Hypoxia‐induced cystic fibrosis transmembrane conductance regulator dysfunction is a universal mechanism underlying reduced mucociliary transport in sinusitis
Introduction Hypoxia due to sinus obstruction is a major pathogenic mechanism leading to sinusitis. The objective of the current study is to define the electrophysiologic characteristics of hypoxia in vitro and in vivo. Methods Cystic fibrosis bronchoepithelial cells expressing wild‐type cystic fibr...
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| Veröffentlicht in: | International forum of allergy & rhinology 2024-06, Vol.14 (6), p.1058-1069 |
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| creator | Cho, Do‐Yeon Zhang, Shaoyan Norwood, T. Graham Skinner, Daniel Hollis, Tonja A. Ehrhardt, Marie L. Yang, Lydia C. Lim, Dong‐Jin Grayson, Jessica W. Lazrak, Ahmed Matalon, Sadis Rowe, Steven M. Woodworth, Bradford A. |
| description | Introduction
Hypoxia due to sinus obstruction is a major pathogenic mechanism leading to sinusitis. The objective of the current study is to define the electrophysiologic characteristics of hypoxia in vitro and in vivo.
Methods
Cystic fibrosis bronchoepithelial cells expressing wild‐type cystic fibrosis transmembrane conductance regulator (CFTR) and human sinonasal epithelial cells were exposed to 1% or atmospheric O2 for 24 h. Time‐dependent production of cytoplasmic free radicals was measured. Cells were subjected to Ussing chamber and patch clamp technique where CFTR currents were recorded in whole‐cell and cell‐attached mode for single channel studies. Indices of mucociliary transport (MCT) were measured using micro‐optical coherence tomography. In a rabbit hypoxic maxillary sinus model, tissue oxygenation, relative mRNA expression of HIF‐1α, pH, sinus potential difference (SPD), and MCT were determined.
Results
Ussing chamber (p |
| doi_str_mv | 10.1002/alr.23309 |
| format | Article |
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Hypoxia due to sinus obstruction is a major pathogenic mechanism leading to sinusitis. The objective of the current study is to define the electrophysiologic characteristics of hypoxia in vitro and in vivo.
Methods
Cystic fibrosis bronchoepithelial cells expressing wild‐type cystic fibrosis transmembrane conductance regulator (CFTR) and human sinonasal epithelial cells were exposed to 1% or atmospheric O2 for 24 h. Time‐dependent production of cytoplasmic free radicals was measured. Cells were subjected to Ussing chamber and patch clamp technique where CFTR currents were recorded in whole‐cell and cell‐attached mode for single channel studies. Indices of mucociliary transport (MCT) were measured using micro‐optical coherence tomography. In a rabbit hypoxic maxillary sinus model, tissue oxygenation, relative mRNA expression of HIF‐1α, pH, sinus potential difference (SPD), and MCT were determined.
Results
Ussing chamber (p < 0.05), whole‐cell (p < 0.001), and single channel patch‐clamp (p < 0.0001) showed significant inhibition of Cl− currents in hypoxic cells. Cytoplasmic free radicals showed time‐dependent elevation peaking at 4 h (p < 0.0001). Airway surface liquid (p < 0.0001), periciliary liquid (p < 0.001), and MCT (p < 0.01) were diminished. Co‐incubation with the free radical scavenger glutathione negated the impact of hypoxia on single channel currents and MCT markers. In sinusitis rabbits, mucosa exhibited low tissue oxygenation (p < 0.0001), increased HIF1α mRNA (p < 0.05), reduced pH (p < 0.01), and decreased MCT (p < 0.001). SPD measurements demonstrated markedly diminished transepithelial Cl− transport (p < 0.0001).
