fibrosis model

Słoniecka

Danielson

2020

J Cellular Molecular Medi

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“…It will be particularly insightful for at least three lung diseases where smoking may partly impact homeostasis: lung cancers, COPD, and COVID-19. (i) nAChRs single nucleotide polymorphisms (SNP) were associated to lung cancer cells [36,37] and nAChRs were shown to be involved in cancer cell proliferation and survival [38][39][40][41]. (ii) nAChRs SNPs were also associated with nicotine dependence and COPD [42][43][44][45][46].…”

Section: Discussionmentioning

confidence: 99%

Nicotinic receptors atlas in the adult human lung

Diabasana

Perotin-Collard

Belgacemi

et al. 2020

Preprint

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ABSTRACTNicotinic acetylcholine receptors (nAChRs) are pentameric ligand-gated ion channels responsible for the rapid neural and neuromuscular signal transmission. Although it is well documented that 16 subunits are encoded by the human genome, their presence in airway epithelial cells (AEC) remains poorly understood, and contribution to pathology is mainly discussed in the context of cancer. We analysed nAChR subunit expression in the human lung of smokers and non-smokers using transcriptomic data for whole lung tissues, isolated large AEC, and isolated small AEC. We identified differential expressions of nAChRs in terms of detection and repartition in the three modalities. Smoking-associated alterations were also unveiled. Then, we identified a nAChR transcriptomic print at a single cell level. Finally, we reported the localizations of detectable nAChRs in bronchi and large bronchioles. Thus, we compiled the first complete atlas of pulmonary nAChRs to open new avenues to further unravel the involvement of these receptors in lung homeostasis and respiratory diseases.

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“…In clinical trials, activation of α7nAChR was used to treat inflammatory diseases such as enteritis and rheumatoid arthritis [23], and inhibition of α7nAChR was used to attenuate tissue fibrosis related to inflammation [24]. The regulatory role of α7nAChR in tissue fibrosis and tissue repair has been related to changes in collagen content [25]. Our previous studies showed that an α7nAChR agonist (nicotine) prolonged normal gestation and inhibited collagen degradation and cervical ripening in pregnant murine.…”

Section: Introductionmentioning

confidence: 99%

Lipopolysaccharide-induced premature cervical ripening and inflammation in pregnant mice can be alleviated by nicotine

Han¹,

Ding²,

Lin³

et al. 2020

Preprint

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Background Clinical treatment of preterm birth (PTB) is usually dependent on inhibiting uterine contractions. Such therapy is only effective in the short-term and cannot fundamentally low the incidence of PTB. Premature cervical maturation is another important cause of PTB; it is associated with invasion of macrophages, which produce proinflammatory cytokines. We previously found that activation of the alpha-7 nicotinic acetylcholine receptor (α7nAChR) by nicotine alleviates the systemic inflammatory response in murine models of lipopolysaccharide (LPS)-induced PTB, but the underlying mechanisms remain unclear. Methods Cervical tissues were collected from women in preterm and term labor. An animal model of PTB was established by administering 25 µg/kg lipopolysaccharide (LPS) to normal pregnant C57BL/6 mice on gestational day 16 (GD16). PTB animals received 1 mg/kg of α7nAChR agonist nicotine or nicotine combined with 1 µg/kg α7nAChR antagonist α-bungarotoxin (α-BGT) from GD14 to GD17. The gestational age, the rates of preterm birth and the survival rate of pups were recorded. Immunofluorescence staining were utilized for the quantification of α7nAChR expression on cervical macrophages and changes in macrophage polarization, RT-PCR was used to determine the mRNA levels of M1 and M2 macrophage biomarkers. Elisa assay was used to detect changes in fetal inflammation. Immunofluorescence staining and western blotting were used to investigate the signaling pathways underlying nicotine’s promoting LPS-induced conversion of M1 macrophage to M2 in the cervix of PTB animals. Results α7nAChR expression on cervical macrophages and cervical collagen content was decreased in PTB patients and murine models of LPS-induced PTB. The number of M1 cervical macrophages, other pro-inflammatory mediators in the cervix and fetal inflammation was unregulated in pregnant mice following LPS administration. Nicotine treatment reduced the rate of PTB, decreased fetal inflammation, improved maternal and neonatal outcome; nicotine also increased polarization of cervical macrophages toward the anti-inflammatory M2 phenotype possibly by suppressing activation of the MAP kinases JNK and ERK1/2 and nuclear translocation of NF-κB and rescuing the inhibited JAK2/STAT3 and PI3K/AKT pathways. The effects of nicotine were reversed by the selective α7nAChR antagonist α-bungarotoxin (α-BGT). Conclusions Our findings indicate that nicotine prevents LPS-induced cervical ripening and inflammatory response by inducing M2 macrophage polarization, and nicotine may serve as potential anti-premature cervical maturation agents for treatment of PTB.

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Deficiency of α7 Nicotinic Acetylcholine Receptor Attenuates Bleomycin-Induced Lung Fibrosis in Mice

Cited by 24 publications

References 69 publications

Acetylcholine decreases formation of myofibroblasts and excessive extracellular matrix production in an in vitro human corneal fibrosis model

Acetylcholine decreases formation of myofibroblasts and excessive extracellular matrix production in an in vitro human corneal fibrosis model

Nicotinic receptors atlas in the adult human lung

Lipopolysaccharide-induced premature cervical ripening and inflammation in pregnant mice can be alleviated by nicotine

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