Vitamin D Attenuates Cytokine‐Induced Remodeling in Human Fetal Airway Smooth Muscle Cells

Britt, Rodney D.; Faksh, Arij; Vogel, Elizabeth R.; Thompson, Michael A.; Chu, Vivian H.; Pandya, Hitesh; Amrani, Yassine; Martin, Richard J.; Pabelick, Christina M.; Prakash, Y. S.

doi:10.1002/jcp.24814

Cited by 40 publications

(45 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Treatment with calcitriol also attenuated TNF-α and TGF-β-induced collagen III expression and deposition and inhibited proliferation of fetal ASM cells mediated by the ERK signaling pathway. 31 Characterization of differences in transcriptome responsiveness to vitamin D between fatal asthma and control ASM cells by RNA sequencing have highlighted 838 differentially expressed genes in fatal asthma. Treatment with vitamin D was shown to induce differential expression of 711 genes in fatal asthma and 867 genes in control ASM cells.…”

Section: Results From Human Studiesmentioning

confidence: 99%

Vitamin D and Bronchial Asthma: An Overview of Data From the Past 5 Years

Hall

Agrawal

2017

Clinical Therapeutics

101

View full text Add to dashboard Cite

Vitamin D is a potent immunomodulator capable of dampening inflammatory signals in several cell types involved in the asthmatic response. Its deficiency has been associated with increased inflammation, exacerbations and overall worse outcomes in patients with asthma. Given the increase in the prevalence of asthma over the last few decades, there has been enormous interest in the use of vitamin D supplementation as a potential therapeutic option. Several studies have found that low serum levels of vitamin D (< 20 ng/ml) are associated with increased exacerbations, increased airway inflammation, decreased lung function and poor prognosis in asthmatic patients. Results from the in vitro and in vivo studies in animals and human have suggested that supplementation with vitamin D can ameliorate several hallmark features of asthma. However, the findings obtained from clinical trials are controversial and do not unequivocally support the beneficial role of vitamin D in asthma. Largely, interventional studies in children, pregnant women and adults have primarily found little-to-no effect of vitamin D supplementation on improved asthma symptoms, onset or progression of the disease. This could be related to the severity of the disease process and other confounding factors. Despite the conflicting data obtained from clinical trials, vitamin D deficiency does influence the inflammatory response in the airways. Further studies are needed to determine the exact mechanisms by which vitamin D supplementation may induce anti-inflammatory effects. Here, we critically reviewed the most recent findings from in vitro studies, animal models, and clinical trials regarding the role of vitamin D in bronchial asthma.

show abstract

Section: Results From Human Studiesmentioning

confidence: 99%

Vitamin D and Bronchial Asthma: An Overview of Data From the Past 5 Years

Hall

Agrawal

2017

Clinical Therapeutics

101

View full text Add to dashboard Cite

show abstract

“…Briefly, ASM cells were enzymatically dissociated from tracheobronchial tissue of de-identified non-viable 18–22 week gestation fetuses (Dr. Pandya or from Novogenix Los Angeles, CA; protocols approved and considered exempt by the Mayo Institutional Review Board and Ethics Committees in the UK). Persistence of smooth muscle phenotype was verified by expression of smooth muscle myosin and actin and Ca 2+ regulatory proteins, but lack of expression of E-cadherin (epithelial marker) [53, 54]. …”

Section: Methodsmentioning

confidence: 99%

cAMP-mediated secretion of brain-derived neurotrophic factor in developing airway smooth muscle

