{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T23:47:22Z","timestamp":1787010442983,"version":"build-2736575974"},"reference-count":77,"publisher":"The Royal Society","issue":"2","license":[{"start":{"date-parts":[[2021,2,12]],"date-time":"2021-02-12T00:00:00Z","timestamp":1613088000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/royalsociety.org\/journals\/ethics-policies\/data-sharing-mining\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"US National Institutes of Health","doi-asserted-by":"crossref","award":["HL-147070"],"award-info":[{"award-number":["HL-147070"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["royalsocietypublishing.org"],"crossmark-restriction":true},"short-container-title":["Interface Focus."],"published-print":{"date-parts":[[2021,4,6]]},"abstract":"<jats:p>\n                    Carbon dioxide (CO\n                    <jats:sub>2<\/jats:sub>\n                    ), a primary product of oxidative metabolism, can be sensed by eukaryotic cells eliciting unique responses via specific signalling pathways. Severe lung diseases such as chronic obstructive pulmonary disease are associated with hypoventilation that can lead to the elevation of CO\n                    <jats:sub>2<\/jats:sub>\n                    levels in lung tissues and the bloodstream (hypercapnia). However, the pathophysiological effects of hypercapnia on the lungs and specific lung cells are incompletely understood. We have recently reported using combined unbiased molecular approaches with studies in mice and cell culture systems on the mechanisms by which hypercapnia alters airway smooth muscle contractility. In this review, we provide a pathophysiological and mechanistic perspective on the effects of hypercapnia on the lung airways and discuss the recent understanding of high CO\n                    <jats:sub>2<\/jats:sub>\n                    modulation of the airway contractility.\n                  <\/jats:p>","DOI":"10.1098\/rsfs.2020.0021","type":"journal-article","created":{"date-parts":[[2021,2,11]],"date-time":"2021-02-11T19:07:05Z","timestamp":1613070425000},"page":"20200021","update-policy":"https:\/\/doi.org\/10.1098\/crossmark-policy","source":"Crossref","is-referenced-by-count":15,"title":["Elevated CO\n                    <sub>2<\/sub>\n                    modulates airway contractility"],"prefix":"10.1098","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7767-6584","authenticated-orcid":true,"given":"Masahiko","family":"Shigemura","sequence":"first","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine, Northwestern University, Chicago, IL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2089-4764","authenticated-orcid":true,"given":"Jacob I.","family":"Sznajder","sequence":"additional","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine, Northwestern University, Chicago, IL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"175","published-online":{"date-parts":[[2021,2,12]]},"reference":[{"key":"e_1_3_6_2_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra050002"},{"key":"e_1_3_6_3_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI62854"},{"key":"e_1_3_6_4_2","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00003.2019"},{"key":"e_1_3_6_5_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-013-1470-6"},{"key":"e_1_3_6_6_2","doi-asserted-by":"publisher","DOI":"10.1113\/JP273781"},{"key":"e_1_3_6_7_2","doi-asserted-by":"publisher","DOI":"10.1038\/497013a"},{"key":"e_1_3_6_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(99)02388-0"},{"key":"e_1_3_6_9_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM200005043421801"},{"key":"e_1_3_6_10_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00134-016-4611-1"},{"key":"e_1_3_6_11_2","doi-asserted-by":"publisher","DOI":"10.1164\/ajrccm.154.4.8887592"},{"key":"e_1_3_6_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/S2213-2600(14)70153-5"},{"key":"e_1_3_6_13_2","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2017.4451"},{"key":"e_1_3_6_14_2","doi-asserted-by":"publisher","DOI":"10.1164\/ajrccm\/138.3.535"},{"key":"e_1_3_6_15_2","doi-asserted-by":"publisher","DOI":"10.1378\/chest.15-0681"},{"key":"e_1_3_6_16_2","doi-asserted-by":"publisher","DOI":"10.1378\/chest.15-1591"},{"key":"e_1_3_6_17_2","doi-asserted-by":"publisher","DOI":"10.3390\/jcm9103207"},{"key":"e_1_3_6_18_2","first-page":"752","article-title":"AMP-activated protein kinase regulates CO2-induced alveolar epithelial dysfunction in rats and human cells by promoting Na,K-ATPase endocytosis","volume":"118","author":"Vadasz I","year":"2008","journal-title":"J. Clin. Invest."