Overexpression of Decay Accelerating Factor Mitigates Fibrotic Responses to Lung Injury
| Autor: | Ragini Vittal, Amanda J. Fisher, Eric L. Thompson, Ellyse M. Cipolla, Hongmei Gu, Elizabeth A. Mickler, Ananya Varre, Manisha Agarwal, Kevin K. Kim, Michael R. Vasko, Bethany B. Moore, Vibha N. Lama |
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| Rok vydání: | 2022 |
| Předmět: |
Pulmonary and Respiratory Medicine
CD55 Antigens Caspase 3 Glycosylphosphatidylinositols Tunicamycin Clinical Biochemistry Complement Membrane Attack Complex Complement System Proteins Lung Injury Cell Biology Cadherins Fibrosis Idiopathic Pulmonary Fibrosis Bleomycin Mice Pertussis Toxin Complement C3a Animals Humans RNA Messenger RNA Small Interfering Molecular Biology Heat-Shock Proteins |
| Zdroj: | American Journal of Respiratory Cell and Molecular Biology. 67:459-470 |
| ISSN: | 1535-4989 1044-1549 |
| Popis: | CD55 or decay accelerating factor (DAF), a ubiquitously expressed glycosylphosphatidylinositol (GPI)-anchored protein, confers a protective threshold against complement dysregulation which is linked to the pathogenesis of idiopathic pulmonary fibrosis (IPF). 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 usingiDaf1 siRNA/idemonstrated worsened lung fibrosis detected by higher mRNA levels ofiCol1a1/iand epithelial injury-relatediMuc1/iandiSnai1,/iwith exacerbated local deposition of C5b-9. Our studies provide a rationale for rescuing fibrotic lungsivia/iDAF induction that will restrain complement dysregulation and lung injury. |
| Databáze: | OpenAIRE |
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