Large pH oscillations promote host defense against human airways infection

Dusik Kim; Jie Liao; Nathan B. Scales; Carolina Martini; Xiaojie Luan; Asmahan Abu-Arish; Renaud Robert; Yishan Luo; Geoffrey A. McKay; Dao Nguyen; Marc A. Tewfik; Charles D. Poirier; Elias Matouk; Juan P. Ianowski; Saul Frenkiel; John W. Hanrahan

doi:10.1084/JEM.20201831

Large pH oscillations promote host defense against human airways infection

Dusik Kim, Jie Liao, Nathan B. Scales, Carolina Martini, Xiaojie Luan, Asmahan Abu-Arish, Renaud Robert, Yishan Luo, Geoffrey A. McKay, Dao Nguyen, Marc A. Tewfik, Charles D. Poirier, Elias Matouk, Juan P. Ianowski, Saul Frenkiel, John W. Hanrahan^*

^*Corresponding author for this work

Pathology

Research output: Contribution to journal › Article › peer-review

16 Scopus citations

Abstract

The airway mucosal microenvironment is crucial for host defense against inhaled pathogens but remains poorly understood. We report here that the airway surface normally undergoes surprisingly large excursions in pH during breathing that can reach pH 9.0 during inhalation, making it the most alkaline fluid in the body. Transient alkalinization requires luminal bicarbonate and membrane-bound carbonic anhydrase 12 (CA12) and is antimicrobial. Luminal bicarbonate concentration and CA12 expression are both reduced in cystic fibrosis (CF), and mucus accumulation both buffers the pH and obstructs airflow, further suppressing the oscillations and bacterial-killing efficacy. Defective pH oscillations may compromise airway host defense in other respiratory diseases and explain CF-like airway infections in people with CA12 mutations.

Original language	English (US)
Article number	20201831
Journal	Journal of Experimental Medicine
Volume	218
Issue number	4
DOIs	https://doi.org/10.1084/JEM.20201831
State	Published - 2021

Funding

This work was supported by research grants from Cystic Fibrosis Canada (grant no. 3022) and the Canada Foundation for Innovation (grant no. 21375) to J.W. Hanrahan and Cystic Fibrosis Canada (grant no. 555681) to J.P. Ianowski. We are grateful to the research subjects who volunteered to participate in the clinical studies. We thank Dr. Jacopo Mortola (McGill University, Montréal, Québec, Canada) for access to infrared CO2 monitoring equipment, Dr. Danuta Radzioch (Research Institute-McGill University Health Centre, Montréal, Québec, Canada) for bacterial strains, Véronique Flynn and Olymel S.E.C. (Saint-Esprit, Québec, Canada) for providing pig tissue, and Hong-Seok Hur for preparing the graphical abstract and graphic in Fig. 1. This work was supported by research grants from Cystic Fibrosis Canada (grant no. 3022) and the Canada Foundation for Innovation (grant no. 21375) to J.W. Hanrahan and Cystic Fibrosis Canada (grant no. 555681) to J.P. Ianowski.

ASJC Scopus subject areas

Immunology and Allergy
Immunology

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10.1084/JEM.20201831

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Kim, D., Liao, J., Scales, N. B., Martini, C., Luan, X., Abu-Arish, A., Robert, R., Luo, Y., McKay, G. A., Nguyen, D., Tewfik, M. A., Poirier, C. D., Matouk, E., Ianowski, J. P., Frenkiel, S., & Hanrahan, J. W. (2021). Large pH oscillations promote host defense against human airways infection. Journal of Experimental Medicine, 218(4), Article 20201831. https://doi.org/10.1084/JEM.20201831

@article{006feecd0a4e4569a0308fc313bf3438,

title = "Large pH oscillations promote host defense against human airways infection",

abstract = "The airway mucosal microenvironment is crucial for host defense against inhaled pathogens but remains poorly understood. We report here that the airway surface normally undergoes surprisingly large excursions in pH during breathing that can reach pH 9.0 during inhalation, making it the most alkaline fluid in the body. Transient alkalinization requires luminal bicarbonate and membrane-bound carbonic anhydrase 12 (CA12) and is antimicrobial. Luminal bicarbonate concentration and CA12 expression are both reduced in cystic fibrosis (CF), and mucus accumulation both buffers the pH and obstructs airflow, further suppressing the oscillations and bacterial-killing efficacy. Defective pH oscillations may compromise airway host defense in other respiratory diseases and explain CF-like airway infections in people with CA12 mutations.",

author = "Dusik Kim and Jie Liao and Scales, {Nathan B.} and Carolina Martini and Xiaojie Luan and Asmahan Abu-Arish and Renaud Robert and Yishan Luo and McKay, {Geoffrey A.} and Dao Nguyen and Tewfik, {Marc A.} and Poirier, {Charles D.} and Elias Matouk and Ianowski, {Juan P.} and Saul Frenkiel and Hanrahan, {John W.}",

