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Since lung fibrosis is associated with downregulation of DAF, we hypothesize that overexpression of DAF in fibrosed lungs will limit fibrotic injury by restraining complement dysregulation. Normal primary human alveolar type II epithelial cells (AECs) exposed to exogenous complement 3a or 5a, and primary AECs purified from IPF lungs demonstrated decreased membrane-bound DAF expression with concurrent increase in the endoplasmic reticulum (ER) stress protein, ATF6. Increased loss of extracellular cleaved DAF fragments was detected in normal human AECs exposed to complement 3a or 5a, and in lungs of IPF patients. C3a-induced ATF6 expression and DAF loss was inhibited using pertussis toxin (an enzymatic inactivator of G-protein coupled receptors), in murine AECs. Treatment with soluble DAF abrogated tunicamycin-induced C3a secretion and ER stress (ATF6 and BiP expression) and restored epithelial cadherin. Bleomycin-injured fibrotic mice subjected to lentiviral overexpression of DAF demonstrated diminished levels of local collagen deposition and complement activation. Further analyses showed diminished release of DAF fragments, as well as reduction in apoptosis (TUNEL and caspase 3\/7 activity), and ER stress-related transcripts. Loss-of-function studies using Daf1 siRNA demonstrated worsened lung fibrosis detected by higher mRNA levels of Col1a1 and epithelial injury-related Muc1 and Snai1, with exacerbated local deposition of C5b-9. Our studies provide a rationale for rescuing fibrotic lungs via DAF induction that will restrain complement dysregulation and lung injury.<\/jats:p>","DOI":"10.1165\/rcmb.2021-0463oc","type":"journal-article","created":{"date-parts":[[2022,7,27]],"date-time":"2022-07-27T13:26:30Z","timestamp":1658928390000},"page":"459-470","update-policy":"https:\/\/doi.org\/10.1164\/crossmarkpolicies","source":"Crossref","is-referenced-by-count":16,"title":["Overexpression of Decay Accelerating Factor Mitigates Fibrotic Responses to Lung Injury"],"prefix":"10.1093","volume":"67","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4520-9663","authenticated-orcid":false,"given":"Ragini","family":"Vittal","sequence":"first","affiliation":[{"name":"Division of Pulmonary and Critical Care, Department of Internal Medicine and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amanda J.","family":"Fisher","sequence":"additional","affiliation":[{"name":"Division of Pulmonary and Critical Care, 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