Nicotine and fibronectin expression in lung fibroblasts: implications for tobacco‐related lung tissue remodeling

Roman, Jesse; Ritzenthaler, Jeffrey D.; Gil-Acosta, Alcides; Rivera, Hilda N.; Roser‐Page, Susanne

doi:10.1096/fj.03-0826fje

Cited by 97 publications

(93 citation statements)

References 60 publications

(69 reference statements)

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“…In these mice, immunohistochemical studies and luciferase detection revealed a pattern of luciferase expression in lung reminiscent of that shown by the endogenous fibronectin gene at baseline and after stimulation with nicotine. 3 We have previously reported that nicotine stimulates fibronectin expression in lung and in cultured primary lung fibroblasts (13). As expected, primary lung fibroblasts isolated from the transgenic animals showed increased expression of luciferase driven by the human fibronectin promoter when exposed to nicotine (14).…”

Section: Generation Of Mice Transgenic For the Human Fibronectin Promsupporting

confidence: 60%

Epithelial-derived Fibronectin Expression, Signaling, and Function in Intestinal Inflammation

Kolachala

Bajaj

Wang

et al. 2007

Journal of Biological Chemistry

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Fibronectin (FN) is a multifunctional extracellular matrix protein that plays an important role in cell proliferation, adhesion, and migration. FN expression or its role in colitis is not known. The goal of this study is to characterize FN expression, regulation, and role during intestinal inflammation. Wild-type and transgenic mice expressing luciferase under the control of the human FN promoter, given water or 3% dextran sodium sulfate, were used as animal models of colitis. The Caco2-BBE model intestinal epithelial cell line was used for in vitro studies. Mucosal tissue damage requiring efficient wound healing is a cardinal feature of inflammatory bowel disease as well as other intestinal inflammatory conditions, including radiation enteritis, chronic ischemic enteritis, and cystic fibrosis. Inappropriate or ineffective tissue repair underlies the persistence of disease symptoms and results in complications such as fibrosis or fistula formation. Epithelial response to injury is a complex process and cell-matrix interactions play important roles in the healing response. Extracellular matrix (ECM) 2 proteins such as fibronectin (FN), collagen, and laminin have been demonstrated to play a critical role in the wound healing process. In this study, we examined the expression and role of fibronectin in intestinal inflammation.FN is a high molecular weight adhesive glycoprotein that is found in basement membrane, lamina propria, and connective tissue matrices in the intestine (insoluble form) and in body fluids (soluble form). FN usually exists as a dimer composed of two nearly identical ϳ250-kDa subunits linked covalently near their C termini by a pair of disulfide bonds (1, 2). Each monomer is an extended and flexible molecule that is folded in a series of repeating protein domains known as type I, II, and III repeats. These domains are resistant to proteolysis and contain binding sites for other ECM proteins (e.g. collagen), cell-surface receptors (integrins), blood protein derivatives (fibrin), and glycosaminoglycans (heparin). There are more than 20 splice variants of FN. FN exists mainly in two forms, soluble plasma FN and less soluble cellular FN. Plasma FN is synthesized predominantly in the liver by hepatocytes and forms a soluble FN dimer as compared with tissue FN, which forms disulfide cross-linked fibrils and is deposited as a matrix.FN is widely expressed by multiple cell types and is critically important in vertebrate development, as demonstrated by the early embryonic lethality of mice with targeted inactivation of the FN gene (3). FN mediates a wide variety of cellular interactions with the ECM and plays important roles in cell adhesion, migration, growth, and differentiation (4, 5). Thus, not surprisingly, altered deposition of FN matrix has been correlated with several pathological states. For example, increased deposition of an FN-rich matrix has been associated with atherosclerosis and fibrosis, while restoration of FN matrix assembly in transformed cells has been correlated with a reduction in ...

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Section: Generation Of Mice Transgenic For the Human Fibronectin Promsupporting

confidence: 60%

Epithelial-derived Fibronectin Expression, Signaling, and Function in Intestinal Inflammation

Kolachala

Bajaj

Wang

et al. 2007

Journal of Biological Chemistry

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“…Fibronectin is usually mesenchymal in origin but also has been described in the epithelium during branching morphogenesis (22a). Fibronectin expression in fetal lung fibroblasts already has been shown to increase with exposure to nicotine through ␣ 7 nAChR-mediated signals (22). We found that both nicotine treatment of lung explant cultures in vitro and prenatal nicotine exposure in vivo results in increased fibronectin expression in the pseudoglandular stage lung.…”

Section: Discussionmentioning

confidence: 54%

“…Fibronectin is a known morphogen that is found in the branching clefts and is considered essential for proper branching (18, 22a). Interestingly, nicotine has been shown to stimulate fibronectin expression in fetal and adult lung fibroblasts (22). Thus we tested the effects of nicotine on fibronectin in our lung explant model.…”

Section: Distribution Of ␣mentioning

confidence: 99%

“…These ligand-gated ion channels represent the most common homomeric form of nAChRs in the body, and although their expression is highest in the central nervous system and muscle, they have been detected in fetal and adult lungs and in other organs (4). ␣ 7 nAChRs mediate the stimulatory effects of nicotine on matrix expression in lung fibroblasts (22). ␣ 7 nAChRs are also under transcriptional regulation by thyroid transcription factor (TTF-1), a transcription factor essential for the development of the lung (17).…”

