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In this two-part explorative proteomic study, we demonstrate how proteins associated with tissue remodeling, inflammation and chemotaxis such as MMP7, CXCL13 and CCL19 are released in response to aberrant extracellular matrix (ECM) in IPF lung. We used a novel ex vivo model where decellularized lung tissue from IPF patients and healthy donors were repopulated with healthy fibroblasts to monitor locally released mediators. Results were validated in longitudinally collected serum samples from 38 IPF patients and from 77 healthy controls. We demonstrate how proteins elevated in the ex vivo model (e.g., MMP7), and other serum proteins found elevated in IPF patients such as HGF, VEGFA, MCP-3, IL-6 and TNFRSF12A, are associated with disease severity and progression and their response to antifibrotic treatment. Our study supports the model\u2019s applicability in studying mechanisms involved in IPF and provides additional evidence for both established and potentially new biomarkers in IPF.<\/jats:p>","DOI":"10.3390\/ijms222413421","type":"journal-article","created":{"date-parts":[[2021,12,14]],"date-time":"2021-12-14T09:34:25Z","timestamp":1639474465000},"page":"13421","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Distal Lung Microenvironment Triggers Release of Mediators Recognized as Potential Systemic Biomarkers for Idiopathic Pulmonary Fibrosis"],"prefix":"10.3390","volume":"22","author":[{"given":"Dimitrios","family":"Kalafatis","sequence":"first","affiliation":[{"name":"Respiratory Medicine Unit, Department of Medicine Solna and Center for Molecular Medicine, Karolinska Institutet, SE-171 76 Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"L\u00f6fdahl","sequence":"additional","affiliation":[{"name":"Department of Experimental Medical Science, Lung Biology, Lund University, SE-221 84 Lund, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7606-8771","authenticated-orcid":false,"given":"Per","family":"N\u00e4sman","sequence":"additional","affiliation":[{"name":"Center for Safety Research, KTH, Royal Institute of Technology, SE-100 44 Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G\u00f6ran","family":"Dellgren","sequence":"additional","affiliation":[{"name":"Department of Cardiothoracic Surgery and Transplant Institute, Sahlgrenska University Hospital, SE-413 45 Gothenburg, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"\u00c5sa M.","family":"Wheelock","sequence":"additional","affiliation":[{"name":"Respiratory Medicine Unit, Department of Medicine Solna and Center for Molecular Medicine, Karolinska Institutet, SE-171 76 Stockholm, Sweden"},{"name":"Department of Respiratory Medicine and Allergy, Karolinska University Hospital, SE-171 76 Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0457-0188","authenticated-orcid":false,"given":"Linda","family":"Elowsson Rendin","sequence":"additional","affiliation":[{"name":"Department of Experimental Medical Science, Lung Biology, Lund University, SE-221 84 Lund, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Magnus","family":"Sk\u00f6ld","sequence":"additional","affiliation":[{"name":"Respiratory Medicine Unit, Department of Medicine Solna and Center for Molecular Medicine, Karolinska Institutet, SE-171 76 Stockholm, Sweden"},{"name":"Department of Respiratory Medicine and Allergy, Karolinska University Hospital, SE-171 76 Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5327-8805","authenticated-orcid":false,"given":"Gunilla","family":"Westergren-Thorsson","sequence":"additional","affiliation":[{"name":"Department of Experimental Medical Science, Lung Biology, Lund University, SE-221 84 Lund, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,12,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e44","DOI":"10.1164\/rccm.201807-1255ST","article-title":"Diagnosis of Idiopathic Pulmonary Fibrosis. 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