},{"key":"e_1_3_6_19_2","doi-asserted-by":"publisher","DOI":"10.1165\/rcmb.2012-0487OC"},{"key":"e_1_3_6_20_2","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aat1662"},{"key":"e_1_3_6_21_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M114.625715"},{"key":"e_1_3_6_22_2","doi-asserted-by":"publisher","DOI":"10.1165\/rcmb.2019-0061OC"},{"key":"e_1_3_6_23_2","doi-asserted-by":"publisher","DOI":"10.3390\/ijms21030955"},{"key":"e_1_3_6_24_2","doi-asserted-by":"publisher","DOI":"10.1096\/fj.09-136895"},{"key":"e_1_3_6_25_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1000701"},{"key":"e_1_3_6_26_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M112.347971"},{"key":"e_1_3_6_27_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1500150"},{"key":"e_1_3_6_28_2","doi-asserted-by":"publisher","DOI":"10.1096\/fj.201701164R"},{"key":"e_1_3_6_29_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-018-32008-x"},{"key":"e_1_3_6_30_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-019-54683-0"},{"key":"e_1_3_6_31_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0001238"},{"key":"e_1_3_6_32_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0046696"},{"key":"e_1_3_6_33_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.febslet.2010.08.002"},{"key":"e_1_3_6_34_2","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.00813-15"},{"key":"e_1_3_6_35_2","doi-asserted-by":"publisher","DOI":"10.1165\/rcmb.2012-0373OC"},{"key":"e_1_3_6_36_2","doi-asserted-by":"publisher","DOI":"10.3390\/ijms21041467"},{"key":"e_1_3_6_37_2","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.200309-1223OC"},{"key":"e_1_3_6_38_2","doi-asserted-by":"publisher","DOI":"10.1136\/thx.2008.110304"},{"key":"e_1_3_6_39_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M111.290056"},{"key":"e_1_3_6_40_2","doi-asserted-by":"publisher","DOI":"10.1165\/rcmb.2019-0354OC"},{"key":"e_1_3_6_41_2","doi-asserted-by":"publisher","DOI":"10.1007\/BF01671026"},{"key":"e_1_3_6_42_2","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.1953.sp004848"},{"key":"e_1_3_6_43_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajplegacy.1957.191.2.411"},{"key":"e_1_3_6_44_2","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.1962.sp006956"},{"key":"e_1_3_6_45_2","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.1966.sp008040"},{"key":"e_1_3_6_46_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0165-1838(00)00079-5"},{"key":"e_1_3_6_47_2","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.1903.sp000947"},{"key":"e_1_3_6_48_2","doi-asserted-by":"publisher","DOI":"10.1152\/jappl.1995.78.1.117"},{"key":"e_1_3_6_49_2","first-page":"539","article-title":"The mechanism of decreased specific airway conductance in man during hypercapnia caused by inhalation of 7 per cent CO2","volume":"37","author":"Sterling GM","year":"1969","journal-title":"Clin. Sci."},{"key":"e_1_3_6_50_2","doi-asserted-by":"publisher","DOI":"10.1016\/0034-5687(73)90057-1"},{"key":"e_1_3_6_51_2","doi-asserted-by":"publisher","DOI":"10.1152\/jappl.1961.16.1.53"},{"key":"e_1_3_6_52_2","doi-asserted-by":"publisher","DOI":"10.1136\/thx.27.4.480"},{"key":"e_1_3_6_53_2","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.1973.sp010407"},{"key":"e_1_3_6_54_2","doi-asserted-by":"publisher","DOI":"10.1152\/jappl.1972.32.1.39"},{"key":"e_1_3_6_55_2","first-page":"472","article-title":"Effects of CO2 and pH on drug-induced contractions of airway smooth muscle","volume":"190","author":"Duckles SP","year":"1974","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"e_1_3_6_56_2","first-page":"885","article-title":"Resistance to breathing during exercise-induced asthma attacks","volume":"101","author":"Fisher HK","year":"1970","journal-title":"Am. Rev. Respir. Dis."