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confidence: 99%

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Nicotine alters lung branching morphogenesis through the α₇ nicotinic acetylcholine receptor

Wongtrakool

Roser‐Page²,

Rivera³

et al. 2007

American Journal of Physiology-Lung Cellular and Molecular Phys

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There is abundant epidemiological data linking prenatal environmental tobacco smoke with childhood asthma and wheezing, but the underlying molecular and physiological mechanisms that occur in utero to explain this link remain unelucidated. Several studies suggest that nicotine, which traverses the placenta, is a causative agent. Therefore, we studied the effects of nicotine on lung branching morphogenesis using embryonic murine lung explants. We found that the expression of α7 nicotinic acetylcholine receptors, which mediate many of the biological effects of nicotine, is highest in pseudoglandular stage lungs compared with lungs at later stages. We then studied the effects of nicotine in the explant model and found that nicotine stimulated lung branching in a dose-dependent fashion. α-Bungarotoxin, an antagonist of α7 nicotinic acetylcholine receptors, blocked the stimulatory effect of nicotine, whereas GTS-21, a specific agonist, stimulated branching, thereby mimicking the effects of nicotine. Explants deficient in α7 nicotinic acetylcholine receptors did not respond to nicotine. Nicotine also stimulated the growth of the explant. Altogether, these studies suggest that nicotine stimulates lung branching morphogenesis through α7 nicotinic acetylcholine receptors and may contribute to dysanaptic lung growth, which in turn may predispose the host to airway disease in the postnatal period.

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“…Evidence that active CHRNA7 can induce lung fibroblast and regulate lung inflammation also supports it may involve the development of both diseases. 30,31 In the current study, we found that the ≥ 4-copy of CNV-3956 that duplicates the CHRNA7 gene conferred increased risks and poor prognoses of lung cancer and COPD, underlying a possible biological mechanism by increasing CHRNA7 expression and inducing carriers to consume more cigarettes because individuals with higher CHRNA7 expressions would be more nicotine sensitive. A challenge on this mechanism is that the loss genotype of CNV-32018, which we did not test due to technical limitation, would possibly induce exon deletion of CHRNA7 and nonfunctional CHRNA7, and thus the ≥ 4-copy of CNV-3956 may cause a upregulation of nonfunctional CHRNA7.…”

Section: Discussionmentioning

confidence: 55%

Duplicated copy of CHRNA7 increases risk and worsens prognosis of COPD and lung cancer

Yang

Qiu

et al. 2014

Eur J Hum Genet

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Recent genome-wide association studies implicated that the nicotinic acetylcholine receptors (nAChRs) are common susceptible genes of two contextual diseases: chronic obstructive pulmonary disease (COPD) and lung cancer. We aimed to test whether the copy number variations (CNVs) in nAChRs have hereditary contributions to development of the two diseases. In two, two-stage, case-control studies of southern and eastern Chinese, a common CNV-3956 that duplicates the cholinergic receptor, nicotinic, α7 (CHRNA7) gene was genotyped in a total of 7880 subjects and its biological phenotype was assessed. The ≥ 4-copy of CNV-3956 increased COPD risk (≥4-copy vs 2/3-copy: OR = 1.44, 95% CI = 1.23-1.68) and caused poor lung function, and it similarly augmented risk (OR = 1.49, 95% CI = 1.29-1.73) and worsened prognosis (hazard ratio (HR) = 1.25, 95% CI = 1.07-1.45) of lung cancer. The ≥ 4-copy was estimated to account for 1.56% of COPD heritability and 1.87% of lung cancer heritability, respectively. Phenotypic analysis further showed that the ≥ 4-copy of CNV-3956 improved CHRNA7 expression in vivo and increased the carriers' smoking amount. The CNV-3956 of CHRNA7 contributed to increased risks and poor prognoses of both COPD and lung cancer, and this may be a genetic biomarker of the two diseases.

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Nicotine and fibronectin expression in lung fibroblasts: implications for tobacco‐related lung tissue remodeling

Cited by 97 publications

References 60 publications

Epithelial-derived Fibronectin Expression, Signaling, and Function in Intestinal Inflammation

Epithelial-derived Fibronectin Expression, Signaling, and Function in Intestinal Inflammation

Nicotine alters lung branching morphogenesis through the α₇ nicotinic acetylcholine receptor

Duplicated copy of CHRNA7 increases risk and worsens prognosis of COPD and lung cancer

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Nicotine and fibronectin expression in lung fibroblasts: implications for tobacco‐related lung tissue remodeling

Cited by 97 publications

References 60 publications

Epithelial-derived Fibronectin Expression, Signaling, and Function in Intestinal Inflammation

Epithelial-derived Fibronectin Expression, Signaling, and Function in Intestinal Inflammation

Nicotine alters lung branching morphogenesis through the α7 nicotinic acetylcholine receptor

Duplicated copy of CHRNA7 increases risk and worsens prognosis of COPD and lung cancer

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Nicotine alters lung branching morphogenesis through the α₇ nicotinic acetylcholine receptor