Conclusion
Hypoxia induces severe CFTR dysfunction via free radical production causing reduced MCT in vitro and in vivo. Improved oxygenation is critical to reducing the impact of persistent mucociliary dysfunction.]]></description><identifier>ISSN: 2042-6976</identifier><identifier>EISSN: 2042-6984</identifier><identifier>DOI: 10.1002/alr.23309</identifier><identifier>PMID: 38073611</identifier><language>eng</language><publisher>United States: Wiley Subscription Services, Inc</publisher><subject>airway surface liquid ; CFTR ; chronic rhinosinusitis ; chronic sinusitis ; Cystic fibrosis ; Epithelial cells ; Free radicals ; functional microanatomy ; Gene expression ; Glutathione ; Hypoxia ; Maxillary sinus ; mucociliary transport ; optical coherence tomography ; Oxygenation ; patch clamp ; periciliary liquid ; potential difference ; rabbit sinusitis ; Sinus ; Sinuses ; Sinusitis</subject><ispartof>International forum of allergy & rhinology, 2024-06, Vol.14 (6), p.1058-1069</ispartof><rights>2023 ARS‐AAOA, LLC.</rights><rights>2023 ARS-AAOA, LLC.</rights><rights>2024 ARS‐AAOA, LLC.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c3539-1030a759b1ef107bf36bd36b83a7f8a9862975da4b96ef712738e3248ef4afda3</citedby><cites>FETCH-LOGICAL-c3539-1030a759b1ef107bf36bd36b83a7f8a9862975da4b96ef712738e3248ef4afda3</cites><orcidid>0000-0003-3292-9167 ; 0000-0002-5173-8959 ; 0000-0002-2131-8005</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2Falr.23309$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Falr.23309$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,776,780,1411,27901,27902,45550,45551</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/38073611$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Cho, Do‐Yeon</creatorcontrib><creatorcontrib>Zhang, Shaoyan</creatorcontrib><creatorcontrib>Norwood, T. Graham</creatorcontrib><creatorcontrib>Skinner, Daniel</creatorcontrib><creatorcontrib>Hollis, Tonja A.</creatorcontrib><creatorcontrib>Ehrhardt, Marie L.</creatorcontrib><creatorcontrib>Yang, Lydia C.</creatorcontrib><creatorcontrib>Lim, Dong‐Jin</creatorcontrib><creatorcontrib>Grayson, Jessica W.</creatorcontrib><creatorcontrib>Lazrak, Ahmed</creatorcontrib><creatorcontrib>Matalon, Sadis</creatorcontrib><creatorcontrib>Rowe, Steven M.</creatorcontrib><creatorcontrib>Woodworth, Bradford A.</creatorcontrib><title>Hypoxia‐induced cystic fibrosis transmembrane conductance regulator dysfunction is a universal mechanism underlying reduced mucociliary transport in sinusitis</title><title>International forum of allergy & rhinology</title><addtitle>Int Forum Allergy Rhinol</addtitle><description><![CDATA[Introduction
Hypoxia due to sinus obstruction is a major pathogenic mechanism leading to sinusitis. The objective of the current study is to define the electrophysiologic characteristics of hypoxia in vitro and in vivo.
Methods
Cystic fibrosis bronchoepithelial cells expressing wild‐type cystic fibrosis transmembrane conductance regulator (CFTR) and human sinonasal epithelial cells were exposed to 1% or atmospheric O2 for 24 h. Time‐dependent production of cytoplasmic free radicals was measured. Cells were subjected to Ussing chamber and patch clamp technique where CFTR currents were recorded in whole‐cell and cell‐attached mode for single channel studies. Indices of mucociliary transport (MCT) were measured using micro‐optical coherence tomography. In a rabbit hypoxic maxillary sinus model, tissue oxygenation, relative mRNA expression of HIF‐1α, pH, sinus potential difference (SPD), and MCT were determined.
Results
Ussing chamber (p < 0.05), whole‐cell (p < 0.001), and single channel patch‐clamp (p < 0.0001) showed significant inhibition of Cl− currents in hypoxic cells. Cytoplasmic free radicals showed time‐dependent elevation peaking at 4 h (p < 0.0001). Airway surface liquid (p < 0.0001), periciliary liquid (p < 0.001), and MCT (p < 0.01) were diminished. Co‐incubation with the free radical scavenger glutathione negated the impact of hypoxia on single channel currents and MCT markers. In sinusitis rabbits, mucosa exhibited low tissue oxygenation (p < 0.0001), increased HIF1α mRNA (p < 0.05), reduced pH (p < 0.01), and decreased MCT (p < 0.001). SPD measurements demonstrated markedly diminished transepithelial Cl− transport (p < 0.0001).
