{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T20:53:00Z","timestamp":1781815980675,"version":"3.54.5"},"reference-count":122,"publisher":"American Physiological Society","issue":"1","content-domain":{"domain":["journals.physiology.org"],"crossmark-restriction":true},"short-container-title":["American Journal of Physiology-Lung Cellular and Molecular Physiology"],"published-print":{"date-parts":[[2026,7,1]]},"abstract":"<jats:p>\n                    This essay addresses the fundamental mechanism underlying the precise regulation of [Formula: see text] during steady states of air-breathing eupnea and hyperpnea. First, an argument is made for CO\n                    <jats:sub>2<\/jats:sub>\n                    \/H\n                    <jats:sup>+<\/jats:sup>\n                    chemoreception as an important compensatory feedback regulator of breathing and breathing stability, especially during nonrapid eye movement (NREM) sleep. Tonic contributions to respiratory drive occur from the carotid chemoreceptors and retrotrapezoid nucleus (RTN). A case against chemoreception of Pco\n                    <jats:sub>2<\/jats:sub>\n                    as the primary homeostatic [Formula: see text] regulator is made based on conditions where precise [Formula: see text] control during air-breathing exists even when ventilatory responsiveness to raised Pco\n                    <jats:sub>2<\/jats:sub>\n                    is markedly subnormal or when a measurable [Formula: see text] error signal is nonexistent. Alternatively, a case is made that homeostatic ventilatory control incorporates information critically dependent on pulmonary CO\n                    <jats:sub>2<\/jats:sub>\n                    exchange, as revealed when: 1) V\u0307co\n                    <jats:sub>2<\/jats:sub>\n                    , per se, is altered at rest or exercise; 2) V\n                    <jats:sub>d<\/jats:sub>\n                    \/V\n                    <jats:sub>T<\/jats:sub>\n                    is raised or lowered; and 3) the resting [Formula: see text] set point is changed, thereby changing respiratory system plant gains. In each of these common conditions, substantial ventilatory adjustments occur to achieve near-proportional V\u0307a:V\u0307co\n                    <jats:sub>2<\/jats:sub>\n                    linkages at rest and\/or exercise with no coincidence changes in CO\n                    <jats:sub>2<\/jats:sub>\n                    chemoreception. We view this V\u0307co\n                    <jats:sub>2<\/jats:sub>\n                    -mediated mechanism as a dedicated tracking system for alveolar ventilation that provides an essential underpinning in a traditional hybrid model of homeostatic ventilatory control. Although some potential mediators of these V\u0307co\n                    <jats:sub>2<\/jats:sub>\n                    effects have been suggested, such as an integrative role for the RTN, they remain inadequately explored. It is time to restart enquiry, using modern neuroscience approaches, into the mediation of V\u0307co\n                    <jats:sub>2<\/jats:sub>\n                    as the critical underpinning to [Formula: see text] homeostasis.\n                  <\/jats:p>","DOI":"10.1152\/ajplung.00141.2026","type":"journal-article","created":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T13:11:41Z","timestamp":1780492301000},"page":"L34-L47","update-policy":"https:\/\/doi.org\/10.1152\/aps-crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["V\u0307\n                    <scp>co<\/scp>\n                    <sub>2<\/sub>\n                    : the essential underpinning to homeostatic control of breathing"],"prefix":"10.1152","volume":"331","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5979-6427","authenticated-orcid":false,"given":"Jerome A.","family":"Dempsey","sequence":"first","affiliation":[{"name":"University of Wisconsin School of Medicine and Public 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