{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,20]],"date-time":"2026-02-20T06:05:20Z","timestamp":1771567520009,"version":"3.50.1"},"reference-count":19,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,2,20]],"date-time":"2026-02-20T00:00:00Z","timestamp":1771545600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["1R01HL161620"],"award-info":[{"award-number":["1R01HL161620"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Primary graft dysfunction (PGD) is the leading cause of early mortality after lung transplantation, yet no targeted therapy exists. We investigated whether the collagen-derived matrikine proline-glycine-proline (PGP) drives neutrophil-predominant injury in PGD and whether its neutralization confers protection.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Human mini-bronchoalveolar lavage (BAL) fluid was collected 72 hours post-transplantation from recipients with grade 3 PGD and non-PGD controls. In parallel, a murine orthotopic lung transplantation model incorporating 18 hours of cold ischemia was used to reproduce PGD; mice received vehicle (PBS) or the PGP-sequestering tripeptide L-arginine-threonine-arginine (RTR) immediately before reperfusion. Histology, immunofluorescence, LC-MS\/MS quantification of acetyl-PGP (acPGP), gelatin zymography for active MMP-9, and ELISA for MMP-9 and prolyl endopeptidase (PE) were performed four hours later.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Human PGD BAL contained approximately fourfold higher acPGP, along with significantly elevated MMP-9 and PE, compared with PGD 0 controls. Murine PGD allografts similarly demonstrated dense neutrophilic infiltrates and increased acPGP, MMP-9, and PE expression. RTR treatment markedly reduced histologic injury, neutrophil accumulation, and composite PGD scores while improving oxygenation and allograft lung function. RTR also restored acPGP, MMP-9, PE, and active MMP-9 levels to near-baseline compared with vehicle-treated PGD allografts.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>These findings delineate a feed-forward PGP-protease circuit linking extracellular matrix degradation to neutrophil recruitment and vascular leak. Neutralizing PGP effectively disrupts this circuit, attenuating graft injury. By connecting extracellular matrix-derived signals to innate immune activation, this work broadens the immunopathologic framework of PGD.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1655536","type":"journal-article","created":{"date-parts":[[2026,2,20]],"date-time":"2026-02-20T05:22:00Z","timestamp":1771564920000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Targeting the proline-glycine-proline-protease feed-forward loop attenuates primary graft dysfunction after lung transplantation"],"prefix":"10.3389","volume":"17","author":[{"given":"Yasufumi","family":"Goda","sequence":"first","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine, Brigham and Women\u2019s Hospital, Harvard Medical School","place":["Boston, MA, United States"]},{"name":"Baylor College of Medicine","place":["Houston, TX, United 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