Early Events in Naphthalene-Induced Acute Clara Cell Toxicity

Plopper, Charles G.; Winkle, Laura S. Van; Fanucchi, Michelle V.; Malburg, S. R C; Nishio, Susan J.; Chang, Andrew; Buckpitt, Alan R.

doi:10.1165/ajrcmb.24.3.4247

Cited by 63 publications

(23 citation statements)

References 19 publications

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“…11 Consistent with this idea, previous publications have suggested the existence of different subpopulations of Clara cells. 9,28,29 Conversely, the presence of CCSP protein, whether derived from the donor CCSP + BMC or surviving host CCSP + cells, may play a role in increasing survival given previous publications that suggest protective roles of CCSP in oxidative stress and inflammation. 2,10,30,31 …”

Section: Discussionmentioning

confidence: 99%

Bone Marrow Cells Expressing Clara Cell Secretory Protein Increase Epithelial Repair After Ablation of Pulmonary Clara Cells

et al. 2013

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We have previously reported a subpopulation of bone marrow cells (BMC) that express Clara cell secretory protein (CCSP), generally felt to be specific to lung Clara cells. Ablation of lung Clara cells has been reported using a transgenic mouse that expresses thymidine kinase under control of the CCSP promoter. Treatment with ganciclovir results in permanent elimination of CCSP+ cells, failure of airway regeneration, and death. To determine if transtracheal delivery of wild-type bone marrow CCSP+ cells is beneficial after ablation of lung CCSP+ cells, transgenic mice were treated with ganciclovir followed by transtracheal administration of CCSP+ or CCSP− BMC. Compared with mice administered CCSP− cells, mice treated with CCSP+ cells had more donor cells lining the airway epithelium, where they expressed epithelial markers including CCSP. Although donor CCSP+ cells did not substantially repopulate the airway, their administration resulted in increased host ciliated cells, better preservation of airway epithelium, reduction of inflammatory cells, and an increase in animal survival time. Administration of CCSP+ BMC is beneficial after permanent ablation of lung Clara cells by increasing bronchial epithelial repair. Therefore, CCSP+ BMC could be important for treatment of lung diseases where airways re-epithelialization is compromised.

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Section: Discussionmentioning

confidence: 99%

Bone Marrow Cells Expressing Clara Cell Secretory Protein Increase Epithelial Repair After Ablation of Pulmonary Clara Cells

et al. 2013

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“…It provides a selectively permeable barrier between the internal tissues and the potentially hazardous agents entering the body via the airways. In particular, the distal airways are exposed at high levels to various environmental oxidants, which may lead to epithelial injury in this specific region [5]. Naphthalene (NA), a harmful environmental toxin, can be found in ambient air, ground water and cigarette smoke and is produced by combustion [6].…”

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confidence: 99%

Keratinocyte growth factor protects against Clara cell injury induced by naphthalene

et al. 2008

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Airway epithelial cells are exposed to environmental toxicants that result in airway injury. Naphthalene (NA) causes site-selective damage to Clara cells in mouse distal airways. Nterminally truncated recombinant human keratinocyte growth factor (DN23-KGF) protects against acute lung injury. The present study investigated whether or not DN23-KGF protects against NAinduced acute Clara cell damage by measuring airway responses specifically and in order to identify underlying molecular mechanisms.Mice were treated with DN23-KGF or PBS 33 h prior to injection of 200 mg?kg body weight -1 NA.Lung function was analysed by head-out body plethysmography. Distal airways isolated by microdissection were assessed for cell permeability using ethidium homodimer-1.Immunohistochemistry of Clara cell-specific protein in conjunction with a physical dissector was used to quantify Clara cell numbers. RNA was isolated from frozen airways in order to analyse gene expression using quantitative RT-PCR. DN23-KGF prevented NA-induced airflow limitation and Clara cell permeability, and resulted in twice as many Clara cells compared with PBS pre-treatment. DN23-KGF-pre-treated mice exhibited increased expression of proliferating cell nuclear antigen mRNA. Cytochrome P 450 isoform 2F2, which converts NA into its toxic metabolite, was reduced by ,50%.The present results demonstrate that pre-treatment with N-terminally truncated recombinant human keratinocyte growth factor protects against naphthalene-induced injury. This suggests that N-terminally truncated recombinant human keratinocyte growth factor exerts its beneficial effect through a decrease in the expression of cytochrome P 450 isoform 2F2.

