A soluble secreted glycoprotein (eCLCA1) is overexpressed due to goblet cell hyperplasia and metaplasia in horses with recurrent airway obstruction.
Abstract: The equine putative chloride channel protein eCLCA1 is thought to be critically involved in the pathogenesis of recurrent airway obstruction (RAO) via modulation of the hydration of airway mucins. A recent study revealed a strong increase of eCLCA1 messenger ribonucleic acid (mRNA) in the lungs of horses with RAO. In this study, eCLCA1 protein and mRNA expression were quantified in airway goblet cells of 9 horses affected with RAO and 9 control horses by using immunohistochemistry and laser microdissection followed by real-time quantitative reverse transcription polymerase chain reaction, respectively. Horses affected by RAO had strong goblet cell metaplasia in bronchioles and goblet cell hyperplasia in bronchi and the trachea. Expression of the eCLCA1 protein was tightly linked to all airway goblet cells in both groups. No differences were detected in the ratio of eCLCA1 mRNA copy numbers to the mRNA copy numbers of the housekeeping gene EF-1a per goblet cell between horses affected with RAO and unaffected horses, suggesting that the increase in eCLCA1 expression is because of increased numbers of goblet cells and not transcriptional upregulation of the eCLCA1 gene. In addition, biochemical analyses of the eCLCA1 protein after in vitro translation and heterologous expression in cultured cells revealed that eCLCA1 is a secreted glycoprotein and not an integral membrane protein. Taken together, the results suggest that eCLCA1 mediates its effect as a soluble constituent of airway mucins that is overexpressed in RAO airways because of goblet cell hyperplasia and metaplasia, not transcriptional upregulation.
Publication Date: 2007-11-28 PubMed ID: 18039903DOI: 10.1354/vp.44-6-901Google Scholar: Lookup
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- Journal Article
- Research Support
- Non-U.S. Gov't
Summary
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The research studied the protein eCLCA1, finding that it is overexpressed in the airways of horses with recurrent airway obstruction (RAO) due to an increase in goblet cells rather than gene upregulation.
Study Overview
- This study explores the putative role of a particular protein termed eCLCA1 in the pathogenesis of an airway disease termed recurrent airway obstruction (RAO) commonly seen in horses.
- The researchers investigated the expression of this protein in the respiratory passages of horses with and without RAO.
- Investigation techniques included immunohistochemistry (use of antibodies to detect specific proteins), laser microdissection (precise isolation of specific cell types), and reverse transcription polymerase chain reactions (a method to measure gene expression).
Findings and Conclusions
- The study found significant goblet cell metaplasia (the transformation of cells into a form resembling goblet cells) in the small airways (bronchioles) and goblet cell hyperplasia (increase in number) in larger airways (bronchi and trachea) in horses affected with RAO.
- In both healthy and RAO-affected horses, the eCLCA1 protein was linked to all airway goblet cells.
- No variation was found in the ratio of eCLCA1 mRNA copy numbers to the copy numbers of expression stable, or “housekeeping”, genes in the goblet cells of horses with RAO and those unaffected. This implies that the rise in eCLCA1 is due to an increase in goblet cells rather than an upregulation (increase activation) of the eCLCA1 gene.
- The eCLCA1 protein was further detected to be a secreted glycoprotein (a sugar-attached protein that is secreted into the cell environment), not a membrane protein.
Implications of the Study
- The findings suggest that eCLCA1 impacts RAO as a soluble constituent of airway mucins (a type of protein that forms mucus) that is overexpressed in the airways of RAO-affected horses.
- This overexpression is due to an increase in goblet cells (hyperplasia and metaplasia) but not because of the increased transcription of the eCLCA1 gene.
- These outcomes may impact potential therapeutic strategies for managing RAO in horses.
Cite This Article
APA
Range F, Mundhenk L, Gruber AD.
(2007).
A soluble secreted glycoprotein (eCLCA1) is overexpressed due to goblet cell hyperplasia and metaplasia in horses with recurrent airway obstruction.
Vet Pathol, 44(6), 901-911.
https://doi.org/10.1354/vp.44-6-901 Publication
Researcher Affiliations
- Department of Veterinary Pathology, Freie Universität Berlin, Robert-von-Ostertag-Strasse 15, D-14163 Berlin, Germany.
MeSH Terms
- Airway Obstruction / metabolism
- Airway Obstruction / pathology
- Airway Obstruction / veterinary
- Animals
- Chloride Channels / genetics
- Chloride Channels / metabolism
- Gene Expression Regulation
- Goblet Cells / metabolism
- Goblet Cells / pathology
- Horse Diseases
- Horses
- Lung / cytology
- Lung / pathology
- RNA, Messenger / genetics
- RNA, Messenger / metabolism
Citations
This article has been cited 9 times.- Bartenschlager F, Klymiuk N, Gruber AD, Mundhenk L. Genomic, biochemical and expressional properties reveal strong conservation of the CLCA2 gene in birds and mammals.. PeerJ 2022;10:e14202.
- Bartenschlager F, Klymiuk N, Weise C, Kuropka B, Gruber AD, Mundhenk L. Evolutionarily conserved properties of CLCA proteins 1, 3 and 4, as revealed by phylogenetic and biochemical studies in avian homologues.. PLoS One 2022;17(4):e0266937.
- Bessonnat A, Hélie P, Grimes C, Lavoie JP. Airway remodeling in horses with mild and moderate asthma.. J Vet Intern Med 2022 Jan;36(1):285-291.
- Erickson NA, Nyström EE, Mundhenk L, Arike L, Glauben R, Heimesaat MM, Fischer A, Bereswill S, Birchenough GM, Gruber AD, Johansson ME. The Goblet Cell Protein Clca1 (Alias mClca3 or Gob-5) Is Not Required for Intestinal Mucus Synthesis, Structure and Barrier Function in Naive or DSS-Challenged Mice.. PLoS One 2015;10(7):e0131991.
- Yurtsever Z, Sala-Rabanal M, Randolph DT, Scheaffer SM, Roswit WT, Alevy YG, Patel AC, Heier RF, Romero AG, Nichols CG, Holtzman MJ, Brett TJ. Self-cleavage of human CLCA1 protein by a novel internal metalloprotease domain controls calcium-activated chloride channel activation.. J Biol Chem 2012 Dec 7;287(50):42138-49.
- Lavoie JP, Lefebvre-Lavoie J, Leclere M, Lavoie-Lamoureux A, Chamberland A, Laprise C, Lussier J. Profiling of differentially expressed genes using suppression subtractive hybridization in an equine model of chronic asthma.. PLoS One 2012;7(1):e29440.
- Plog S, Mundhenk L, Klymiuk N, Gruber AD. Genomic, tissue expression, and protein characterization of pCLCA1, a putative modulator of cystic fibrosis in the pig.. J Histochem Cytochem 2009 Dec;57(12):1169-81.
- Patel AC, Brett TJ, Holtzman MJ. The role of CLCA proteins in inflammatory airway disease.. Annu Rev Physiol 2009;71:425-49.
- Bothe MK, Braun J, Mundhenk L, Gruber AD. Murine mCLCA6 is an integral apical membrane protein of non-goblet cell enterocytes and co-localizes with the cystic fibrosis transmembrane conductance regulator.. J Histochem Cytochem 2008 May;56(5):495-509.
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