Conclusion
Hypoxia induces severe CFTR dysfunction via free radical production causing reduced MCT in vitro and in vivo. Improved oxygenation is critical to reducing the impact of persistent mucociliary dysfunction.]]></description><subject>airway surface liquid</subject><subject>CFTR</subject><subject>chronic rhinosinusitis</subject><subject>chronic sinusitis</subject><subject>Cystic fibrosis</subject><subject>Epithelial cells</subject><subject>Free radicals</subject><subject>functional microanatomy</subject><subject>Gene expression</subject><subject>Glutathione</subject><subject>Hypoxia</subject><subject>Maxillary sinus</subject><subject>mucociliary transport</subject><subject>optical coherence tomography</subject><subject>Oxygenation</subject><subject>patch clamp</subject><subject>periciliary liquid</subject><subject>potential difference</subject><subject>rabbit sinusitis</subject><subject>Sinus</subject><subject>Sinuses</subject><subject>Sinusitis</subject><issn>2042-6976</issn><issn>2042-6984</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><recordid>eNp1kd9qFTEQxhdRbKm98AUk4I1enDZ_djeby1LUCgcE0euQzU7qlGxyTDbq3vkIPoLP5pOYurUXgoFhwvCbbzL5muYpo2eMUn5ufDrjQlD1oDnmtOW7Xg3tw_u77I-a05xvaD0d6zomHzdHYqBS9IwdNz-v1kP8hubX9x8YpmJhInbNC1ricEwxYyZLMiHPMI81A7HxFltMsEASXBdvlpjItGZXgl0wBlJbDCkBv0DKxpMZ7CcTMM-1NkHyK4br2rnNmouNFj2atG5zDjEtBAPJGErGBfOT5pEzPsPpXT5pPr5-9eHyard_9-bt5cV-Z0Un1I5RQY3s1MjAMSpHJ_pxqjEII91g1NBzJbvJtKPqwUnGpRhA8HYA1xo3GXHSvNh0Dyl-LpAXPWO24H1dOpasuaJcCUUVq-jzf9CbWFKor9OC9oJxxoe-Ui83ytZvzAmcPiSc66KaUX3rnK7O6T_OVfbZnWIZZ5juyb8-VeB8A76ih_X_Svpi_36T_A1Lr6fU</recordid><startdate>202406</startdate><enddate>202406</enddate><creator>Cho, Do‐Yeon</creator><creator>Zhang, Shaoyan</creator><creator>Norwood, T. Graham</creator><creator>Skinner, Daniel</creator><creator>Hollis, Tonja A.</creator><creator>Ehrhardt, Marie L.</creator><creator>Yang, Lydia C.</creator><creator>Lim, Dong‐Jin</creator><creator>Grayson, Jessica W.</creator><creator>Lazrak, Ahmed</creator><creator>Matalon, Sadis</creator><creator>Rowe, Steven M.</creator><creator>Woodworth, Bradford A.</creator><general>Wiley Subscription Services, Inc</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>K9.</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0003-3292-9167</orcidid><orcidid>https://orcid.org/0000-0002-5173-8959</orcidid><orcidid>https://orcid.org/0000-0002-2131-8005</orcidid></search><sort><creationdate>202406</creationdate><title>Hypoxia‐induced cystic fibrosis transmembrane conductance regulator dysfunction is a universal mechanism underlying reduced mucociliary transport in sinusitis</title><author>Cho, Do‐Yeon ; Zhang, Shaoyan ; Norwood, T. Graham ; Skinner, Daniel ; Hollis, Tonja A. ; Ehrhardt, Marie L. ; Yang, Lydia C. ; Lim, Dong‐Jin ; Grayson, Jessica W. ; Lazrak, Ahmed ; Matalon, Sadis ; Rowe, Steven M. ; Woodworth, Bradford A.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c3539-1030a759b1ef107bf36bd36b83a7f8a9862975da4b96ef712738e3248ef4afda3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2024</creationdate><topic>airway surface liquid</topic><topic>CFTR</topic><topic>chronic rhinosinusitis</topic><topic>chronic sinusitis</topic><topic>Cystic fibrosis</topic><topic>Epithelial cells</topic><topic>Free radicals</topic><topic>functional microanatomy</topic><topic>Gene expression</topic><topic>Glutathione</topic><topic>Hypoxia</topic><topic>Maxillary sinus</topic><topic>mucociliary transport</topic><topic>optical coherence tomography</topic><topic>Oxygenation</topic><topic>patch clamp</topic><topic>periciliary liquid</topic><topic>potential difference</topic><topic>rabbit sinusitis</topic><topic>Sinus</topic><topic>Sinuses</topic><topic>Sinusitis</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Cho, Do‐Yeon</creatorcontrib><creatorcontrib>Zhang, Shaoyan</creatorcontrib><creatorcontrib>Norwood, T. Graham</creatorcontrib><creatorcontrib>Skinner, Daniel</creatorcontrib><creatorcontrib>Hollis, Tonja A.</creatorcontrib><creatorcontrib>Ehrhardt, Marie L.</creatorcontrib><creatorcontrib>Yang, Lydia C.</creatorcontrib><creatorcontrib>Lim, Dong‐Jin</creatorcontrib><creatorcontrib>Grayson, Jessica W.