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“…1,2naphthoquinone). GSH is a key detoxification pathway and its depletion is a major determinant of NA respiratory toxicity (Phimister et al, 2004;Plopper et al, 2013b).…”

Section: Discussionmentioning

confidence: 99%

“…Naphthalene (NA) is a polyaromatic hydrocarbon (PAH) and exposure to this environmental toxicant can promote ROS, DNA damage and disrupt cellular glutathione levels (ATSDR, 2005; D. Bagchi, Bagchi, Balmoori, Vuchetich, & Stohs, 1998;M. Bagchi, Bagchi, Balmoori, Ye, & Stohs, 1998;Carratt et al, 2019;Lin et al, 2005;Plopper et al, 2013a). NA is found in cigarette smoke, gasoline, and mothballs (Jia & Batterman, 2010;Kakareka & Kukharchyk, 2003;Sudakin, Stone, & Power, 2011) as well as being derived in a number of industrial processes.…”

Section: Introductionmentioning

confidence: 99%

Epitranscriptomic regulation of the response to the air pollutant naphthalene in mouse lungs: from the perspectives of specialized translation and tolerance linked to the writer ALKBH8

Leonardi

Kovalchuk

Yin

et al. 2019

Preprint

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Background:The epitranscriptomic writer Alkylation Repair Homolog 8 (ALKBH8) is a tRNA methyltransferase that modifies the wobble uridine of selenocysteine tRNA to promote the specialized translation, via stop codon recoding, of proteins that contain selenocysteine. Corresponding selenoproteins play critical roles in protecting against reactive oxygen species and environmental stress. Using a novel animal model deficient in Alkbh8, we have investigated the importance of epitranscriptomic systems in the response to naphthalene (NA), an abundant polycyclic aromatic hydrocarbon, glutathione depleter and lung toxicant found in tobacco smoke, gasoline and mothballs.Objectives: Our goal was to define the molecular reprogramming of Alkbh8 deficient (Alkbh8 def ) mice and evaluate the roles that the epitranscriptomic writer ALKBH8 and selenoproteins play in mitigating NA-induced toxicity and lung dysfunction. Methods:We performed basal lung analysis and NA exposure studies using WT, Alkbh8 def and Cyp2abfgs-null mice, the latter of which lack the cytochrome P450 enzymes required for NA bioactivation. We characterized gene expression, molecular markers of damage, viability and tolerance to NA.Results: Under basal conditions, lungs from Alkbh8 def mice have increased oxidationreduction potential (ORP) and 8-isoprostane levels, and have reprogrammed at the molecular level to display increased stress response transcripts. In addition, the ALKBH8 writer deficient lungs have a decreased GSH/GSSG ratio. Alkbh8 def mice are more sensitive to NA than WT, showing higher susceptibility to lung damage both at the cellular and molecular levels. WT mice develop a tolerance to NA after 3 days, defined as resistance to a high challenging dose after repeated exposures, which is absent in Alkbh8 def mice, with writer deficient not surviving NA exposure. Discussion:We conclude that the epitranscriptomic writer ALKBH8 plays a protective role against NA-induced lung dysfunction and promotes NA tolerance. Our work provides an early example of how epitranscriptomic systems can regulate the response to environmental stress in vivo.

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Early Events in Naphthalene-Induced Acute Clara Cell Toxicity

Cited by 63 publications

References 19 publications

Bone Marrow Cells Expressing Clara Cell Secretory Protein Increase Epithelial Repair After Ablation of Pulmonary Clara Cells

Bone Marrow Cells Expressing Clara Cell Secretory Protein Increase Epithelial Repair After Ablation of Pulmonary Clara Cells

Keratinocyte growth factor protects against Clara cell injury induced by naphthalene

Epitranscriptomic regulation of the response to the air pollutant naphthalene in mouse lungs: from the perspectives of specialized translation and tolerance linked to the writer ALKBH8

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