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Heterogeneous ventilation due to (micro)atelectases imparts injurious strains on open alveoli (known as volutrauma). Hence, recruitment of (micro)atelectases by positive end-expiratory pressure (PEEP) is necessary to interrupt this vicious circle of injury but needs to be balanced against acinar overdistension. In this study, the lung-protective potential of alveolar recruitment was investigated and balanced against overdistension in pre-injured lungs. Mice, treated with empty vector (AdCl) or adenoviral active TGF-\u03b21 (AdTGF-\u03b21) were subjected to lung mechanical measurements during descending PEEP ventilation from 12 to 0 cmH<jats:sub>2<\/jats:sub>O. At each PEEP level, recruitability tests consisting of two recruitment maneuvers followed by repetitive forced oscillation perturbations to determine tissue elastance (H) and damping (G) were performed. Finally, lungs were fixed by vascular perfusion at end-expiratory airway opening pressures (Pao) of 20, 10, 5 and 2 cmH<jats:sub>2<\/jats:sub>O after a recruitment maneuver, and processed for design-based stereology to quantify derecruitment and distension. H and G were significantly elevated in AdTGF-\u03b21 compared to AdCl across PEEP levels. H was minimized at PEEP\u2009=\u20095\u20138 cmH<jats:sub>2<\/jats:sub>O and increased at lower and higher PEEP in both groups. These findings correlated with increasing septal wall folding (=\u2009derecruitment) and reduced density of alveolar number and surface area (=\u2009distension), respectively. In AdTGF-\u03b21 exposed mice, 27% of alveoli remained derecruited at Pao\u2009=\u200920 cmH<jats:sub>2<\/jats:sub>O. A further decrease in Pao down to 2 cmH<jats:sub>2<\/jats:sub>O showed derecruitment of an additional 1.1 million alveoli (48%), which was linked with an increase in alveolar size heterogeneity at Pao\u2009=\u20092\u20135 cmH<jats:sub>2<\/jats:sub>O. In AdCl, decreased Pao resulted in septal folding with virtually no alveolar collapse. In essence, in healthy mice alveoli do not derecruit at low PEEP ventilation. The potential of alveolar recruitability in AdTGF-\u03b21 exposed mice is high. H is optimized at PEEP 5\u20138 cmH<jats:sub>2<\/jats:sub>O. Lower PEEP folds and larger PEEP stretches septa which results in higher H and is more pronounced in AdTGF-\u03b21 than in AdCl. The increased alveolar size heterogeneity at Pao\u2009=\u20095 cmH<jats:sub>2<\/jats:sub>O argues for the use of PEEP\u2009=\u20098 cmH<jats:sub>2<\/jats:sub>O for lung protective mechanical ventilation in this animal model.<\/jats:p>","DOI":"10.1038\/s41598-024-58213-5","type":"journal-article","created":{"date-parts":[[2024,4,6]],"date-time":"2024-04-06T04:01:43Z","timestamp":1712376103000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Exploring alveolar recruitability using positive end-expiratory pressure in mice overexpressing TGF-\u03b21: a structure\u2013function analysis"],"prefix":"10.1038","volume":"14","author":[{"given":"Franziska","family":"Roeder","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tina","family":"R\u00f6pke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lara-Kristin","family":"Steinmetz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Kolb","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ulrich A.","family":"Maus","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bradford J.","family":"Smith","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lars","family":"Knudsen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,4,6]]},"reference":[{"key":"58213_CR1","doi-asserted-by":"publisher","first-page":"788","DOI":"10.1001\/jama.2016.0291","volume":"315","author":"G Bellani","year":"2016","unstructured":"Bellani, G. et al. 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