note = "Funding Information: This work was supported by research grants from Cystic Fibrosis Canada (grant no. 3022) and the Canada Foundation for Innovation (grant no. 21375) to J.W. Hanrahan and Cystic Fibrosis Canada (grant no. 555681) to J.P. Ianowski. Funding Information: We are grateful to the research subjects who volunteered to participate in the clinical studies. We thank Dr. Jacopo Mortola (McGill University, Montr{\'e}al, Qu{\'e}bec, Canada) for access to infrared CO2 monitoring equipment, Dr. Danuta Radzioch (Research Institute-McGill University Health Centre, Montr{\'e}al, Qu{\'e}bec, Canada) for bacterial strains, V{\'e}ronique Flynn and Olymel S.E.C. (Saint-Esprit, Qu{\'e}bec, Canada) for providing pig tissue, and Hong-Seok Hur for preparing the graphical abstract and graphic in Fig. 1. This work was supported by research grants from Cystic Fibrosis Canada (grant no. 3022) and the Canada Foundation for Innovation (grant no. 21375) to J.W. Hanrahan and Cystic Fibrosis Canada (grant no. 555681) to J.P. Ianowski. Publisher Copyright: {\textcopyright} 2021 Kim et al.",

year = "2021",

doi = "10.1084/JEM.20201831",

language = "English (US)",

volume = "218",

journal = "Journal of Experimental Medicine",

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T1 - Large pH oscillations promote host defense against human airways infection

AU - Kim, Dusik

AU - Liao, Jie

AU - Scales, Nathan B.

AU - Martini, Carolina

AU - Luan, Xiaojie

AU - Abu-Arish, Asmahan

AU - Robert, Renaud

AU - Luo, Yishan

AU - McKay, Geoffrey A.

AU - Nguyen, Dao

AU - Tewfik, Marc A.

AU - Poirier, Charles D.

AU - Matouk, Elias

AU - Ianowski, Juan P.

AU - Frenkiel, Saul

AU - Hanrahan, John W.

N1 - Funding Information: This work was supported by research grants from Cystic Fibrosis Canada (grant no. 3022) and the Canada Foundation for Innovation (grant no. 21375) to J.W. Hanrahan and Cystic Fibrosis Canada (grant no. 555681) to J.P. Ianowski. Funding Information: We are grateful to the research subjects who volunteered to participate in the clinical studies. We thank Dr. Jacopo Mortola (McGill University, Montréal, Québec, Canada) for access to infrared CO2 monitoring equipment, Dr. Danuta Radzioch (Research Institute-McGill University Health Centre, Montréal, Québec, Canada) for bacterial strains, Véronique Flynn and Olymel S.E.C. (Saint-Esprit, Québec, Canada) for providing pig tissue, and Hong-Seok Hur for preparing the graphical abstract and graphic in Fig. 1. This work was supported by research grants from Cystic Fibrosis Canada (grant no. 3022) and the Canada Foundation for Innovation (grant no. 21375) to J.W. Hanrahan and Cystic Fibrosis Canada (grant no. 555681) to J.P. Ianowski. Publisher Copyright: © 2021 Kim et al.

PY - 2021

Y1 - 2021

N2 - The airway mucosal microenvironment is crucial for host defense against inhaled pathogens but remains poorly understood. We report here that the airway surface normally undergoes surprisingly large excursions in pH during breathing that can reach pH 9.0 during inhalation, making it the most alkaline fluid in the body. Transient alkalinization requires luminal bicarbonate and membrane-bound carbonic anhydrase 12 (CA12) and is antimicrobial. Luminal bicarbonate concentration and CA12 expression are both reduced in cystic fibrosis (CF), and mucus accumulation both buffers the pH and obstructs airflow, further suppressing the oscillations and bacterial-killing efficacy. Defective pH oscillations may compromise airway host defense in other respiratory diseases and explain CF-like airway infections in people with CA12 mutations.

AB - The airway mucosal microenvironment is crucial for host defense against inhaled pathogens but remains poorly understood. We report here that the airway surface normally undergoes surprisingly large excursions in pH during breathing that can reach pH 9.0 during inhalation, making it the most alkaline fluid in the body. Transient alkalinization requires luminal bicarbonate and membrane-bound carbonic anhydrase 12 (CA12) and is antimicrobial. Luminal bicarbonate concentration and CA12 expression are both reduced in cystic fibrosis (CF), and mucus accumulation both buffers the pH and obstructs airflow, further suppressing the oscillations and bacterial-killing efficacy. Defective pH oscillations may compromise airway host defense in other respiratory diseases and explain CF-like airway infections in people with CA12 mutations.

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DO - 10.1084/JEM.20201831

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JO - Journal of Experimental Medicine

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IS - 4

M1 - 20201831

ER -

Large pH oscillations promote host defense against human airways infection

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ASJC Scopus subject areas

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