},{"key":"e_1_3_6_57_2","first-page":"861","article-title":"Site of action of inhaled 6 per cent carbon dioxide in the lungs of asthmatic subjects before and after exercise","volume":"114","author":"Fisher HK","year":"1976","journal-title":"Am. Rev. Respir. Dis."},{"key":"e_1_3_6_58_2","doi-asserted-by":"publisher","DOI":"10.1152\/jappl.1968.25.4.376"},{"key":"e_1_3_6_59_2","first-page":"L207","article-title":"Role of intracellular pH in relaxation of porcine tracheal smooth muscle by respiratory gases","volume":"268","author":"Croxton TL","year":"1995","journal-title":"Am. J. Physiol."},{"key":"e_1_3_6_60_2","doi-asserted-by":"publisher","DOI":"10.1016\/0034-5687(86)90078-2"},{"key":"e_1_3_6_61_2","first-page":"L642","article-title":"Intracellular pH regulates voltage-dependent Ca2+ channels in porcine tracheal smooth muscle cells","volume":"268","author":"Yamakage M","year":"1995","journal-title":"Am. J. Physiol."},{"key":"e_1_3_6_62_2","doi-asserted-by":"publisher","DOI":"10.1139\/y11-052"},{"key":"e_1_3_6_63_2","doi-asserted-by":"publisher","DOI":"10.1152\/jappl.1971.31.5.651"},{"key":"e_1_3_6_64_2","doi-asserted-by":"publisher","DOI":"10.1152\/jappl.1963.18.5.881"},{"key":"e_1_3_6_65_2","doi-asserted-by":"publisher","DOI":"10.1152\/jappl.1969.26.6.806"},{"key":"e_1_3_6_66_2","doi-asserted-by":"publisher","DOI":"10.1177\/000348946307200301"},{"key":"e_1_3_6_67_2","doi-asserted-by":"publisher","DOI":"10.1152\/jappl.1971.31.5.708"},{"key":"e_1_3_6_68_2","doi-asserted-by":"publisher","DOI":"10.1152\/jappl.1964.19.4.745"},{"key":"e_1_3_6_69_2","first-page":"277","article-title":"The mechanism of bronchoconstriction due to hypocapnia in man","volume":"34","author":"Sterling GM","year":"1968","journal-title":"Clin. Sci."},{"key":"e_1_3_6_70_2","first-page":"192","article-title":"The effect of CO2 on peripheral airways","volume":"98","author":"Nielsen TM","year":"1976","journal-title":"Acta Physiol. Scand."},{"key":"e_1_3_6_71_2","doi-asserted-by":"publisher","DOI":"10.1152\/jappl.1970.28.5.570"},{"key":"e_1_3_6_72_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI104316"},{"key":"e_1_3_6_73_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrm2820"},{"key":"e_1_3_6_74_2","doi-asserted-by":"publisher","DOI":"10.1016\/0024-3205(94)00497-G"},{"key":"e_1_3_6_75_2","doi-asserted-by":"publisher","DOI":"10.1016\/0034-5687(94)00137-O"},{"key":"e_1_3_6_76_2","doi-asserted-by":"publisher","DOI":"10.1016\/0034-5687(79)90056-2"},{"key":"e_1_3_6_77_2","doi-asserted-by":"publisher","DOI":"10.1183\/09031936.98.12051046"},{"key":"e_1_3_6_78_2","first-page":"408","article-title":"Effect of respiratory acidosis and activity on airway smooth muscle intracellular pH","volume":"42","author":"Stephens NL","year":"1977","journal-title":"J. Appl. Physiol. Respir. Environ. Exerc. Physiol."}],"container-title":["Interface Focus"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/royalsocietypublishing.org\/doi\/pdf\/10.1098\/rsfs.2020.0021","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/royalsocietypublishing.org\/doi\/full-xml\/10.1098\/rsfs.2020.0021","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/royalsocietypublishing.org\/doi\/pdf\/10.1098\/rsfs.2020.0021","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T21:19:01Z","timestamp":1778620741000},"score":1,"resource":{"primary":{"URL":"http:\/\/royalsocietypublishing.org\/rsfs\/article\/116266"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,2,12]]},"references-count":77,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2021,4,6]]}},"alternative-id":["10.1098\/rsfs.2020.0021"],"URL":"https:\/\/doi.org\/10.1098\/rsfs.2020.0021","relation":{},"ISSN":["2042-8901"],"issn-type":[{"value":"2042-8901","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,2,12]]},"assertion":[{"value":"2020-12-09","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-02-12","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}