Zinc metabolism in airway epithelium and airway inflammation: basic mechanisms and clinical targets. A review

Zalewski, Peter D.; Truong-Tran, Ai Q.; Grosser, Dion; Jayaram, Lata; Murgia, Chiara; Ruffin, Richard E.

doi:10.1016/j.pharmthera.2004.09.004

Cited by 174 publications

(165 citation statements)

References 168 publications

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“…The regulation of Zn homeostasis in bronchial epithelial cell lines has been extensively investigated. 43 It is intriguing to speculate that the increase of [Ca 2+ ] i may be associated with increased ROS production and oxidative stress 44 followed by the activation of (85) 17 (2) 5 (2) a Standard deviation. an antioxidant response such as increased expression of the metallothioneins that has been reported in IB3-1 cells following treatments aimed at restoring CFTR function.…”

Section: Paper Molecular Biosystemsmentioning

confidence: 99%

Proteomic and ionomic profiling reveals significant alterations of protein expression and calcium homeostasis in cystic fibrosis cells

et al. 2013

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Cystic fibrosis (CF) is an autosomal recessive disorder associated with mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene and defective chloride transport across the epithelial cell membranes. Abnormal epithelial ion transport is the primary cause of persistent airway infections and chronic inflammation in CF patients. In order to gain further insight into the mechanisms of epithelial dysfunctions linked to CFTR mutations, we performed and integrated proteomic and ionomic analysis of human bronchial epithelial IB3-1 cells and compared them with a CFTR-complemented isogenic cell line (C38). Aside from changes that were consistent with known effects related to CFTR mutations, such as differences in glycolytic and gluconeogenic pathways and unfolded protein responses, differential proteomics highlighted significant alteration of protein expression and, in particular, of the 14-3-3 signalling pathway that is known to be involved in cellular calcium (Ca) homeostasis. Of note, restoring chloride efflux by acting on Ca cellular homeostasis has been shown to be a promising therapeutic intervention for CF. Ionomic analysis showed significant changes in the IB3-1 element profile compared with C38 cells and in particular we observed an increase of intracellular Ca that significantly correlates with intracellular zinc (Zn) levels, suggesting a synergistic role of Ca and Zn influx. This finding is particularly intriguing because Zn has been reported to be effective in CF treatment increasing Ca influx. Taken together, our proteomic and ionomic data reveal that CFTR mutation sets in motion endogenous mechanisms counteracting impaired chloride transport mainly acting on epithelial ion transport and increasing intracellular Ca, suggesting potential links between protein expression and this response

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Section: Paper Molecular Biosystemsmentioning

confidence: 99%

Proteomic and ionomic profiling reveals significant alterations of protein expression and calcium homeostasis in cystic fibrosis cells

et al. 2013

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“…It is a co-factor for at least 300 known enzymes including several key antioxidants, and is vital for the function of thousands of transcription factors; as such it is critically involved in cell growth, differentiation, and function (14,15). Although zinc deficiency is known to impact function in the ciliated epithelium within the upper airway (14,16), there is very little known about zinc homeostasis within the alveolar space. Further, although alcohol abuse has long been associated with zinc deficiency, the mechanisms for and the potential impact of this zinc deficiency have not been systematically examined.…”

Section: Abstract: Gm-csf; Phagocytosis; Tight Junctions; Zinc Transpmentioning

confidence: 99%

“…Further, although alcohol abuse has long been associated with zinc deficiency, the mechanisms for and the potential impact of this zinc deficiency have not been systematically examined. Based on the evolving understanding of the critical role of zinc in maintaining normal epithelial and immune function (13,16,17), alcohol-induced zinc deficiency within the alveolar space would have severe consequences for lung health (16).…”

Section: Abstract: Gm-csf; Phagocytosis; Tight Junctions; Zinc Transpmentioning

confidence: 99%

Zinc Deficiency Mediates Alcohol-Induced Alveolar Epithelial and Macrophage Dysfunction in Rats