Thompson

Britt

Kuipers

et al. 2015

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

Self Cite

View full text Add to dashboard Cite

Moderate hyperoxic exposure in preterm infants contributes to subsequent airway dysfunction and to risk of developing recurrent wheeze and asthma. The regulatory mechanisms that can contribute to hyperoxia-induced airway dysfunction are still under investigation. Recent studies in mice show that hyperoxia increases brain-derived neurotrophic factor (BDNF), a growth factor that increases airway smooth muscle (ASM) proliferation and contractility. We assessed the mechanisms underlying effects of moderate hyperoxia (50% O2) on BDNF expression and secretion in developing human ASM. Hyperoxia increased BDNF secretion, but did not alter endogenous BDNF mRNA or intracellular protein levels. Exposure to hyperoxia significantly increased [Ca2+]i responses to histamine, an effect blunted by the BDNF chelator TrkB-Fc. Hyperoxia also increased ASM cAMP levels, associated with reduced PDE4 activity, but did not alter protein kinase A (PKA) activity or adenylyl cyclase mRNA levels. However, 50% O2 increased expression of Epac2, which is activated by cAMP and can regulate protein secretion. Silencing RNA studies indicated that Epac2, but not Epac1, is important for hyperoxia-induced BDNF secretion, while PKA inhibition did not influence BDNF secretion. In turn, BDNF had autocrine effects of enhancing ASM cAMP levels, an effect inhibited by TrkB and BDNF siRNAs. Together, these novel studies suggest that hyperoxia can modulate BDNF secretion, via cAMP-mediated Epac2 activation in ASM, resulting in a positive feedback effect of BDNF-mediated elevation in cAMP levels. The potential functional role of this pathway is to sustain BDNF secretion following hyperoxic stimulus, leading to enhanced ASM contractility and proliferation.

show abstract

“…The 1,25(OH) 2 D 3 was also able to downregulate the protein and mRNA expression of matrix metalloproteinase-9 (MMP-9) and a disintegrin metalloprotease-33 (ADAM-33), both of which play a role in airway remodeling and increased disease severity associated with allergic asthma [63]. The vitamin D 3 metabolite was also able to inhibit proliferation of fetal ASM cells induced by TNF-α and TGF-β via the ERK-mediated signaling pathway [64]. Treatment of human ASM cells with calcitriol inhibited platelet-derived growth factor (PDGF)-induced ASM growth by inhibiting phosphorylation of retinoblastoma protein (Rb) and checkpoint kinase 1 (Chk1).…”

Section: Vitamin D and Airway Smooth Muscle Cell Functionmentioning

confidence: 99%

“…Using human fetal ASM cells as a model of the early post natal airways, it was found that calcitriol attenuated TNF-α enhancement of MMP-9 expression and activity as well as TNF-α and TGF-β induced collagen II expression and deposition [64]. These mediators are known to contribute to epithelial-mesenchymal transition (EMT) and airway remodeling [66].…”

Section: Vitamin D and Airway Smooth Muscle Cell Functionmentioning

confidence: 99%

The impact of vitamin D on asthmatic human airway smooth muscle

Hall

Fischer

Agrawal

2015

Expert Review of Respiratory Medicine

View full text Add to dashboard Cite

Asthma is a chronic heterogeneous disorder, which involves airway inflammation, airway hyperresponsiveness (AHR) and airway remodeling. The airway smooth muscle (ASM) bundle regulates the broncho-motor tone and plays a critical role in AHR as well as orchestrating inflammation. Vitamin D deficiency has been linked to increased severity and exacerbations of symptoms in asthmatic patients. It has been shown to modulate both immune and structural cells, including ASM cells, in inflammatory diseases. Given that current asthma therapies have not been successful in reversing airway remodeling, vitamin D supplementation as a potential therapeutic option has gained a great deal of attention. Here, we highlight the potential immunomodulatory properties of vitamin D in regulating ASM function and airway inflammation in bronchial asthma.

show abstract

Vitamin D Attenuates Cytokine‐Induced Remodeling in Human Fetal Airway Smooth Muscle Cells

Cited by 40 publications

References 40 publications

Vitamin D and Bronchial Asthma: An Overview of Data From the Past 5 Years

Vitamin D and Bronchial Asthma: An Overview of Data From the Past 5 Years

cAMP-mediated secretion of brain-derived neurotrophic factor in developing airway smooth muscle

The impact of vitamin D on asthmatic human airway smooth muscle

Contact Info

Product

Resources

About