</creatorcontrib><creatorcontrib>Lazrak, Ahmed</creatorcontrib><creatorcontrib>Matalon, Sadis</creatorcontrib><creatorcontrib>Rowe, Steven M.</creatorcontrib><creatorcontrib>Woodworth, Bradford A.</creatorcontrib><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>MEDLINE - Academic</collection><jtitle>International forum of allergy & rhinology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Cho, Do‐Yeon</au><au>Zhang, Shaoyan</au><au>Norwood, T. Graham</au><au>Skinner, Daniel</au><au>Hollis, Tonja A.</au><au>Ehrhardt, Marie L.</au><au>Yang, Lydia C.</au><au>Lim, Dong‐Jin</au><au>Grayson, Jessica W.</au><au>Lazrak, Ahmed</au><au>Matalon, Sadis</au><au>Rowe, Steven M.</au><au>Woodworth, Bradford A.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Hypoxia‐induced cystic fibrosis transmembrane conductance regulator dysfunction is a universal mechanism underlying reduced mucociliary transport in sinusitis</atitle><jtitle>International forum of allergy & rhinology</jtitle><addtitle>Int Forum Allergy Rhinol</addtitle><date>2024-06</date><risdate>2024</risdate><volume>14</volume><issue>6</issue><spage>1058</spage><epage>1069</epage><pages>1058-1069</pages><issn>2042-6976</issn><eissn>2042-6984</eissn><abstract><![CDATA[Introduction
Hypoxia due to sinus obstruction is a major pathogenic mechanism leading to sinusitis. The objective of the current study is to define the electrophysiologic characteristics of hypoxia in vitro and in vivo.
Methods
Cystic fibrosis bronchoepithelial cells expressing wild‐type cystic fibrosis transmembrane conductance regulator (CFTR) and human sinonasal epithelial cells were exposed to 1% or atmospheric O2 for 24 h. Time‐dependent production of cytoplasmic free radicals was measured. Cells were subjected to Ussing chamber and patch clamp technique where CFTR currents were recorded in whole‐cell and cell‐attached mode for single channel studies. Indices of mucociliary transport (MCT) were measured using micro‐optical coherence tomography. In a rabbit hypoxic maxillary sinus model, tissue oxygenation, relative mRNA expression of HIF‐1α, pH, sinus potential difference (SPD), and MCT were determined.
Results
Ussing chamber (p < 0.05), whole‐cell (p < 0.001), and single channel patch‐clamp (p < 0.0001) showed significant inhibition of Cl− currents in hypoxic cells. Cytoplasmic free radicals showed time‐dependent elevation peaking at 4 h (p < 0.0001). Airway surface liquid (p < 0.0001), periciliary liquid (p < 0.001), and MCT (p < 0.01) were diminished. Co‐incubation with the free radical scavenger glutathione negated the impact of hypoxia on single channel currents and MCT markers. In sinusitis rabbits, mucosa exhibited low tissue oxygenation (p < 0.0001), increased HIF1α mRNA (p < 0.05), reduced pH (p < 0.01), and decreased MCT (p < 0.001). SPD measurements demonstrated markedly diminished transepithelial Cl− transport (p < 0.0001).
Conclusion
Hypoxia induces severe CFTR dysfunction via free radical production causing reduced MCT in vitro and in vivo. Improved oxygenation is critical to reducing the impact of persistent mucociliary dysfunction.]]></abstract><cop>United States</cop><pub>Wiley Subscription Services, Inc</pub><pmid>38073611</pmid><doi>10.1002/alr.23309</doi><tpages>12</tpages><orcidid>https://orcid.org/0000-0003-3292-9167</orcidid><orcidid>https://orcid.org/0000-0002-5173-8959</orcidid><orcidid>https://orcid.org/0000-0002-2131-8005</orcidid></addata></record> |
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| source | Wiley Online Library Journals Frontfile Complete |
| subjects | airway surface liquid CFTR chronic rhinosinusitis chronic sinusitis Cystic fibrosis Epithelial cells Free radicals functional microanatomy Gene expression Glutathione Hypoxia Maxillary sinus mucociliary transport optical coherence tomography Oxygenation patch clamp periciliary liquid potential difference rabbit sinusitis Sinus Sinuses Sinusitis |
| title | Hypoxia‐induced cystic fibrosis transmembrane conductance regulator dysfunction is a universal mechanism underlying reduced mucociliary transport in sinusitis |
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