Joshi¹,

Mehta²,

Jabber³

et al. 2009

Am J Respir Cell Mol Biol

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Chronic alcohol abuse impairs both alveolar epithelial and macrophage function, and renders individuals susceptible to acute lung injury, pneumonia, and other serious lung diseases. Zinc deficiency, which is known to impact both epithelial and immune cell functions, is also associated with alcohol abuse. In this study, chronic alcohol ingestion (6 wk) in rats altered expression of key zinc transporters and storage proteins in the small intestine and the lung, and decreased zinc levels in the alveolar compartment. Zinc supplementation of alveolar epithelial monolayers derived from alcohol-fed rats in vitro, or of the diets of alcohol-fed rats in vivo, restored alveolar epithelial barrier function, and these improvements were associated with salutary changes in tight junction protein expression and membrane localization. In parallel, dietary zinc supplementation increased intracellular zinc levels, GM-CSF receptor expression, and bacterial phagocytic capacity in the alveolar macrophages of alcoholfed rats. Together, these studies implicate zinc deficiency as a novel mechanism mediating alcohol-induced alveolar epithelial and macrophage dysfunction. Importantly, these findings argue that dietary supplementation can overcome alcohol-induced zinc deficiency and restore alveolar epithelial and macrophage function, and therefore could be an effective treatment for the susceptible alcoholic lung phenotype.

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“…Decreased zinc content was also described in post-mortem pancreata of diabetic individuals over 75 years ago (Scott and Fisher 1938), and the role of this metal ion in insulin secretion and glucose homeostasis was confirmed since then by several reports (Chimienti 2013;Sladek et al 2007). Airways inflammation, one of the main hallmarks of asthma, has also been associated with deregulated zinc homeostasis (Zalewski et al 2005). Gut mucosal integrity also requires zinc, and zinc dyshomeostasis has been associated with several intestinal pathologies.…”

Section: Introductionmentioning

confidence: 94%

“…It is especially enriched in protein-rich foods such as meat, seafood and legumes. The World Health Organization (WHO) recommends a daily zinc intake of 10 mg/day for children, 12 mg/day for women and 15 mg/day for men (WHO and Organization 1996). Specific population groups such as children and adolescents, pregnant women and the elderly display higher zinc requirements and a corresponding increased risk of deficiency.…”

Section: Introductionmentioning

confidence: 99%

Zinc proteome interaction network as a model to identify nutrient-affected pathways in human pathologies

et al. 2014

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Zinc is an essential micronutrient playing fundamental roles in cellular metabolism. It acts mostly through binding a wide range of proteins, thus affecting a broad spectrum of biological processes, which include cell division, growth and differentiation. Full annotation of zinc-binding proteins showed them to represent about 10 % of the human proteome, with over 300 enzymes containing zinc ions within their catalytic domains. Also, hundreds of key regulatory proteins, including transcription factors, require zinc for their activity. In this study, the whole set of zinc-binding proteins together with their direct interactors was listed and defined as the zinc proteome (ZNP). We interrogated pathway analysis tools to identify the cellular processes that are predicted to be affected by zinc availability. Network and functional enrichment analyses highlighted biological processes potentially affected by deregulated zinc homeostasis. This computational approach was also tested on a real case study: The possible involvement of ZNP network proteins in Crohn's disease pathogenesis was assessed on genes transcriptionally regulated in the intestine of patients affected by this condition. The analysis produced a network of pathways likely to be influenced by zinc and associated with Crohn's disease. These results highlight a central role for zinc in the tissue remodeling process which occurs upon gut inflammation, pointing at novel disease pathways whose effect could be worsened by zinc dyshomeostasis and impaired zinc fluxes in specific damaged areas. Overall, our computational approach could provide novel insights into pathological conditions and could therefore be used to drive mechanistic research in under-investigated fields of research. An interactive version of the determined ZNP network is available at URL http://93.63.165.11/ZNnetwork/.

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Zinc metabolism in airway epithelium and airway inflammation: basic mechanisms and clinical targets. A review

Cited by 174 publications

References 168 publications

Proteomic and ionomic profiling reveals significant alterations of protein expression and calcium homeostasis in cystic fibrosis cells

Proteomic and ionomic profiling reveals significant alterations of protein expression and calcium homeostasis in cystic fibrosis cells

Zinc Deficiency Mediates Alcohol-Induced Alveolar Epithelial and Macrophage Dysfunction in Rats

Zinc proteome interaction network as a model to identify nutrient-affected pathways in human pathologies

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