Complement inhibition decreases early fibrogenic events in the lung of septic baboons

作者：Robert Silasi‐Mansat, Hua Zhu, Constantin Georgescu, Narcis I. Popescu, Ravi S. Keshari, Glenn Peer, Cristina Lupu, Fletcher B. Taylor, H. Anne Pereira, Gary T. Kinasewitz, John D. Lambris, Florea Lupu · 发表于：Journal of Cellular and Molecular Medicine · 年份：2015 · DOI：10.1111/jcmm.12667 · 被引用次数：39 · 研究领域：S100 Proteins and Annexins、Neonatal Respiratory Health Research、Inflammation biomarkers and pathways

Acute respiratory distress syndrome (ARDS) induced by severe sepsis can trigger persistent inflammation and fibrosis. We have shown that experimental sepsis in baboons recapitulates ARDS progression in humans, including chronic inflammation and long-lasting fibrosis in the lung. Complement activation products may contribute to the fibroproliferative response, suggesting that complement inhibitors are potential therapeutic agents. We have been suggested that treatment of septic baboons with compstatin, a C3 convertase inhibitor protects against ARDS-induced fibroproliferation. Baboons challenged with 10(9) cfu/kg (LD50) live E. coli by intravenous infusion were treated or not with compstatin at the time of challenge or 5 hrs thereafter. Changes in the fibroproliferative response at 24 hrs post-challenge were analysed at both transcript and protein levels. Gene expression analysis showed that sepsis induced fibrotic responses in the lung as early as 24 hrs post-bacterial challenge. Immunochemical and biochemical analysis revealed enhanced collagen synthesis, induction of profibrotic factors and increased cell recruitment and proliferation. Specific inhibition of complement with compstatin down-regulated sepsis-induced fibrosis genes, including transforming growth factor-beta (TGF-β), connective tissue growth factor (CTGF), tissue inhibitor of metalloproteinase 1 (TIMP1), various collagens and chemokines responsible for fibrocyte recruitment (e.g. chemokine (C-C motif) ligand 2 ...